（2025.V3）NCCN临床实践指南—中国版：卵巢癌包括输卵管癌和原发性腹膜癌

指南肿瘤内科· 泌尿生殖肿瘤 · 2025

Version 3.2025

Ovarian Cancer

NCCN Guidelines Index

Table of Contents Discussion

*Deborah K. Armstrong, MD/Chair Ω † Johns Hopkins Kimmel Cancer Center

Ronald D. Alvarez, MD, MBA/Vice Chair Ω Vanderbilt-Ingram Cancer Center

* Floor J. Backes, MD Ω The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Lisa Barroilhet, MD Ω University of Wisconsin Carbone Cancer Center

Kian Behbakht, MD Ω University of Colorado Cancer Center

Andrew Berchuck, MD Ω Duke Cancer Institute

* Lee-may Chen, MD Ω UCSF Helen Diller Family Comprehensive Cancer Center

Joshua Cohen, MD Ω City of Hope National Medical Center

Marie DeRosa, RN ￥

*Eric L. Eisenhauer, MD Ω Mass General Cancer Center

*David M. Gershenson, MD Ω The University of Texas MD Anderson Cancer Center

*Heidi J. Gray, MD Ω Fred Hutchinson Cancer Center

Rachel Grisham, MD Ω Memorial Sloan Kettering Cancer Center

Ardeshir Hakam, MD # Moffitt Cancer Center

Angela Jain, MD † Fox Chase Cancer Center

Gottfried E. Konecny, MD Ω UCLA Jonsson Comprehensive Cancer Center

*Charles A. Leath III, MD, MSPH Ω O'Neal Comprehensive Cancer Center Cancer Center at UAB

Gary Leiserowitz, MD Ω UC Davis Comprehensive Cancer Center

Babak Litkouhi, MD Ω Stanford Cancer Institute

$\bullet$ Joyce Liu, MD MPH ‡‡ Dana-Farber/Brigham and Women's Cancer Center

Lainie Martin, MD † Abramson Cancer Center at the University of Pennsylvania

* Daniela Matei, MD †‡ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Michael McHale, MD Ω UC San Diego Moores Cancer Center

*David S. Miller, MD Ω UT Southwestern Simmons Comprehensive Cancer Center

John Moroney, MD Ω The UChicago Medicine Comprehensive Cancer Center

Sanja Percac-Lima, MD, PhD Mass General Cancer Center

Elena Ratner, MD, MBA Ω Yale Cancer Center/Smilow Cancer Hospital

Sharon Robertson, MD, MPH Ω Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Kerry Rodaugh, MD Ω Fred & Pamela Buffett Cancer Center

John Schorge, MD Ω St. Jude Children's Research Hospital/The University of Tennessee Health Science Center

* Premal H. Thaker, MD Ω Sisteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Shitanshu Uppal, MBBS, MBA Ω University of Michigan Rogel Cancer Center

Roberto Vargas, MD Ω Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

*Andrea Wahner Hendrickson, MD † Mayo Clinic Comprehensive Cancer Center

*Theresa L. Werner, MD ‡ Huntsman Cancer Institute at the University of Utah

*Emese Zsiros, MD, PhD Ω Roswell Park Comprehensive Cancer Center

NCCN Emily Kovach Swathi Ramakrishnan, PhD

Ω Gynecology oncology # Nursing

Hematology/ Hematology oncology # Patient advocacy

D Internal medicine † Medical oncology

Nursing

Hematology/ — Pathology

Hematology oncology

* Discussion writing committee member

NCCN Guidelines Panel Disclosures

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Cancer

Ovarian Cancer

NCCN Guidelines Index Table of Contents Discussion

CHINESE EDITORIAL COMMITTEE — OVARIAN CANCER EXPERT

PANEL MEMBERS

Honorary Chair: D Ma, MD, PhD Chief Physician Obstetrics and Gynecology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Panel Chair: XH Wu, MD, PhD Chief Physician Gynecologic Oncology Fudan University Shanghai Cancer Center

Lead Authors: H Wen, MD Associate Chief Physician Gynecologic Oncology Fudan University Shanghai Cancer Center DL Zou, MD Chief Physician Gynecologic Oncology Gynecologic Oncology Chongqing University Cancer Hospital

NCCN

Deborah K. Armstrong, MD/Chair Ω † Johns Hopkins Kimmel Cancer Center

Ω Gynecology oncology † Medical oncology

DY Cao, MD Chief Physician Gynecologic Oncology Peking Union Medical College Hospital Gen, MD, PhD Chief Physician Gynecologic Oncology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology XJ Chen, MD, PhD Chief Physician Obstretrics and Gynecology Obstetrics and Gynecology Hospital, Fudan University YN Gao, MCM Chief Physician Gynecologic Oncology Gynecologic Oncology Peking University Cancer Hospital YJ Hu, MD, PhD Chief Physician Gynecologic Oncology Tianjin Central Hospital of Obstetrics and Gynecology Gynecology

B Li, MD Chief Physician Gynecology Cancer Hospital, Chinese Academy of Medical Sciences L Li, MD Chief Physician Gynecology Guangxi Medical University Cancer Hospital QL Li, MD Associate Chief Physician Radiation and Medical Oncology West China Second Hospital of Sichuan University University ZQ Lin, MD Chief Physician Obstetrics and Gynecology Gynecologic Oncology Sun Yat-sen Memorial Hospital, Sun Yat-sen University JH Liu, MD Chief Physician Gynecology Gynecology Sun Yat-sen University Cancer Center HW Lu, MD Chief Physician Gynecologic Oncology Sun Yat-sen Memorial Hospital, Sun Yat-sen University WAL, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, MD Chief Physician Gynecologic Oncology Wan, MD, M

X Lu, MD Chief Physician Gynecologic Oncology Obstretrics and Gynecology Hospital, Fudan University Wen, MD Associate Chief Physician Gynecologic Oncology Gyneologic Oncology Wan, MD Chief Medic and Gynecology Peking University People's Hospital J Wang, MD Chief Physician Gyneologic Oncology Gyneologic Oncology Hunan Cancer Hospital K Wang, MCM Chief Physician Gynecologic Oncology Tianjin Medical University Cancer Institute and Hospital YM Wang, MD, PhD Chief Psychics and Gynecology Obstretrics and Gynecology Tianjin Medical University General Hospital Y Xiang, MD Chief Physician Gynecologic Oncology Gynecologic Oncology Wan, MD Gyneologic Oncology Gyneologic Oncology T Zang, MD Chef, MD Chief Pharmacist Center for Evidence-Based Pharmacy West China Second Hospital of Sichuan University LN Zeng, PhD Chief Pharmacist Center for Evidence-Based Pharmacy West China Second Hospital of Sichuan University FQ Zhang, MCM Chief Physician Radiation Oncology Department Peking Union Medical College Hospital Q Zhou, MMSc Chief Physician Gynecologic Oncology Chongqing University Cancer Hospital JQ Zhu, MD Chief Physician Gynecologic Oncology Surgery Zhejiang Cancer Hospital T Zhu, MCM Chief Physician Gynecologic Oncology Gynecologic Oncology Zhejiang Cancer Hospital

FX Xue, MD, PhD Chief Physician Obstetrics and Gynecology Tianjin Medical University General Hospital

Gynecologic Oncology Liaoning Cancer Hospital RT Yin, MD, PhD Chief Physician Radiation and Medical Oncology West China Second Hospital of Sichuan University Land University LN Zeng, PhD Chief Pharmacist Center for Evidence-Based Pharmacy West China Second Hospital of Sichuan University K Wang, MCM Chief China Second Hospital of Sichuan University FQ Zhang, MCM Chief Physician Radiation Oncology Department Peking Union Medical College Hospital

West China Second Hospital of Sichuan University

LN Zeng, PhD Chief Pharmacist Center for Evidence-Based Pharmacy West China Second Hospital of Sichuan University

FQ Zhang, MCM Chief Physician Radiation Oncology Department Peking Union Medical College Hospital

Q Zhou, MMSc Chief Physician Gynecologic Oncology Chongqing University Cancer Hospital

JQ Zhu, MD Chief Physician Gynecologic Oncology Surgery Zhejiang Cancer Hospital

T Zhu, MCM Chief Physician Gynecologic Oncology Zhejiang Cancer Hospital

NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines for China Version 3.2025

Ovarian Cancer

Version 3.2025, 11/20/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and

Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Ovarian Cancer Panel Members

Chinese Editorial Committee – Ovarian Cancer Expert Panel Members

NCCN Guidelines for China Deinitions (DEF-1)

Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer:Clinical Presentation, Workup, Clinical Stage, Primary Treatment (OV-1)

Poor Surgical Candidate or Low Likelihood of Optimal Cytoreduction (OV-2)Diagnosis by Previous Surgery: Findings and Primary Treatment (OV-3)

Pathologic Staging, Primary Chemotherapy/Primary Adjuvant Therapy (OV-4)Post Primary Treatment: Maintenance Therapy (OV-5)

Monitoring/Follow-Up, Recurrent Disease (OV-6)

Disease Status, Therapy for Persistent Disease or Recurrence (OV-7)

Less Common Ovarian Cancers:

Diagnosis (LCOC-1)

Carcinosarcoma (Malignant Mixed Müllerian Tumors) of the Ovary (LCOC-2)

Clear Cell Carcinoma of the Ovary (LCOC-3)

Mucinous Neoplasms of the Ovary (LCOC-4)

Grade 1 Endometrioid Carcinoma (LCOC-5)

Low-Grade Serous Carcinoma (LCOC-6)

Ovarian Serous Borderline Epithelial Tumors (Low Malignant Potential) (LCOC-8)

Malignant Sex Cord-Stromal Tumors (LCOC-11)

Malignant Germ Cell Tumors (LCOC-12)

Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord-Stromal Tumors (LCOC-A)

Surveillance - Malignant Germ Cell/Sex Cord-Stromal Tumors (LCOC-B)

Principles of Surgery (OV-A)

Principles of Pathology (OV-B)

Principles of Systemic Therapy (OV-C)

Management of Drug Reactions (OV-D)

WHO Histologic Classiication (OV-E)

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS (CHINA-MS-1)Staging (ST-1)Abbreviations (ABBR-1)

See International Adaptations

Table of Contents for other NCCN Guidelines for China.

The most recent version of the

NCCN Guidelines is available at www.NCCN.org.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.

DEF-1

RECOMMENDATIONS ARE REPRESENTED AS FOLLOWS:Black Text: Recommendations that are widely applicable

Italicized Blue Text: Country/region-speciic modiications that are appropriate and/or feasible

Gray Text: Recommendations that may be costly, technically challenging, and/or not widely available in the speciic country/region*Gray Text with Strikethrough: Recommendations that are not feasible or available in the speciic country/region**

* Recommendations that are considered clinically appropriate by national/regional experts but are not currently available due to lack of reimbursement by the national/regional healthcare financing system.

**Recommendations that are considered as inconsistent with national/regional medical practice.

Note: Drugs and biologics included in the NCCN Guidelines® are approved by the United States Food and Drug Administration (FDA). Alternate agents based on the local regulations and availability may be substituted provided evidence supports their

e冪cacy and safety. Generic drugs should be used only when studies have proven bioequivalence and the drugs have met the same standards for identity, strength, purity, and quality as the innovator drugs. The WHO Model Lists of Essential Medicines

can be found here: http://www.who.int/medicines/publications/essentialmedicines/en/.

NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines for China Version 3.2025

Ovarian Cancer

Chinese Editorial Committee Categories of Consensus†[a] Uniform consensus among Chinese editorial committee members

[b] Non-uniform consensus among Chinese editorial committee members

[c] Major disagreement among Chinese editorial committee members

† All recommendations are [a] unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[CLINICAL PRESENTATION] --> A2[Suspicious/palpable pelvic mass on abdomen/pelvis exam and/or ascites, abdominal distention and/or Symptoms without source of malignancy.ie, bloating, pelvis/abdomen pain, difficulty eating or feeling full quickly, urinary symptoms [urgency or frequency]\n A2 --> A3[● Abdominal/pelvic exam ● Pelvis ultrasound, abdomen/pelvis CT/MRI as clinically indicateda,b ● Chest CT as clinically indicateda,c ● Complete blood count(CBC), chemistry profile with liver function test(LFT) ● CA-125 or other tumor markers as clinically indicatedd ● Evaluate performance status and nutritional status ● Gastrointestinal(GI) evaluation as clinically indicated ● Reproductive endocrinology and infertility(REI) evaluation as clinically indicatede ● Obtain family historyf,g,h ● Refer to gynecologic oncologist for clinically suspicious lesionsi]\n A3 --> A4[WORKUP]\n A4 --> A5[CLINICAL STAGEi]\n A4 --> A12[PRIMARY TREATMENTi,j,k]\n A5 --> A6[IA(fertility desired)]\n A5 --> A8[IB(fertility desired)]\n A5 --> A10[IA-IV, surgical candidate, optimal cytoreduction likely(fertility not desired)]\n A5 --> A11[Poor surgical candidate or Low likelihood of optimal cytoreduction]\n A6 --> A7[Unilateral salpingo-oophorectomy(USO)+ comprehensive surgical stagingi,j,k,l,m]\n A7 --> A13[Patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer should have genetic risk evaluation and germline and somatic testing(if not previously done)f,g,h,k]\n A8 --> A9[Bilateral salpingo-oophorectomy(BSO)+ comprehensive surgical stagingi,j,k,l,m]\n A9 --> A13\n A10 --> A14[Hysterectomy/BSO+ comprehensive staging and debulking as needed]\n A11 --> A16[Neoadjuvant Therapy(OV-2)n]\n A12 --> A14\n A13 --> A15[Pathologic Staging (OV-4)]\n A14 --> A15\n A15 --> A16\n A16 --> A17[Workup, Findings, and Primary Treatment(OV-3)]\n A17 --> A18[Diagnosis by previous surgery or tissue biopsy(cytopathology)]\n](1/parseimages/figurebf6f3d952a6a4510a03a76ebc972018a_0_6.png) aCT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

b PET/CT, MRI, or PET/MRI may be indicated for indeterminate lesions if results will alter management.

c If there is concern for metastatic or disseminated disease.

d Other tumor markers may include inhibin, beta-human chorionic gonadotropin (β-hCG), alpha-fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), CA 19-9, and HE4. See Discussion for usefulness of diagnostic tests.

e Reconsider REI as clinically indicated once pathologic diagnosis is available.

$^{f}$ See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{9}$ Germline and somatic BRCA1/2 status informs maintenance therapy.

h In the absence of a BRCA1/2 mutation, homologous recombination deficiency (HRD) status may provide information on the magnitude of benefit of PARP inhibitor (PARPi) therapy. For PARPi therapy in advanced stage disease, include measure of homologous recombination (HR) (OV-B).

$^{1}$ Evaluation by a gynecologic oncologist is recommended for:

* All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage.

$\bullet$ Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate.

$\bullet$ Management of occult STICs.

$\bullet$ Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients.

$\bullet$ Endometrial biopsy as clinically indicated.

¡ Principles of Surgery (OV-A).

k Principles of Pathology (OV-B).

$^{1}$ May be an option for select patients with stage IC based on histology.

m Uterine preservation for potential future assisted reproductive approaches.

$^{n}$ See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

o Carcinarcoma, clear cell, mucinous, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal tumors, and germ cell tumors.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

POOR SURGICAL CANDIDATE OR LOW LIKELIHOOD OF OPTIMAL CYTOREDUCTION

NEOADJUVANT THERAPY

![graph TD\n A1[Evaluation by gynecologic oncologist and Histologic confirmation(biopsy preferred) and/or Laparoscopic evaluation to determine feasibility of resection] --> A2[Confirmed poor surgical candidate or low likelihood of optimal cytoreduction]\n A2 --> A3[Neoadjuvant therapy(category 1) and Genetic risk evaluation and germ line and somatic testing(if not previously done)]\n A3 --> A4[Stable disease]\n A3 --> A5[Progressive disease]\n A4 --> A6[IDS with completion hysterectomy/BSO and cytoreduction. Consider HIPEC or Continue current therapy for a total of at least 6 cycles]\n A4 --> A7[Interval debulking surgery(IDS) with completion hysterectomy/BSO and cytoreduction. Consider hyperthermic intraperitoneal chemotherapy(HIPC).]\n A5 --> A10[Therapy for Persistent Disease or Recurrence(OV-7)]\n A5 --> A11[LCOC]\n A6 --> A8[IDS with completion hysterectomy/BSO and cytoreduction. Consider HIPEC or Therapy for Persistent Disease or Recurrence(OV-7)]\n A7 --> A9[Adjuvant therapy]\n A8 --> A9\n A8 --> A6\n A9 --> A12[Maintenance Therapy(OV-5)]\n A11 --> A14[LCOC-1]\n A12 --> A13[IDS with completion hysterectomy/BSO and cytoreduction. Consider HIPEC or Therapy for Persistent Disease or Recurrence(OV-7)]\n A13 --> A9\n A13 --> A6\n](1/parseimages/figure1c0883602731404ea3727fc4d33dc547_0_7.png) f See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{9}$ Germline and somatic BRCA1/2 status informs maintenance therapy.

h In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV-B).

i Evaluation by a gynecologic oncologist is recommended for:

$\bullet$ All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage.

$\bullet$ Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate.

$\bullet$ Management of occult STICs.

$\bullet$ Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients.

$\bullet$ Endometrial biopsy as clinically indicated.

$^{j}$ Principles of Systemic Therapy (OV-C)

$^{k}$ Principles of Pathology (OV-B).

$^{n}$ See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$^{p}$ If biopsy is not feasible, cytopathology from ascites or pleural effusion combined with CA-125:CEA ratio of >25 can be used.

$^{9}$ Completion surgery after 3-4 cycles is preferred; however, surgery may be performed after 4-6 cycles based on the clinical judgment of the gynecologic oncologist.

$^{f}$ Neoadjuvant therapy does not apply to low malignant potential (LMP) or other noninvasive cancers (see LCOC-1).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

DIAGNOSIS BY PREVIOUS SURGERY

FINDINGS

![graph TD\n A1[Patient referred with newly diagnosed ovarian cancer, including less common ovarian cancers(LCOs), after recent surgical procedure] --> A2[Evaluation by gynecologic oncologisti Obtain family history Genetic risk evaluation and germline and somatic testingf,g,h Review prior imaging studies, operative notes, and pathologyk Imaging as clinically indicateda eg,C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT, and/or pelvis ultrasound]\n A2 --> A3[No evidence of residual disease on workup （suspect stage I）]\n A2 --> A5[No evidence of residual disease on workup （suspect stage II-IV）]\n A2 --> A8[Evidence of residual disease on workup]\n A3 --> A4[Consider surgical stagingj,k（if not previously done）if considering observation or to inform systemic therapy decisionss]\n A4 --> A24[Adjuvant Therapy（OV-4）]\n A5 --> A6[Consider surgical stagingj,k（if not previously done）to inform systemic therapy decisionss]\n A6 --> A23[Adjuvant Therapy（OV-4）]\n A7[Suspect resectable residual disease] --> A8\n A8 --> A9[Tumor cytoreductive surgeryj,k]\n A8 --> A10[Suspect unresectable residual diseasef]\n A9 --> A24\n A10 --> A11[Neoadjuvant Therapy（OV-2）]\n](1/parseimages/figuree709fff4aa82493eac8e31dd9825cce6_0_8.png) a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

d Other tumor markers may include inhibin, β-hCG, alpha-fetoprotein, LDH, CEA, CA 19-9, and HE4. See Discussion for usefulness of diagnostic tests.

† See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{9}$ Germline and somatic BRCA1/2 status informs maintenance therapy.

h In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV-B).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

$^{1}$ Evaluation by a gynecologic oncologist is recommended for:

* All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage.

$\bullet$ Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate.

$\bullet$ Management of occult STICs.

$\bullet$ Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients.

$\bullet$ Endometrial biopsy as clinically indicated.

$^{1}$ Principles of Surgery (OV-A).

$^{k}$ Principles of Pathology (OV-B).

$^{1}$ Neoadjuvant therapy does not apply to LMP and other noninvasive cancers (see LCOC-1).

$^{5}$ Although comprehensive surgical staging has not been shown to improve survival in patients with no evidence of residual disease, it can be important for determining the most appropriate postoperative management options, including selection of adjuvant and maintenance therapy.

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC STAGING$^{t,u}$

PRIMARY CHEMOTHERAPY/PRIMARY ADJUVANT THERAPYV

![graph TD\n A1[Stage IIA or IB] --> A2[Grade 2 endometrioid]\n A1 --> A3[Grade 3 endometrioid/high-grade serious carcinomat]\n A2 --> A4[Observe or Intravenous(IV) platinum-based therapy see primary regimens for stage I disease[OV-C, 5 of 12]\n A3 --> A6[IV platinum-based therapy(see primary regimens for stage I disease[OV-C, 5 of 12]\n A4 --> A5[Provide symptom management and best supportive care. Refer for palliative care assessment, if appropriate. • See NCCN Guidelines for Palliative Care • See NCCN Guidelines for Survivorship]\n A6 --> A5\n A7[Stage IC (High-grade serious or grade 2/3 endometrioid)] --> A6\n A8[Stage II Stage III Stage IV] --> A9[Platinum-based chemotherapy(see primary regimens for stage II-IV disease[OV-C,6 of 12]\n A9 --> A10[Provide symptom management and best supportive care. Refer for palliative care assessment, if appropriate. → See NCCN Guidelines for Palliative Care • See NCCN Guidelines for Survivorship]\n A10 --> A11[Imaging as clinically indicated: CT, chest eg, C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT(skull base to mid-thigh)]\n A11 --> A12[Complete Response(CR)∗/Partial Response(PR)]\n A11 --> A13[Stable disease or progression]\n A12 --> A14[Maintenance Therapy(OV-5)]\n A13 --> A15[Therapy for Persistent Disease or Recurrence(OV-7)]\n A16[Less common ovarian cancers(LCOC), any stage⁵,⁶] --> A17[LCOC-1]\n A18[Monitoring/Follow-up(OV-6)] --> A19[]\n](1/parseimages/figured97f717ca92846d0a0217d725be3eb92_0_6.png) a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

$^{n}$ See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

° Carcinosarcoma, clear cell, mucinous, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal tumors, and germ cell tumors.

† Pathologists recommend categorizing serous ovarian cancer as either low-grade or high-grade. Grade 2 serous is considered high-grade.

$^{u}$ Consider expert pathologic review to confirm histologic diagnosis. See WHO Histologic Classification (OV-E).

$\bullet$ Patients receiving primary chemotherapy will be monitored as follows:

1. Every 1-3 cycles: Physical exam and consider pelvic exam

2. As indicated: Interim CBC and chemistry profiles

3. CA-125 levels or other tumor markers as clinically indicated prior to each cycle of chemotherapy

4. C/A/P CT or MRI with contrast, PET/CT (skull base to mid-thigh), or PET as indicated.

x No definitive evidence of disease.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[CRx/PR] --> A2[No bevacizumab used during primary therapy]\n A1 --> A3[Bevacizumab used as part of primary therapy]\n A2 --> A4[BRCAl/2 wild-type or unknown⁵]\n A2 --> A5[Germline or somatic BRCA1/2 mutation]\n A3 --> A6[BRCAl/2 wild-type or unknown⁵]\n A3 --> A7[Germline or somatic BRCA1/2 mutation]\n A4 --> A8[Maintenance Therapy⁵⁻⁷,n.y Observe if CR or Niraparib(HR-deficient)⁶ or Rucaparib or Fluozaparib or Senaparib⁵⁻⁷ Observe for select stage II disease or HR-deficient(categories 2B) or Olaparib(HR deficient)(categories 2B) or Therapy for Persistent Disease or Recurrence(OV-7)]\n A5 --> A9[Olaparib(category 1) or Niraparib(category 1) or Rucaparib or Fluozaparib or Senaparib or Observe for select stage II disease with CR]\n A6 --> A10[Homologous recombination(HR) proficient or status unknown]\n A6 --> A11[HR deficient]\n A7 --> A12[Olaparib(category 1) or Niraparib(category 1) or Rucaparib or Fluozaparib or Senaparib or Observe for select stage II disease with CR]\n A8 --> A13[Monitoring/Follow-Up(OV-6)]\n A9 --> A13\n A10 --> A14[Bevacizumab]\n A11 --> A15[Bevacizumab+ Olaparib(category 1) or Bevacizumab+ Niraparib(if unable to tolerate olaparib) or Bevacizumab or Olaparib(category 2B) or Bevacizumab+ Olaparib(category 1) or Bevacizumab+ Niraparib(if unable to tolerate olaparib)]\n A11 --> A16[Olaparib⁵⁶ or Niraparib⁵⁵ or Rucaparib⁵⁵ or Fluozaparib⁵⁵ or Senaparib⁵⁵]\n A14 --> A13\n A15 --> A13\n A16 --> A13\n](1/parseimages/figure2bf59924018f4c4385f38eb45f5a6d81_0_6.png) Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

Footnotes and References on OV-5A

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

h In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage

disease, include measure of HR (OV-B).

n See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

w Post primary treatment recommendations for stage II–IV high-grade serous or grade 2/3 endometrioid carcinoma; consider for clear cell carcinoma or carcinosarcoma with a BRCA1/2 mutation.

x No definitive evidence of disease.

y Data are limited for maintenance therapy with a PARPi for patients with stage II disease.

z After first-line therapy with bevacizumab, data are limited on maintenance therapy with a single-agent PARPi (olaparib, niraparib, or rucaparib fluzoparib or senaparib) for patients with a germline or somatic BRCA1/2 mutation. However, based on the magnitude of benefit of PARPi maintenance therapy for other subgroups, singleagent PARPi can be considered.

Footnotes

References

* Li N et al. JAMA Oncol. 2023;9(9):1230-1237. González-Mart制n, A, et al. N Engl J Med. 2019;381(25):2391-2402. Monk BJ et al. Ann Oncol. 2024;35(11):981-992.

**Wu XH et al. Nat Med 2024;30:1612-1621.

OV-5A

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NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Staging II, III, and IV after primary treatment] --> A2[Visits every 2-4 mo for 2 y, then 3-6 mo for 3 y, then annually after 5 y ● Physical exam including pelvis exam as clinically indicated ● Imaging as clinically indicateda(eg, C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT) (skull base to mid-thigh) ● CBC and chemistry profile as indicated ● CA-125aa or other tumor markers if initially elevated ● Refer for genetic risk evaluation, if not previously donef ● Long-term wellness care (See NCCN Guidelines for Survivorship)]\n A2 --> A3[Rising CA-125, no previous chemotherapy or Clinical relapse, no previous chemotherapy]\n A2 --> A4[Clinical relapse, previous chemotherapy]\n A2 --> A5[Seriously rising CA-125, previous chemotherapy]\n A3 --> A6[Imaging studies as clinically indicateda,cc: C/A/P CT, MRI, PET/CT, or PET ● Tumor molecular testingdd if not previously done]\n A4 --> A7[Imaging studies as clinically indicateda,cc: C/A/P CT, MRI, PET/CT, or PET ● Tumor molecular testingdd if not previously done]\n A5 --> A8[Imaging studies as clinically indicateda,cc: C/A/P CT, MRI, PET/CT, or PET ● Tumor molecular testingdd]\n A6 --> A9[Primary Treatment (OV-1)]\n A7 --> A10[Therapy for Persistent Disease or Recurrence (OV-7)]\n A8 --> A11[Delay treatment until clinical relapse or immediate treatment for recurrent disease]\n A11 --> A10\n](1/parseimages/figure19c1090296f747e19068982296fdab87_0_4.png) a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

$^{n}$ See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

aa There are data regarding the utility of CA-125 for monitoring of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion.

bb Consider symptom management and best supportive care. See NCCN Guidelines for Palliative Care. Refer for palliative care assessment, if appropriate.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

$^{cc}$ Surveillance imaging may be indicated when tumor markers are considered unreliable, the physical exam is unreliable, and/or there is a high risk of recurrence. $^{dd}$ Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

DISEASE STATUSf,dd,ee

THERAPY FOR PERSISTENT DISEASE OR RECURRENCEn,gg,hh,ii

Platinum-resistant diseaseff: Progression on primary, maintenance or recurrence therapy or Stable or persistent disease (if not on maintenance therapy) or Complete remission and relapse <6 mo after completing chemotherapy

Best supportive care (See NCCN Guidelines for Palliative Care) and/or Recurrence therapy (OV-C, 9 of 12) n,j,j,k

Platinum-sensitive diseaseff: Complete remission and relapse ≥6 mo after completing prior chemotherapy

$^{n}$ See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

`dd` Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

$^{ee}$ Tumor molecular testing prior to initiation of therapy for persistent/recurrent disease, if not previously done.

ff Definitions of platinum-sensitive and platinum-resistant disease represent a spectrum of disease; clinical judgment and flexibility should be utilized in determining treatment options.

$^{99}$ Data are limited on primary and maintenance therapy for recurrent/persistent LCOC.

hh During and after treatment for recurrence, patients should be evaluated as indicated with tumor markers and repeat imaging (with modalities previously used) to document response and/or disease status.

ii "Ancillary Palliative Surgical Procedures (OV-A 4 of 4).

i) Patients who do not respond and progress on two consecutive regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58-65). Decisions to offer clinical trials, supportive care, or additional therapy should be made on an individual basis.

kk Localized radiation therapy (RT) can be considered to palliate symptoms and/or for oligometastatic disease.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Platinum-sensitive diseasef: Complete remission and relapse ≥6 mo after completing prior chemotherapy] --> A2[Radioographic and/or clinical relapse]\n A1 --> A3[Biochemical relapse(rising CA-125 and no radiographic evidence of disease)]\n A2 --> A4[Consider secondary cytoreductive surgeryi,k]\n A3 --> A2\n A4 --> A5[Combination platinum-based chemotherapy,n preferred for first recurrence(category 1) or Recurrence therapyn,kk and/or Best supportive care(See NCCN Guidelines for Palliative Care)]\n A5 --> A6[Maintenance therapy(if PR or CR) • Useful in certain circumstances: > Continue bevacizumab if previously treated with chemotherapy + bevacizumab; or > PARPi therapy(for those with BRCA 1/2 mutation): ◆ If not previously used(category 1) ◆ If disease has not progressed during prior PARPi treatment* or > PARPi therapy(for those with BRCA 1/2 wild-type or unknown): ◆ If not previously used ◆ If disease has not progressed during prior PARPi treatment* or Observe]\n A6 --> A7[Monitoring/Follow-up(OV-6)]\n A8[Delay treatment until radiographic and/or clinical relapse] --> A9[Immediate platinum-based recurrence therapy(n)(category 2B) and/or Best supportive care(See NCCN Guidelines for Palliative Care)]\n A9 --> A6\n A10[Consider secondary cytoreductive surgeryi,k] --> A5\n](1/parseimages/figureed2b0ede535541b98f96311b1adec3e6_0_4.png) dd Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics (OV-B), specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

* e Tumor molecular testing prior to initiation of therapy for persistent/recurrent disease, if not previously done.

ff Definitions of platinum-sensitive and platinum-resistant disease represent a spectrum of disease; clinical judgment and flexibility should be utilized in determining treatment options.

$^{99}$ Data are limited on primary and maintenance therapy for recurrent/persistent LCOC.

th During and after treatment for recurrence, patients should be evaluated as indicated with tumor markers and repeat imaging (with modalities previously used) to document response and/or disease status.

i Ancillary Palliative Surgical Procedures (OV-A 4 of 4).

kk Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.

II PARPi options include niraparib, olaparib, or rucaparib ในuroparib (Li N et al. J Clin Oncol. 2022;40(22):2436-2446) in patients with BRCA-mutated platinum-sensitive disease who have completed two or more lines of platinum-based therapy. Based on NMPA indications, olaparib, niraparib, and fuzuloparib may be used regardless of BRCA status (preferred for those with a BRCA mutation). However, based on FDA indication, niraparib is limited to those with a deleterious or suspected deleterious germline BRCA mutation. Based on FDA indications, olaparib and rucaparib are is limited to those with a deleterious or suspected deleterious BRCA mutation (germline or somatic). Caution should be used when using maintenance PARPi for longer than 24 months. There are limited data on the use of a maintenance PARPi in patients who previously received a PARPi. Combination bevacizumab/PARPi is not recommended for maintenance after recurrence therapy.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

![DIAGNOSISa,bCarcinosarcomaLCOC-2(malignant mixed Mullerian tumor [MMMT]Clear cell carcinoma of the ovaryLCOC-3Mucinous neoplasms of the ovaryLCOC-4Grade 1 endometrioid carcinomaLCOC-5Surgeryc,d and histologic diagnosisb,LCOC-6Low-grade serous carcinomaOvarian serous borderline epitheliaLCOC-8 toLCOC-10tumors (low malignant potential [LMP])LCOC-11Malignant sex cord-stromal tumorsLCOC-12 toMalignant germ cell tumorsLCOC-14\n](1/parseimages/figure63c4f59f15af40239400dd427716b224_0_4.png) a WHO Histologic Classification (OV-E).

b Due to emerging therapeutics for LCOC, there is value in identifying potential pathways for rare cancers and it may be useful for clinical trial recruitment. Tumor molecular testing can be considered, if not previously done, as it may help guide treatment. There are limited data in these cancers given their infrequency and it will be difficult to acquire prospective data. Individualized treatment may be the best treatment for these rare tumors. [Committee on the State of the Science in Ovarian Cancer, et al. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US) Copyright 2016 by the National Academy of Sciences. All rights reserved; 2016.]

c Principles of Surgery (OV-A).

d Principles of Pathology (OV-B).

e LCOC are typically diagnosed after surgery. See Workup (OV-1).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT$^{f}$

MONITORING/ FOLLOW-UP

![graph TD\n A1[Carcinosarcoma(MMMTs) of the ovaryᠧh,i] --> A2[IV paclitaxel/carboplatin every 3 weeks(pREFERRED) or Other systemic therapy • Stage I(OV-C, 5 of 12) • Stage II-IV(OV-C, 6 of 12)]\n A2 --> A3[Stage I]\n A2 --> A4[Stage II-IV]\n A3 --> A5[Monitoring/Follow-up(including tumor testing) and Recurrence therapyj (OV-6)]\n A4 --> A6[If known BRCA1/2 mutation, consider maintenance therapy(post-primary therapy)(OV-5)]\n](1/parseimages/figure73047aa125474a7b8d85bbfee06ac822_0_7.png) a WHO Histologic Classification (OV-E).

f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$^{9}$ If not previously done, consider surgical staging and resection of residual disease (OV-3).

$^{h}$ If not previously done, consider germline and somatic testing (OV-B).

$^{1}$ Germline and somatic BRCA1/2 status informs maintenance therapy. In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV-B).

$^{j}$ Data are limited on primary and maintenance therapy for recurrent/persistent LCOC.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT$^{f}$

MONITORING/ FOLLOW-UP

![graph TD\n A1[Clear cell carcinoma of the ovary9,h,i] --> A2[Stage IA IB, IC1]\n A1 --> A5[Stage IC2- IC3]\n A1 --> A8[Stage II-IV]\n A2 --> A3[IV platinum-based therapy(see primary regimens for stage I disease[OV-C, 5 of 12]\n A3 --> A4[Monitoring/Follow-up(including tumor testing) and Recurrence therapyl[OV-6]\n A5 --> A6[IV platinum-based therapy(see primary regimens for stage I disease[OV-C, 5 of 12]\n A6 --> A4\n A8 --> A7[Systemic therapy(OV-C, 6 of 12)]\n A7 --> A8\n](1/parseimages/figuree624390b7a2745f897e4ea8ae86560fc_0_7.png) NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12,19:17在医脉通平台下载,仅供个人使用,严禁分发。2026 美国国家综合癌症网络版权所有。

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Mucinous Carcinoma of the Ovary

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Mucinous neoplasms of the ovary[d,g,h]] --> A2[If not previously done: •GI evaluationk •Carcinoembryonic antigen(CEA) •CA 19-9]\n A2 --> A3[Stage IA carcinoma]\n A2 --> A4[Stage IB carcinoma]\n A2 --> A5[Stage IC carcinoma]\n A2 --> A6[Stage II-IV carcinoma]\n A2 --> A7[Borderline]\n A3 --> A8[Expansile]\n A3 --> A9[Infiltrative]\n A4 --> A10[Expansile]\n A4 --> A11[Infiltrative]\n A5 --> A12[Expansile]\n A5 --> A13[Infiltrative]\n A6 --> A14[Systemic therapy(OV-C, 6 of 12)f]\n A7 --> A15[Observe]\n A8 --> A16[Observe]\n A9 --> A17[Systemic therapy(OV-C, 5 of 12)f]\n A10 --> A18[Observe]\n A11 --> A19[Systemic therapy(OV-C, 5 of 12)f]\n A12 --> A20[Observe]\n A13 --> A21[Systemic therapy(OV-C, 5 of 12)f]\n A14 --> A22[Monitoring/Follow-up(including tumor testing) and Recurrence therapyj(OV-6)]\n](1/parseimages/figure8004d022a2bb4319be1b468920ed0c4e_0_6.png) a WHO Histologic Classification (OV-E).

d Principles of Pathology (OV-B).

f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$^{9}$ If not previously done, consider surgical staging and resection of residual disease (OV-3).

h If not previously done, consider germline and somatic testing (OV-B).

i Data are limited on primary and maintenance therapy for recurrent/persistent LCOC.

k Consider additional testing, including but not limited to upper and lower endoscopic evaluation, to aid in the identification of metastatic GI malignancies versus primary mucinous ovarian cancer.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025 Grade 1 Endometrioid Carcinoma

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT

MONITORING/ FOLLOW-UP

![####################################################################################################################################################################################################################################################################################################################################################################################################################################################################################################################\n](1/parseimages/figure3cc5d3b4a4274fe999e80384efc09f6b_0_7.png) a WHO Histologic Classification (OV-E).

f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$^{9}$ If not previously done, consider surgical staging and resection of residual disease (OV-3).

h If not previously done, consider germline and somatic testing (OV-B).

$^{1}$ Data are limited on primary and maintenance therapy for recurrent/persistent LCOC.

$^{1}$ MSI/MMR testing is recommended for all patients with endometrioid carcinoma.

m Other hormonal therapy options include: aromatase inhibitors (ie, anastrozole, exemestane), leuprolide acetate, goserelin acetate, and tamoxifen.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT

MONITORING/ FOLLOW-UP

![NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12,19:17在医脉通平台下载,仅供个人使用,严禁分发。2026 美国国家综合癌症网络版权所有。\n\nNCCN Guidelines Index\nTable of Contents\nNCCN Guide\n#NCCN Guide\n##Low-Grade\nDIAGNOSISa\n\n###ADJUVANT TREATMENT\n\n###MONITORING/FOLLOW-UP\n\n####LOW-grade\nserous\ncarcinoma$^{g,h}$\n\nStage\nIA-IB\n\nObserve\ng\n(category 2B)\nSystemic therapy (OV-C, 5 of 12)$^{f}$\n\nObserve\nor\nSystemic therapy (OV-C, 5 of 12)$^{f}$\n\nObserve\nor\nMaintenance letroz\nor\nOther hormonal therapy\ncategory 2B)$^{n}$\n\nMonitoring/\nFollow-up for\nRecurrent\nDisease\n(LOC-7)\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\nII-IV\n\nStage\n\n](1/parseimages/figure3f7c6e17469a4266a7eea562006207f1_0_7.png) ª WHO Histologic Classification (OV-E).

f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$^{9}$ If not previously done, consider surgical staging and resection of residual disease (OV-3).

h If not previously done, consider germline and somatic testing (OV-B).

n Other hormonal therapy options include: aromatase inhibitors (ie, anastrozole, exemestane), leuprolide acetate, and goserelin acetate.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

MONITORING/FOLLOW-UP FOR RECURRENCE

RECURRENCE THERAPYS

* Visits every 2–4 mo for 2 y, then 3–6 mo for 3 y, then annually after 5 y

* Physical exam including pelvic exam as clinically indicated

* Tumor molecular testing if not previously done$^{º}$

$\bullet$ Imaging as clinically indicated$^{p}$ (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI) (skull base to mid-thigh)

* CBC and chemistry profile as indicated

$\bullet$ CA-125$^{9}$ or other tumor markers if initially elevated

* Refer for genetic risk evaluation, if not previously done$^{f}$

$\bullet$ Long-term wellness care (See NCCN Guidelines for Survivorship)

Hormonal therapy$^{u}$

Chemotherapy (if not previously used), see OV-C (6 of 12)

Systemic therapyf, v

$\bullet$ For platinum-sensitive disease, see OV-C (8 of 12)

$\bullet$ For platinum-resistant disease, see OV-C (9 of 12)

Observation

f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).

$\circ$ Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

PCT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

$^{q}$ There are data regarding the utility of CA-125 for monitoring of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion.

* See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{5}$ There is no standard sequencing of drugs for recurrent disease. Considerations include prior therapies, disease burden, relative efficacy, and relative toxicity profile.

† Consider secondary cytoreduction in patients with long disease-free interval, isolated masses rather than diffuse carcinomatosis on imaging, and/or bowel obstruction.

$^{u}$ An aromatase inhibitor (ie, letrozole, anastrozole, exemestane) is preferred if not used previously. Fulvestrant, leuprolide acetate, or goserelin acetate is recommended if an aromatase inhibitor was given previously.

$\bullet$ V Data are limited on maintenance therapy for recurrent/resistant LCOC. See OV-8 for maintenance options after platinum-based therapy, and patient selection criteria.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Ovarian Serous Borderline Epithelial Tumors

(Low Malignant Potential)

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT*

![NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12 19:17在医脉通平台下载，仅供个人使用，严禁分发。2026 美国国家综合癌症网络版权所有。\nNCCN Guidelines Index\nTable of Contents\nDiscussion\nPATHOLOGIC\nDIAGNOSISª\n\nPATHOLOGIC DIAGNOSISª\n\nOvarian serous borderline epithelial tumors (LMP)a\n\nPrior complete surgical resectionc,d\n\nLow-grade serous carcinoma\n\nSee adjuvant options (LCOC-6)\n\nMonitoring/ Follow-up (LCOC-10)\n\nOvarian serous borderline epithelial tumors (LMP)a\n\nPrior incomplete surgical resectionc,d\n\nLCOC-9\n](1/parseimages/figurea319d389dcc84b3f8c0be2056d1b7eb6_0_8.png) a WHO Histologic Classification (OV-E).

c Principles of Surgery (OV-A).

d Principles of Pathology (OV-B).

W Chemotherapy (IV or IP) has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP).

x Standard recommendation includes a patient evaluation by a gynecologic oncologist.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Serous Borderline Epithelial Tumors (Low Malignant Potential)

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

ADJUVANT TREATMENT*

![Ovarian serous borderline epithelial tumor (LMP), incomplete surgical staging, or tumor reductive surgery\n\nImagingp if not previously done\n\n- eg, C/A/P CT, chest CT, A/P MRI, PET/ CT, PET/ MRI\n\nNo residual disease remaining after first procedure and/or on imaging\n\nFertility-sparing surgery (if fertility desired) and resection of residual disease$^{y,z}$\n\nCorridor surgical intervention for select patients$^{a}$\n\nDissection\n\nBorderline on final pathology\n\nMonitoring/(LCOC-10)\n\nLOCC-6\n\nConsider no surgical intervention for select patients$^{a}$\n\nNCCN Guidelines Index\nTable of Contents\nDiscussion\n](1/parseimages/figure247069f93fbf406bb1e40f0e349174f1_0_6.png) a WHO Histologic Classification (OV-E).

c Principles of Surgery (OV-A).

d Principles of Pathology (OV-B).

P CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

* Chemotherapy (IV or IP) has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP).

$\bullet$ Standard recommendation includes a patient evaluation by a gynecologic oncologist.

$^{y}$ For pathologically proven ovarian borderline epithelial tumors, lymph node evaluation may be considered on a case-by-case basis.

$^{2}$ In patients who underwent USO, consider completion surgery (eg, contralateral USO, hysterectomy) after completion of childbearing (category 2B).

aa If patient is medically unfit, or for those with unresectable residual disease.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Serous Borderline Epithelial Tumors (Low Malignant Potential)

NCCN Guidelines Index Table of Contents Discussion

MONITORING/FOLLOW-UP

RECURRENT DISEASE

RECURRENCE THERAPY

![Visits every 3-12 mo for up to 5 y, then as clinically indicated\nPhysical exam including pelvic exam as clinically indicated\nCA-125$^{q}$ or other tumor markers every visit if initially elevated\nCBC, chemistry profile as indicated\nImaging$^{p}$ as clinically indicated: eg C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI (skull base to mid-thigh)\nUltrasound as indicated for patients with fertility-sparing surgery\n\nClinical relapse\n\nSurgical evaluation + debulking if appropriate\n\nNoninvasive disease\n\nObserve\n\nLow-grade invasive carcinoma\n\nSee appropriate LCOC page based on histology™ (LCOC-1)\n\nHigh-grade invasive carcinoma\n\nTreatment as epithelial ovarian cancer™ (OV-4)\n](1/parseimages/figure6c1ae26cf6934b689a4c2cac6275be80_0_7.png) $^{P}$ CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

$^{9}$ There are data regarding the utility of CA-125 for monitoring of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion.

W Chemotherapy (IV or IP) has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Malignant Sex Cord-Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL PRESENTATION/DIAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[ALD]SAGNOSIS\n\n[A\n](1/parseimages/figure3202fa26bdff46a190504bc28ad5a05c_0_6.png) a WHO Histologic Classification (OV-E).

c Principles of Surgery (OV-A).

d Principles of Pathology (OV-B).

bb Lymphadenectomy may be omitted.

$^{cc}$ Inhibin levels can be followed for granulosa cell tumors.

dd Acceptable options include paclitaxel/carboplatin (preferred), EP (etoposide, cisplatin), or BEP (bleomycin, etoposide, cisplatin) (category 2B).

ee See Principles of Systemic Therapy (OV-C) and Systemic Therapy Regimens for Malignant Germ Cell/Sex Cord-Stromal Tumors (LCOC-A).

ff Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL PRESENTATION/\nDIAGNOSIS\n\nTREATMENTX\n\nFertility desired\n\nFertility not desired\n\nMalignant germ cell tumors\n\nPrior surgery$^{99}$\n\nDysgerminoma or Grade 1 immature teratoma\n\nPior imaging of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI)\n\nEmbryonal, endodermal sinus tumor (yolk sac tumor), grade 2-3 immature teratoma, nongestational choriocarcinoma, or mixed histology\n\nPositive imaging and positive tumor markers\n\nPert of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI)\n\nPositive imaging and positive tumor markers\n\nPert of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI)\n\nEmbronyal, endodermal sinus tumor (yolk sac tumor), grade 2-3 immature teratoma, nongestational choriocarcinoma, or mixed histology\n\nPCT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.\n\nNote: This is the NCCN Guidelines for China. For definitions, see page DEF-1.\nNote: All recommendations are category 2A unless otherwise indicated.\n\nLococ-12\n](1/parseimages/figure65de1f5feefb4531a29987befae8df3a_0_4.png) P CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

* Standard recommendation includes a patient evaluation by a gynecologic oncologist. 99 Surgical principles for pediatric/young adult patients may differ from those for adult patients. See Principles of Surgery (OV-A).

$^{nh}$ Repeat imaging if tumor markers plateau at significant abnormal level or rise. If imaging positive, follow pathway above for positive imaging and positive tumor markers.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025 Malignant Germ Cell Tumors

NCCN Guidelines Index Table of Contents Discussion

![PATHOLOGIC DIAGNOSISª\n\nAJDUVANT TREATMENT MONITORING/FOLLOW-UP\n\nTHERAPY FOR RECURRENT/PERSISTENT DISEASEff\n\nStage I dysgerminomaII or Stage I, grade 1 immature teratomaII\n\nObserve Surveillance (LCOC-B)\n\nAny stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumor) or Stage II-IV dysgerminoma or Stage I, grade 2 or 3 or Stage II-IV immature teratoma or Any stage nongestational choriocarcinoma\n\nImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, and, A/P MRI, PET/ CT, or PET/ MRI (skull base to mid-thigh)\n\nImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh)\n\nResidual tumor on imaging; markers normalkk\n\nObserve�evillance (LCOC-B)\n\nComplete clinical response LCOC-14\n\nNCCN Guidelines Index\nTable of Contents\nDiscussion\n\nPATHOLOGIC DIAGNOSISA\n\nADJUVANT TREATMENT MONITORING/FOLLOW-UP\n\nTHERAPY FOR RECURRENT/PERSISTENT DISEASEff\n\nStage I dysgerminomaII or Stage I, grade 1 damage in immature teratoma II\n\nObserveávillance (LCOC-B)\n\nAny stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumor) or\nChemotherapyji\n\nChemotherapyji\n\nImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh)\n\nImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh)\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or Consider surgical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reteratoma\n\nBiospy or consider musical reterat\n](1/parseimages/figuref965f8bb5159497994a27e608ab016e8_0_4.png) ª WHO Histologic Classification (OV-E).

P CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.

ff Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.

$^{1}$ Pediatric/adolescent patients with the following clinical presentations may consider observation or chemotherapy as treatment options: stage IA, IB dysgerminoma; stage IA, grade 1 immature teratoma; stage IA embryonal carcinomas; or stage IA yolk sac tumors. Consultation with a pediatric oncologist for pediatric/adolescent patients is recommended.

jJ Primary Systemic Therapy Regimens for Malignant Germ Cell Tumors (LCOC-A).

kk See OV-1 for markers.

II High-dose chemotherapy regimens vary among institutions. Some patients are potentially curable with HCT. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution for HCT consultation and potentially curative therapy.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

NCCN Guidelines Index Table of Contents Discussion

PATHOLOGIC DIAGNOSISª

Malignant Germ Cell Tumors

MONITORING/FOLLOW-UP AFTER ADJUVANT TREATMENT

THERAPY FOR RECURRENT/ PERSISTENT DISEASE$^{ff}$

![Any stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumorii) or Stage II–IV dysgerminoma or 3 or Stage II–IV immature teratoma or Any stage nongestational choriocarcinoma\n\nComplete clinical response\n\nObserve (LCOC-B)\n\nAbnormal markers, definitive recurrent disease\n\nSecond-line chemotherapy$^{ee}$ (category 2B) or High-dose chemotherapy$^{II}$ + HCT (category 2B) or Consider surgery for select patients\n\nComplete clinical response\n\nSecond-line chemotherapy$^{ee}$ (category 2B) or High-dose chemotherapy$^{II}$ + HCT (category 2B) or Consider surgery for select patients\n\nLCOC-A\n](1/parseimages/figure103083e73a8e4fa286c047469d2915de_0_8.png) ª WHO Histologic Classification (OV-E).

* ee See Principles of Systemic Therapy (OV-C) and Systemic Therapy Regimens for Malignant Germ Cell/Sex Cord-Stromal Tumors (LCOC-A).

ff Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.

ii. Pediatric/adolescent patients with the following clinical presentations may consider observation or chemotherapy as treatment options: stage IA, IB dysgerminoma; stage IA, grade 1 immature teratoma; stage IA embryonal carcinomas; or stage IA yolk sac tumors. Consultation with a pediatric oncologist for pediatric/adolescent patients is recommended.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Malignant Germ Cell/Sex Cord-Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY REGIMENSª

MALIGNANT GERM CELL/SEX CORD-STROMAL TUMORS

MALIGNANT GERM CELL TUMORSa,b,c

Primary Therapy

Preferred Regimens

$\bullet$ BEP (bleomycin, etoposide, cisplatin)$^{d}$

$\blacktriangleright$ Bleomycin 30 units IV per week plus etoposide 100 mg/m$^{2}$ IV daily on days 1–5 plus cisplatin 20 mg/m$^{2}$ IV daily on days 1–5; repeat every 21 days for 3 cycles for good risk (category 2B), or 4 cycles for poor risk.

Other Recommended Regimens

$\bullet$ None

Useful in Certain Circumstances

$\bullet$ Etoposide/carboplatina, c (for select patients with stage II–III resected dysgerminoma for whom minimizing toxicity is critical)

$\bullet$ Carboplatin 400 mg/m$^{2}$ IV on day 1 plus etoposide 120 mg/m$^{2}$ IV on days 1, 2, and 3 every 28 days for 3 cycles.

Recurrence Therapy

Preferred Regimens

(Potentially curative)

* High-dose chemotherapy$^{b}$

* TIP (paclitaxel, ifosfamide, cisplatin)

Other Recommended Regimens

(Palliative only)

$\bullet$ Etoposide/cisplatin (EP), if not previously used

* Docetaxel

Docetaxel/carboplatin

* Etoposide (oral)

* Etoposide/ifosfamide/cisplatin (VIP)

$\bullet$ Gemcitabine/paclitaxel/oxaliplatin

$\cdot$ Gemcitabine/oxaliplatin

$\bullet$ Paclitaxel

$\bullet$ Paclitaxel/carboplatin

$\bullet$ Paclitaxel/gemcitabine

$\bullet$ Paclitaxel/ifosfamide

$\bullet$ Pembrolizumab (if microsatellite instability-high [MSI-H]/mismatch repair deficient [dMMR] or tumor mutational burden-high [TMB-H])

$\bullet$ VeIP (vinblastine, ifosfamide, cisplatin)

$\bullet$ VAC (vincristine, dactinomycin, cyclophosphamide)

$\bullet$ Supportive care (See NCCN Supportive Care Guidelines)

MALIGNANT SEX CORD-STROMAL TUMORS$^{a,c}$

Primary

Preferred Regimens

Other Recommended Regimens

Recurrence Therapy

$\bullet$ Paclitaxel/carboplatin

$\bullet$ Etoposide/cisplatin (EP)

Other Recommended Regimens

$\bullet$ EP, if not previously used

$\bullet$ Paclitaxel/ifosfamide

* Docetaxel

$\bullet$ Paclitaxel

$\bullet$ Supportive care only (See NCCN Supportive Care Guidelines)

* Targeted therapy: Bevacizumab (single agent)

Useful in Certain Circumstances

$\bullet$ BEP (category 2B)$^{d}$

Useful in Certain Circumstances

$\bullet$ Aromatase inhibitors (ie, anastrozole, exemestane, letrozole)

$\bullet$ Leuprolide acetate or goserelin acetate (for granulosa cell tumors)

$\bullet$ Tamoxifen

$\bullet$ BEP (category 2B),$^{d}$ if not previously used

$\cdot$ VAC (category 2B)

a See Principles of Systemic Therapy (OV-C) and see Discussion for references.

b High-dose chemotherapy regimens vary among institutions. Some patients are potentially curable with HCT. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution for HCT consultation and potentially curative therapy.

c WHO Histologic Classification (OV-E).

d. Recommended pulmonary function test if considering bleomycin.

e Consultation with a pediatric oncologist for pediatric/adolescent patients is recommended.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Malignant Germ Cell/Sex Cord-Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

SURVEILLANCE

MALIGNANT GERM CELL/SEX CORD-STROMAL TUMORS

|Malignant Germ Cell Tumors|||||| |---|---|---|---|---|---| ||Year 1|Year 2|Year 3|Years 4-5|After 5 Years| |Clinical evaluation|Every 3 mo|Every 3 mo|Every 6 mo|Every 12 mo|Every 12 mo| |Pelvic $USA^{a}$|Every 3 mo|Every 3 mo|Every 6 mo|--|--| |Tumor $markers^{b}$|Every 2 mo|Every 3 mo|Every 6 mo|Every 12 mo|Every 12 mo up to 10 y| |Chest x-ray|--|--|--|Every 6 mo|As clinically indicated| |C/A/P CT|Every 3 mo|Every 3 mo|Every 6-12 mo|As clinically indicated|As clinically indicated|

|Malignant Sex $Cord-Stromal$ Tumors^{c}$|||| |---|---|---|---| ||0–2 Years|After 2 Years|After 2 Years| |Physical exam|As clinically indicated based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)|As clinically indicated based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)|(ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)| |Serum tumor $markers^{b}$|Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)|Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)|Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)| |$Imaging^{d}$|Reserved for patients with symptoms, elevated biomarkers, or suspicious findings on physical exam|Reserved for patients with symptoms, elevated biomarkers, or suspicious findings on physical exam||

ª Only for those patients who have a residual ovary.

b See OV-1 for markers.

c Salani R, Khanna N, Frimer M, et al. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3-10.

d Chest x-ray, C/A/P CT, MRI, PET/CT, or PET; with contrast unless contraindicated.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

OV-A 1 OF 4

PRINCIPLES OF SURGERY1

General Considerations

• It is recommended that a gynecologic oncologist perform the appropriate surgery.

• An open laparotomy including a vertical midline abdominal incision should be used in most patients with a suspected malignant ovarian/

fallopian tube/primary peritoneal neoplasm in whom a surgical staging procedure, a primary debulking procedure, an interval debulking

procedure, or secondary cytoreduction is planned.

For select patients, a minimally invasive surgical approach may be used by an experienced surgeon to manage early-stage disease.

Laparoscopy may be useful to evaluate whether optimal cytoreduction can be achieved in patients with newly diagnosed advanced-stage

or recurrent disease.

Minimally invasive techniques can be used for select patients for interval debulking procedures. Patients who are unable to be optimally

debulked using minimally invasive techniques should be converted to an open procedure.

• Intraoperative pathologic evaluation with frozen sections may assist in management.

• Prior to surgery for ovarian cancer, counsel patients about port placement if intraperitoneal (IP) chemotherapy is being considered.

Operative Reports

• Surgeons should describe the following in the operative report:

Extent of initial disease before debulking pelvis, mid-abdomen, or upper abdomen (cuto冩s: pelvic brim to lower ribs).

Amount of residual disease in the same areas after debulking.

Complete or incomplete resection; if incomplete, indicate the size of the major lesion and total number of lesions. Indicate if miliary or

small lesions.

Continued

1 Fleming GF, Seidman J, Yemelyanova A, and Lengyl E. Epithelial Ovarian Cancer. In: Chi DS, Berchuck A, Dizon D, et al (eds). Principles and Practice of Gynecologic Oncology, 7th ed, Philadelphia, Lippincott Williams & Wilkins, 2017:611-705.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Newly Diagnosed Invasive Epithelial Ovarian Cancer Apparently Conined to the Ovaries, Fallopian Tubes, and Uterus (apparent stage IA–IIA)In general, every e冩ort should be made during a primary cytoreduction procedure to achieve maximum cytoreduction of all pelvic disease and to evaluate for occult disease in the upper abdomen or retroperitoneum.

• On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations.

• All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be

selectively excised or biopsied. In the absence of any suspicious areas, random peritoneal biopsies should be taken from the pelvis,

paracolic gutters, and undersurfaces of the diaphragm (diaphragm scraping for Papanicolaou stain is an acceptable alternative).

• BSO and hysterectomy should be performed with every e冩ort to keep an encapsulated mass intact during removal.

• For selected patients desiring to preserve fertility, USO or BSO with uterine preservation may be considered. Uterine preservation allows for potential future assisted reproductive approaches.

• Omentectomy should be performed.

• Para-aortic lymph node dissection should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels.

• The preferred method of dissecting pelvic lymph nodes is bilateral removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a

minimum anterior to the obturator nerve.2

Newly Diagnosed Invasive Epithelial Ovarian Cancer Involving the Pelvis and Upper Abdomen (stage >IIB)

In general, every e冩ort should be made during a primary cytoreduction procedure to achieve maximum cytoreduction of all abdominal, pelvic, and retroperitoneal disease. Residual disease <1 cm deines optimal cytoreduction; however, maximal e冩ort should be made to remove all gross disease since this o冩ers superior survival outcomes.3

• Aspiration of ascites (if present) should be performed for peritoneal cytologic examinations. All involved omentum should be removed.

• Suspicious and/or enlarged nodes, identiied on preoperative imaging or during surgical exploration, should be resected, if possible. Resection of clinically negative nodes is not required.4

• Procedures that may be considered for optimal surgical cytoreduction (in all stages) include bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial

gastrectomy, cholecystectomy, and/or distal pancreatectomy.

• Select patients with low-volume residual disease after surgical cytoreduction for invasive epithelial ovarian or peritoneal cancer are potential candidates for IP therapy. In these patients, consideration should be given to placement of IP catheter with initial surgery.

OV-A

2 OF 4 PRINCIPLES OF SURGERY1

2 Whitney CW, Spirtos N. Gynecologic Oncology Group Surgical Procedures Manual. Philadelphia: Gynecologic Oncology Group; 2010.

3 Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm.

Gynecol Oncol 2009;114:26-31.

4 Harter P, Sehouli J, Lorusso D, et al. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N Engl J Med 2019;380:822-832.

Continued

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SURGERY$^{1}$

Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer

As with a primary debulking procedure, every effort should be made to achieve maximum cytoreduction during an interval debulking procedure. Maximal effort should be made to remove all gross disease in the abdomen, pelvis, and retroperitoneum. Consultation with a gynecologic oncologist is recommended.

$\bullet$ IDS, including completion hysterectomy and BSO with staging, should be performed after 3-4 cycles of neoadjuvant chemotherapy for patients with a response to chemotherapy or stable disease. Alternate timing of surgery has not been prospectively evaluated but may be considered based on individual patient-centered factors.

* HIPEC with cisplatin (100 mg/m$^{2}$) can be considered at the time of IDS for stage III disease. HIPEC can also be considered for suitable stage IV patients (category 2B) who have had a favorable response to neoadjuvant therapy both intraperitoneally and extraperitoneally, or in whom stage IV diseases have completely resolved (eg, resolution of malignant pleural effusion) or are now deemed resectable. Sodium thiosulfate may be administered at the start of perfusion, followed by a continuous infusion, to allow for renal protection during HIPEC.

* All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied.

* An omentectomy should be performed.

* While systematic lymphadenectomy of clinical-negative nodes is not recommended, suspicious and/or enlarged nodes should be resected, if possible.

$\bullet$ Procedures that may be considered for optimal surgical debulking include bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.

Risk-Reducing Salpingo-Oophorectomy (RRSO) Protocol

$\bullet$ For information on when RRSO is indicated, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.

$\bullet$ Perform minimally invasive laparoscopic surgery.

* Survey upper abdomen, bowel surfaces, omentum, appendix (if present), and pelvic organs.

$\bullet$ Biopsy any abnormal peritoneal findings.

$\bullet$ Obtain pelvic washing for cytology (50 cc normal saline instilled and aspirated immediately).

$\bullet$ Perform total BSO, removing 2 cm of proximal ovarian vasculature/IP ligament, all tube up to the cornua, and all peritoneum surrounding the ovaries and tubes, especially peritoneum underlying areas of adhesion between tube and/or ovary and the pelvic sidewall.$^{5}$

$\bullet$ Engage in minimal instrument handling of the tubes and ovaries to avoid traumatic exfoliation of cells.$^{5}$

$\bullet$ Both ovaries and tubes should be placed in an endobag for retrieval from the pelvis.

$\bullet$ Both ovaries and tubes should be processed by sectioning and extensively examining the fimbriated end (SEE-FIM) protocol.$^{6}$

* If occult malignancy or serous tub intraepithelial carcinoma (STIC) is identified, provide referral to a gynecologic oncologist.

The prevention benefits of salpingectomy alone are not yet proven. If considered, the fallopian tube from the fimbria to its insertion into the uterus should be removed. In addition, the fallopian tube should be processed and assessed as described above. The concern for risk-reducing salpingectomy alone is that patients are still at risk for developing ovarian cancer. In addition, in premenopausal patients, oophorectomy reduces the risk of developing breast cancer but the magnitude is uncertain. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.

developing ovarian cancer. In addition, in premenopausal patients, oophorectomy reduces the risk of developing breast cancer but the magnitude is uncertain. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Special Circumstances

• Fertility-sparing surgery:

Fertility-sparing surgery with USO (preserving the uterus and contralateral ovary) or BSO (preserving the uterus) can be considered for

patients with apparent early-stage disease and/or low-risk tumors (early-stage invasive epithelial tumors, LMP lesions, malignant germ cell

tumors, mucinous tumors, or malignant sex cord-stromal tumors) who wish to preserve fertility. Consider endometrial sampling to exclude

synchronous primary or hyperplasia. Refer to reproductive endocrinologist for evaluation and REI consultation as clinically indicated.

Comprehensive surgical staging should still be performed to rule out occult higher stage disease but may be omitted in pediatric,

adolescent, and young adult patients with clinically apparent early-stage malignant germ cell tumors based on the pediatric surgical

literature.7

• Mucinous tumors: Primary invasive mucinous tumors of the ovary are uncommon. Thus, the upper and lower GI tract should be carefully

evaluated to rule out an occult GI primary with ovarian metastases, and an appendectomy need only be performed in patients with a

suspected or conirmed mucinous ovarian neoplasm if it appears to be abnormal. A normal appendix does not require surgical resection in this setting. If mucinous histology is conirmed by intraoperative frozen section analysis and there are no suspicious lymph nodes, consider

omitting lymphadenectomy.

• Ovarian borderline epithelial (LMP) tumors: Although data show upstaging with lymphadenectomy, other data show that lymphadenectomy

does not a冩ect overall survival. However, omentectomy and multiple biopsies of peritoneum (the most common sites of peritoneal implants) may upstage patients in approximately 30% of cases and may a冩ect prognosis.

• Secondary cytoreduction: A secondary cytoreduction procedure can be considered in patients with recurrent ovarian cancer who develop a recurrence more than 6 months since completion of initial chemotherapy, have a good performance status, have no ascites, and have

an isolated focus or limited foci of disease amenable to complete resection. In addition to preoperative imaging, laparoscopy may be used to determine if complete resection can be achieved. Secondary cytoreduction can be performed with either open or minimally invasive

approaches. Consider using validated scoring methods to assess suitability for secondary cytoreduction.

Ancillary Palliative Surgical Procedures8

These procedures may be appropriate in select patients:

• Paracentesis/indwelling peritoneal catheter

• Thoracentesis/pleurodesis/video-assisted thoracoscopy/indwelling pleural catheter

• Ureteral stents/nephrostomy

• Gastrostomy tube/intestinal stents/surgical relief of intestinal obstruction

PRINCIPLES OF SURGERY1

7 Billmire D, Vinocur C, Rescorla F, et al. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study.

J Pediatr Surg 2004;39:424-429.

8 Decisions on the use of ancillary procedures should be made in conjunction with a gynecologic oncology surgeon or a practitioner familiar with ovarian cancer patterns of recurrence.

OV-A 4 OF 4

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NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

PRINCIPLES OF PATHOLOGY

General

* The complete histologic classification from the WHO is included in the NCCN Guidelines (WHO Histologic Classification on OV-E).$^{1}$ The WHO pathology manual is also a useful resource.$^{1}$

* Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen. Fine-needle aspiration (FNA) should be avoided for diagnosis of ovarian cancer in patients with presumed early-stage disease to prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity. However, FNA may be necessary in patients with bulky disease who are not candidates for primary debulking.$^{2,3}$

$\bullet$ Both primary peritoneal and fallopian tube cancers are usually diagnosed postoperatively (if there is no major involvement of the ovary) or preoperatively (if there is a biopsy and the patient has already had a bilateral salpingo-oophorectomy). Primary peritoneal and fallopian tube cancers are treated in the same manner as epithelial ovarian cancer.

* The CAP protocol is a useful tool for pathology reports.$^{4}$

Pathologic assessment should include:

$\bullet$ Elements from CAP protocol$^{4}$:

$\bullet$ Tumor site(s) (eg, ovary, fallopian tube, or primary peritoneum)

$\bullet$ Tumor size(s)

* Other tissue/organ involvement

$\bullet$ Ovarian/fallopian tumors: surface involvement (present/absent/ cannot determine), specimen integrity (capsule/serosa intact/ fractured/fragmented)

$\bullet$ Histologic type and grade

$\bullet$ Extension and/or implants (if sampled/identified)

$\bullet$ Cytology: peritoneal or ascitic fluid or washings/pleural fluid

$\bullet$ Lymph nodes: number and location of nodes examined, size of largest metastatic deposits

$\bullet$ STIC, endometriosis (particularly if in continuity with endometrioid or clear cell carcinoma), and/or endosalpingiosis

$\bullet$ Staging information (FIGO and TNM)

Tumor molecular analyses

$\bullet$ In the upfront setting, choice of somatic testing should, at a minimum, optimize identification of molecular alterations that can inform use of interventions that have demonstrated benefit in this setting, including BRCA1/2, loss of heterozygosity (LOH), or homologous recombination deficiency (HRD) status in the absence of a germline BRCA mutation.

$\bullet$ In the recurrence setting, tumor molecular analysis is recommended to include, as appropriate, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in less common histologies with limited approved therapeutic options. It is recommended that such testing be performed on the most recent available tumor tissue.

$\bullet$ Molecular analyses may be performed on circulating tumor DNA (ctDNA or liquid biopsy) when tissue-based analysis is not clinically feasible.

$\bullet$ Validated molecular testing should be performed in a CLIA-approved facility.

References on OV-B (3 of 3) Continued

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Less Common Ovarian Cancers (LCOC)

• A borderline tumor is a primary epithelial lesion with cytologic characteristics suggesting malignancy but without frank invasion. The terms for borderline epithelial tumors (also known as LMP tumors or atypical proliferative tumors) have changed over the years.5 The 2023 CAP

protocol for ovarian cancer uses borderline and does not use LMP.4 Borderline epithelial tumors are typically serous or mucinous; other

histologic subtypes can also occur (WHO Histologic Classiication on OV-E).1,6 The characteristic pathologic hallmark of typical epithelial

ovarian cancer is the identiication of peritoneal implants, which microscopically and/or macroscopically invade the peritoneum. A borderline epithelial tumor may grossly resemble an invasive cancer. However, microscopic evaluation fails to reveal evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the diagnosis of borderline epithelial lesions) can be identiied microscopically by the pathologist.

• Clear cell carcinomas are high-grade tumors that may arise in endometriosis. Most clear cell carcinomas express napsin A and are negative for WT1 and estrogen receptors.5

• It is di冪cult to distinguish based on histology between primary mucinous ovarian carcinomas and GI metastases.7,8,9 PAX8 immunostaining is typical of primary ovarian tumors, although the absence of PAX8 does not rule out ovary as the primary site,10 while SATB2 is consistent with colonic origin.11 Features favoring primary ovarian carcinoma versus metastasis are: unilateral, "expansile" pattern of invasion,

complex papillary pattern, size >10 cm, smooth external surface, microscopic cystic glands, necrotic luminal debris, mural nodules and

accompanying teratoma, adenoibroma, endometriosis, or Brenner tumor.12

• Most early stage invasive mucinous ovarian cancers have an expansile pattern of growth characterized by complex glandular, papillary and/or cribriform architecture with a labyrinthine or anastomosing pattern and little or no intervening stroma. About 20% have an iniltrative

pattern of destructive invasion of haphazardly arranged and angulated tumor cell nests into a desmoplastic stroma and measuring at least 5 mm in linear extent–and this has been associated with an increased risk of relapse and mortality.13,14

• Metastatic colorectal adenocarcinomas also usually are positive for CK20.

• Endometrioid carcinomas may be associated with endometriosis.10,15 Endometrioid adenocarcinomas are usually positive for cytokeratin 7 (CK7), PAX8, and estrogen receptors. Endometrioid tumors are also very similar in appearance to sex cord-stromal tumors.5

• Most pathologists now consider MMMTs to be a variant of poorly di冩erentiated epithelial ovarian cancer (metaplastic carcinoma).16

Special Circumstances

• Other cancers17,18 that can commonly involve the adnexa include:

Uterine

Cervical

GI (small and large bowel, pancreatic)

Lymphoma

• For risk-reducing surgery, pathologic assessment should include the following:

Fallopian tubes should be processed by SEE-FIM of the tubes and then assessed to determine whether any evidence of cancer is present.4 The ovaries should also be carefully sectioned, processed, and assessed.4 The 2023 CAP protocol describes the process for sectioning the

fallopian tubes and ovaries.4

• Patients who have equivocal pathologic indings or who are referred to NCCN Member Institutions after having a previous diagnosis of

ovarian cancer should have their pathology reviewed by pathologists at NCCN Member Institutions.

OV-B 2 OF 3 PRINCIPLES OF PATHOLOGY

References on OV-B (3 of 3)

NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer OV-B 3 OF 3 PRINCIPLES OF PATHOLOGY NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

References

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

OV-C

PRINCIPLES OF SYSTEMIC THERAPY

General Principles

General Principles of Systemic Therapy OV-C (1 of 12)

Principles of Neoadjuvant Therapy OV-C (2 of 12)

Principles of Maintenance PARP Inhibitor Therapy OV-C (3 of 12)

Principles of Recurrence Therapy OV-C (4 of 12)

Primary Systemic Therapy Regimens - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Stage I Disease OV-C (5 of 12)

Stage II–IV Disease OV-C (6 of 12)

Recommended Dosing OV-C (7 of 12)

Acceptable Recurrence Therapies - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Platinum-Sensitive Disease OV-C (8 of 12)

Platinum-Resistant Disease OV-C (9 of 12)

NCCN National Comprehensive Cancer Network®

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Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY

General

$\bullet$ Patients with ovarian, fallopian tube, or peritoneal cancer should be encouraged to participate in clinical trials during all aspects of their diagnosis and treatment.

* Prior to recommending chemotherapy, requirements for adequate organ function and performance status should be met.

* Prior to the initiation of any therapy:

$\bullet$ All patients with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy to determine whether they are candidates for primary cytoreductive surgery (PCS).

$\bullet$ Patients of childbearing potential who desire fertility-sparing procedures should be referred to an appropriate fertility specialist (see Fertility, Reproductive Endocrine, and Sexual Health Considerations for Individuals with Ovaries in the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology).

$\bullet$ Goals of systemic therapy should be discussed.

$\bullet$ Consider scalp cooling to reduce incidence of alopecia for patients receiving chemotherapy with high rates of alopecia.

* Patients should be observed closely and treated for any complications during chemotherapy. Appropriate blood chemistry tests should be monitored. Appropriate dose reductions and modifications of chemotherapy should be performed depending on toxicities experienced and goals of therapy.

$\bullet$ After completion of chemotherapy, patients should be assessed for response during and following treatment and monitored for any long-term complications.

$\bullet$ Chemosensitivity/resistance and/or other biomarker assays are being used at some NCCN Member Institutions for decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available. The current level of evidence is not sufficient to supplant standard-of-care chemotherapy (category 3).

$\bullet$ An FDA-approved biosimilar A biosimilar validated with the reference biologic product is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Definitions Used in the NCCN Guidelines for Ovarian Cancer

$\bullet$ Adjuvant therapy: Drugs, radiation, or other forms of supplemental treatment following cancer surgery intended to decrease the risk of disease recurrence or to primarily treat residual disease, whether gross or microscopic, following surgical cytoreduction.

$\bullet$ Neoadjuvant therapy: Drugs, radiation, or other forms of treatment given prior to cancer surgery intended to reduce tumor burden in preparation for surgery.

* Recurrence therapy: Drugs, radiation, or other forms of treatment used to treat recurrent cancer, control symptoms, or increase length and/or quality of life at the time of clinical, biochemical, or radiographic evidence of recurrent cancer following the initial treatment.

For Patients with Newly Diagnosed Ovarian, Fallopian Tube, or Primary Peritoneal Cancer:

* If they are eligible for chemotherapy, patients should be informed about the different primary therapy options that are available—such as IV chemotherapy, a combination of IP and IV chemotherapy, or a clinical trial—so they can decide which is the most appropriate option.

* Prior to the administration of the combined IP and IV regimen, patients must be apprised of the increased toxicities with the combined regimen when compared to using IV chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, GI toxicities, metabolic toxicities, and hepatic toxicities).

* Patients considered for the IP cisplatin and IP/IV pacitaxel regimen should have normal renal function prior to starting, a medically appropriate performance status based on the future toxicities of the IP/IV regimen, and no prior evidence of medical problems that could significantly worsen during chemotherapy (eg, pre-existing neuropathy).

$\bullet$ Prior to receiving and after receiving each cycle of IP cisplatin, adequate amounts of IV fluids need to be administered in order to prevent renal toxicity. After each cycle has been completed, patients need to be monitored carefully for myelosuppression, dehydration, electrolyte loss, end-organ toxicities (such as renal and hepatic damage), and all other toxicities. Patients often require IV fluids postchemotherapy in the outpatient setting to prevent or help treat dehydration.

$\bullet$ Refer to the original references (Discussion) for full toxicity data, doses, schedule, and dose modifications.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

Continued

OV-C 1 OF 12

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

OV-C 2 OF 12

PRINCIPLES OF SYSTEMIC THERAPY

Continued

Principles of Neoadjuvant Therapy

• Consider the histology of the primary tumor and the potential response to primary chemotherapy when evaluating for neoadjuvant

chemotherapy.

• Any of the primary IV regimens for stage II–IV high-grade serous carcinoma and respective LCOCs can be used as neoadjuvant therapy

before surgery. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A.

• Bevacizumab-containing regimens should be used with caution before surgery due to potential interference with postoperative healing. If bevacizumab is being used as part of a neoadjuvant regimen, bevacizumab should be withheld from therapy for 4–6 weeks prior to surgery.

• After neoadjuvant therapy and surgery, any of the adjuvant therapy options for high-grade serous carcinoma (IV or IP/IV) and respective

LCOCs can be considered. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A.

• There are limited data for the use of IP chemotherapy regimens after neoadjuvant therapy and surgery. The following is an additional IP

option after surgery: paclitaxel 135 mg/m2 IV on Day 1, carboplatin area under the curve (AUC) 6 IP on Day 1, and paclitaxel 60 mg/m2 IP on Day 8.a

• A minimum of 6 cycles of treatment is recommended, including at least 3 cycles of adjuvant therapy after surgery. Patients with stable

disease who are tolerating therapy may continue past 6 cycles.

a Provencher DM, Gallagher CJ, Parulekar WR, et al. OV21/PETROC: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer. Ann Oncol 2018;29:431-438.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY See Insights and Modifications (CHINA MS-2, MS-3)

Principles of Maintenance PARP Inhibitor (PARPi) Therapy

* Post Primary Treatment

$\bullet$ Certain patients with newly diagnosed stage II–IV disease (high-grade serous, grade 2/3 endometrioid, or BRCA1/2-mutated clear cell carcinoma or carcinosarcoma) may benefit from maintenance therapy with PARPi if CR or PR is achieved after primary treatment with surgery and platinum-based first-line therapy. See OV-5 for PARPi options and patient selection criteria.

* Data are limited for use of maintenance PARPi post primary treatment in patients with stage II disease and for those with LCOC.

* Post Recurrence Treatment

* Patients with BRCA(-mutated recurrent disease may benefit from maintenance therapy with PARPi after recurrence therapy, if in CR or PR after platinum-based recurrence therapy, and if no prior progression on a PARPi. See OV-8 for PARPi options and patient selection criteria.

* General Information on PARPi

$\bullet$ For patients receiving PARPi, careful monitoring of blood counts is required.

* Monitoring of renal and hepatic function is recommended.

* Appropriate dose holds and modifications should be made depending on the toxicity noted.

* Data are limited on the use of maintenance PARPi in LCOC.

$\bullet$ Refer to the package insert for more detailed information.

Current clinical HRD tests are proxy measures of HRD and lack accuracy in fully predicting functional HRD. HRD testing is recommended for those patients without germline BRCA1/2 mutations as HRD test status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy in these patients. The Panel considers the use of PARPi in patients who have HRP tumors, at present, to be of minimal benefit.

|Regimen|Setting|Dose/Administration|Duration| |---|---|---|---| |Olaparib + bevacizumab1|Maintenance post primary chemotherapy + bevacizumab|• Olaparib 300 mg PO twice daily • Bevacizumab 15 mg/kg IV every 21 days|• Olaparib: Until disease progression or unacceptable toxicity or up to 2 years • Bevacizumab: Until disease progression or unacceptable toxicity or up to 15 months| |Niraparib + bevacizumab2|Maintenance post primary chemotherapy + bevacizumab|• Niraparib: 300 mg PO once daily (or 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3) • Bevacizumab: 15 mg/kg IV every 21 days|• Niraparib: Until disease progression or unacceptable toxicity or up to 3 years • Bevacizumab: Until disease progression or unacceptable toxicity or up to 15 months| |Niraparib monotherapy3,4|Maintenance post primary chemotherapy|300 mg PO once daily (or 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3)|Until disease progression or unacceptable toxicity or up to 36 months| |Niraparib monotherapy3,4|Maintenance post recurrence chemotherapy|300 mg PO once daily (or an initial dose of 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3); after 2 to 3 months, in the absence of hematologic toxicity, may consider escalation to 300 mg once daily)|Until disease progression or unacceptable toxicity| |Olaparib monotherapy5-7|Maintenance post primary chemotherapy|300 mg PO twice dailyb|Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity| |Olaparib monotherapy5-7|Maintenance post recurrence chemotherapy|300 mg PO twice dailyb|Until disease progression or unacceptable toxicity| |Rucaparib monotherapy8,9|Maintenance post primary chemotherapy|600 mg PO twice dailyb|Until disease progression or unacceptable toxicity or up to 24 months| |Rucaparib monotherapy8,9|Maintenance post recurrence chemotherapy|600 mg PO twice dailyb|Until disease progression or unacceptable toxicity| |Fluzoparib monotherapy*|Maintenance post primary chemotherapy|150 mg PO twice daily|Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity| |Fluzoparib monotherapy*|Maintenance post recurrence chemotherapy|150 mg PO twice daily|Until disease progression or unacceptable toxicity| |Senaparib monotherapy|Maintenance post primary chemotherapy|100 mg PO once daily|Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity|

* See Chinese Editorial Committee Insights and Modifications (CHINA-MS-2).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

Continued

OV-C

3 OF 12

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer:

• Refer to the original references (Discussion) for full toxicity data, doses, schedule, and dose modiications.

• Patients should be informed about the following:

1) Availability of clinical trials, including the risks and beneits of various treatments, which will depend on the number of prior lines of

chemotherapy the patient has received, and

2) Performance status, end-organ status, and pre-existing toxicities from prior regimens. If appropriate, palliative care should also be

discussed as a possible treatment choice. See NCCN Guidelines for Palliative Care.

• Tumor molecular testing is recommended if not previously done for persistent/recurrent disease. See Principles of Pathology (OV-B).

• Because of prior platinum exposure, myelosuppression occurs more frequently with any myelotoxic agent given in the recurrent setting.

• With repeat use of either carboplatin and/or cisplatin, patients are at an increased risk of developing a hypersensitivity reaction (also

called an allergic reaction) that could be life-threatening. Thus, patients should be counseled about the risk that a hypersensitivity reaction may occur, educated about the signs and symptoms of hypersensitivity reactions, treated by medical sta冩 who know how to manage

hypersensitivity reactions, and treated in a medical setting where appropriate medical equipment is available in case of an allergic reaction. See Management of Drug Reactions (OV-D).

• Before any chemotherapy drug is given in the recurrent setting, the clinician should be familiar with the drug’s metabolism (ie, renal,

hepatic) and should make certain that the patient is an appropriate candidate for the drug (eg, that the patient has adequate renal or hepatic function).

• Clinicians should be familiar with toxicity management and appropriate dose reduction.

• The schedule, toxicity, and potential beneits of any treatment should be thoroughly discussed with the patient and caregivers. Patient

education should also include a discussion of precautions and measures to reduce the severity and duration of complications.

• Patients who do not respond and progress on two consecutive regimens without evidence of clinical beneits have diminished likelihood of beneitting from additional therapy (Gri冪ths RW, et al. Int J Gynecol Cancer 2011;21:58-65). Decisions to o冩er clinical trials, supportive care, or additional therapy should be made on an individual basis.

OV-C 4 OF 12 PRINCIPLES OF SYSTEMIC THERAPY

Continued Acceptable Recurrence Therapies for Platinum-Sensitive Disease (OV-C, 8 of 12)

Acceptable Recurrence Therapies for Platinum-Resistant Disease (OV-C, 9 of 12)

References on OV-C 10 of 12

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NCCN Guidelines Index Table of Contents Discussion

Primary Systemic Therapy Regimensc - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal

Primary Therapy for Stage I Disease

|Primary Therapy for Stage I Disease|||| |---|---|---|---| |High-grade serousEndometrioid (grade 2/3)Clear cell carcinomadCarcinosarcomad|Preferred RegimensPaclitaxel/carboplatin every 3 weeks9,h|Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin|Useful in Certain CircumstancesPaclitaxel/cisplatinFor carcinosarcoma:Carboplatin/ifosfamideCisplatin/ifosfamidePaclitaxel/ifosfamide (category 2B)9| |Mucinous carcinoma(stage IA, IB, and IC,grades 1-3)d|Preferred Regimens5-FU/leucovorin/oxaliplatinCapacitabine/oxaliplatinPaclitaxel/carboplatin every 3 weeks9,h|Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin|Useful in Certain Circumstances| |Low-grade serous(stage IC)/Grade I endometrioid (stage IC)d,e,f|Preferred RegimensPaclitaxel/carboplatin every 3 weeks9,h± maintenance letrozole (category 2Bf)or other hormonal therapy (category 2Bf)Hormone therapy (aromataseinhibitors: anastrozole,letrozole,exemestane) (category 2Bf)|Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin|Useful in Certain CircumstancesPaclitaxel/cisplatin|

Stage II-IV (OV-C, 6 of 12)

Primary Systemic Therapy Dosing (OV-C, 7 of 12)

c See Discussion for references.

d There are limited data on the primary systemic therapy regimens for these LCOC.

e Borderline disease with invasive implants may be treated as low-grade serous disease. See LCOC-6 and LCOC-8.

f For low-grade serous, maintenance letrozole is a category 2A recommendation. For grade I endometrioid, maintenance letrozole is a category 2B recommendation.

$^{9}$ Albumin-bound paclitaxel may be substituted for those experiencing a hypersensitivity reaction to paclitaxel. However, albumin-bound paclitaxel will not overcome infusion reactions in all patients.

$^{1}$ Individuals >70 years of age and those with comorbidities may be intolerant to the combination chemotherapy regimens recommended in these NCCN Guidelines. Based on clinical judgment and expected tolerance to therapies, alternate dosing (OV-C, 7 of 12) may be appropriate for these individuals with epithelial ovarian cancer (including carcinosarcoma, clear cell, mucinous, and low-grade serous). Algorithms have been developed for predicting chemotherapy toxicity.

i Other hormonal therapy options include: aromatase inhibitors (ie, anastrozole, exemestane), leuprolide acetate, goserelin acetate, or tamoxifen.

j Tamoxifen is not recommended for low-grade serous carcinoma.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY

Primary Systemic Therapy Regimensc - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal

Primary Therapy for Stage II-IV Disease (Principles of Maintenance PARPi Therapy on OV-C, 3 of 12)

|High-grade serous Endometroidi (grade 2/3) Clear cell $carcinoma^{d}$ $Carcinosarcoma^{d}$|Preferred Regimens • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218)|Other Recommended Regimens • Paclitaxel/carboplatin weekly$^{g,h,k}$ • Docetaxel/carboplatin • Carboplatin/liposomal doxorubicin • Paclitaxel/carboplatin every 3 $weeks^{g}$ • Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab (GOG-218)|Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab • IV/IP paclitaxel/carboplatin • IV/IP paclitaxel/cisplatin (for optimally debulked stage II-III disease) • For carcinosarcoma: • Carboplatin/ifosfamide • Pisclatin/ifosfamide • Paclitaxel/ifosfamide (category 2B)$^{g}$ •| |---|---|---|---| |Mucinous $carcinoma^{d}$|Preferred Regimens • 5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab) • Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab) • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218)|Other Recommended Regimens • Paclitaxel/kyarboplatin • Docetaxel/carboplatin • Carboplatin/liposomal doxorubicin • Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab (GOG-218)|Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab| |Low-grade serous/Grade I endometrioid$^{d,e,f}$|Preferred Regimens • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ ± maintenance letrozole (category $2B^{1}$) or other hormonal therapy (category $2B^{1}$) • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218) • Hormone therapy (aromatase inhibitors: anastrozole, letrozole, exemestane) (category 2B)|Other Recommended Regimens • Paclitaxel/kyarboplatin weekly$^{g,h,k}$ • Docetaxel/carboplatin ± maintenance letrozole (category $2B^{1}$) or other hormonal therapy (category $2B^{1}$) • Carboplatin/liposomal doxorubicin • Docetaxel/kyarboplatin.bevacizumab + maintenance bevacizumab|Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab (category $2B^{1}$)|

c See Discussion for references.

d There are limited data on the primary systemic therapy regimens for these LCOC.

e Borderline disease with invasive implants may be treated as low-grade serous disease.

c See [COC-6] and [LCOC-8].

f For low-grade serous, maintenance letrozole is a category 2A recommendation. For grade 1 endometrioid, maintenance letrozole is a category 2B recommendation.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

Primary Systemic Therapy Dosing (OV-C, 7 of 12)

h Individuals >70 years of age and those with comorbidities may be intolerant to the combination chemotherapy regimens recommended in these NCCN Guidelines. Based on clinical judgment and expected tolerance to therapies, alternate dosing (OV-C, 7 of 12) may be appropriate for these individuals with epithelial ovarian cancer (including carinosarcoma, clear cell, mucinous, and low-grade serous). Algorithms have been developed for predicting chemotherapy toxicity.

i Other hormonal therapy options include: aromatase inhibitors (ie, anastrozole, exemestane), leuprolide acetate, goserelin acetate, or tamoxifen.

j Tamoxifen is not recommended for low-grade serous carcinoma.

k Regimen may be considered for those with poor performance status.

Continued

OV-C

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PRINCIPLES OF SYSTEMIC THERAPY

Primary Systemic Therapy Regimens$^{c}$ - Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal

|Primary Systemic Therapy Recommended Dosing||| |---|---|---| |Paclitaxel/carboplatin every 3 weeks$^{9,1}$|Docetaxel/carboplatin$^{1}$|Docetaxel/carboplatin$^{1}$| |Paclitaxel 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1|Docetaxel 60–75 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1|Docetaxel 60–75 mg/m$^{2}$ AV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1| |Repeat every 21 days x 3–6 cycles$^{10,11}$|Recetaxel lip/liposomal doxorubicin$^{1}$|Recetaxel lip/liposomal doxorubicin$^{1}$| |Paclitaxel/cisplatin every 3 weeks$^{10,11}$|Carboplatin AUC 5 IV + pegylated liposomal doxorubicin 30 mg/m$^{2}$ IV|Carboplatin AUC 5 IV + pegylated liposomal doxorubicin 30 mg/m$^{2}$ IV| |Paclitaxel 175 mg/m$^{2}$ IV followed by cisplatin 75 mg/m$^{2}$ IV|Recetaxy 28 days for 3–6 cycles$^{1}$|Recetaxy 28 days for 3–6 cycles$^{1}$| |Repeat every 21 days x 3–9 cycles|Acitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{9}$ (ICON-7)|Acitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{9}$ (ICON-7)| |IV/IP Paclitaxel/cisplatin|Paclitaxel 135 mg/m$^{2}$ IV continuous infusion$^{1}$ Day 1; cisplatin 75–100 mg/m$^{2}$ IP Day 2 after IV paclitaxel; paclitaxel 60 mg/m$^{2}$ IP Day 8|Paclitaxel 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV, and bevacizumab 7.5 mg/kg IV Day 1| |Repeat every 21 days x 6 cycles|Recetaxy 21 days x 6 cycles|Recetaxy 21 days x 5–6 cycles| |IV/IP Paclitaxel/carboplatin$^{12}$|Paclitaxel 80 mg/m$^{2}$ IV on days 1, 8, and 15; carboplatin AUC 6 IP Day 1 after IV paclitaxel|Recetaxy 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 6 IV Day 1. Repeat every 21 days x 6 cycles| |Paclitaxel 80 mg/m$^{2}$ IV on days 1, 8, and 15; carboplatin AUC 6 IP Day 1 after IV paclitaxel|Recetaxy 21 days x 6 cycles|Recetaxy 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 6 IV Day 1. Repeat every 21 days x 6 cycles| |Repeat every 21 days x 6–8 cycles|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Paclitaxel weekly/carboplatin every 3 weeks$^{9}$|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Dose-dense paclitaxel 80 mg/m$^{2}$ IV Days 1, 8, and 15 followed by carboplatin$^{1}$ AUC 5–6 V IDV Day 1|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Repeat every 21 days x 6 cycles|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Paclitaxel 60 mg/m$^{2}$ IV followed by carboplatin AUC 2 IV|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Daclitaxel weekly/carboplatin $^{12}$|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Docetaxel 75 mg/m$^{2}$ IV followed by oxaliplatin 85 mg/m$^{2}$ IV, and bevacizumab 15 mg/kg IV|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Repeat every 21 days x 6 cycles|Recetaxy 19 days x 6 cycles|Recetaxy 19 days x 6 cycles| |Continue bevacizumab 15 mg/kg IV every 21 days to complete 1 year of therapy||| |Individuals >70 Years and/or Those with Comorbidities||| |Paclitaxel 135 /carboplatin$^{9,13}$||| |Paclitaxel 135 mg/m$^{2}$ IV + carboplatin AUC 5 IV given every 21 days x 3–6 cycles$^{1}$||| |Paclitaxel weekly/carboplatin weekly$^{9}$||| |Paclitaxel 60 mg/m$^{2}$ IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes||| |Days 1, 8, and 15; repeat every 21 days x 6 cycles (18 weeks)|||

c See Discussion for references.

$^{k}$ Regimen may be considered for those with poor performance status.

$^{1}$ For stage I disease: 6 cycles is recommended for high-grade serous; 3-6 cycles for all other ovarian cancer types. For stage II–IV disease: 6 cycles is recommended.

$^{m}$ Due to changes in creatinine methodology, changes regarding carboplatin dosing can be considered. See carboplatin dosing guidelines.

$^{n}$ The published randomized trial regimen used IV continuous infusion paclitaxel over 24 hours.

References on OV-C 10 of 12

OV-C

|Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.| |---|

NCCN National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAP See Insights and Modifications (CHINA MS-2, MS-5, MS-7 to MS-10)

Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)°/Fallopian Tube/Primary Peritoneal Cancer

Recurrence Therapy for Platinum-Sensitive Disease$^{4}$ (apathetical order)

|Preferred Regimens|Other Recommended Regimens$^{5}$|Useful in Certain Circumstances| |---|---|---| |Carboplatin/ gemcitabine$^{14}$|Capecitabine|For mucinous carcinoma:| |± bevacizumab|$Carboplatin^{14}$|1.5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab)$^{9}$| |Carboplatin/liposomal|Carboplatin/docetaxel^{23,24}$|• Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab)$^{9}$| |doxorubicin$^{16}$|Carboplatin/pacitaxel (weekly)$^{9,25}$|• Carboplatin/paclitaxel (for age >70)$^{9,9}$| |± bevacizumab$^{q,17}$|$Cisplatin^{18}$|• Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)| |Carboplatin/paclitaxel$^{g,18}$|Doxorubicin|• Iranotecan/cisplatin (for clear cell carcinoma)$^{31}$| |± bevacizumab$^{q,19}$||Targeted Therapy$^{X}$| |Cisplatin/gemcitabine$^{20}$||Dabrafenib + trametinib (for BRAF V600E-positive tumors)$^{32}$| |Targeted Therapy (single-agents)|Niraparib/bevacizumab (category 2B)$^{q,26}$|Entretinib$^{33}$ or larrotectinib$^{34}$ or reprotectinib$^{35}$ (for NTRK gene fusion-positive tumors)| |Bevacizumab$^{q,21,22}$|Niraparib (category 3)$^{1,27}$|Fam-trastuzumab deruxtecan-nxki (for HER2-positive tumors) [ICH 3+ 2+](category 2B)$^{36}$ Mirvetuximab soratvansine-gynx$^{1}$ (for FRα-expressing tumors [≥575 positive tumor cells])$^{37}$| ||Olaparib (category 3)$^{1,28}$|Mirvetuximab soratvansine-gynx$^{1}$ (for FRα-expressing tumors [≥50% positive tumor cells])$^{39}$| ||Pazopanib (category 2B)$^{29}$|Selpercatinib (for RET gene fusion-positive tumors)$^{39}$| ||Rucaparib (category 3)$^{7,30}$|For low-grade serous carcinoma:| ||Fluzoparib [c]*, u|• Avutometinib/defactinib (for KRAS-mutated tumors)$^{40}$| ||Pamiparib [c]*, u|• Trametinib$^{41}$| ||Hormone Therapy|• Binimetinib (category 2B)$^{42,43}$| ||Aromatase inhibitors (anastrozole, exemestane, letrozole)|Hormone Therapy| ||Goserelin acetate|Fulvestrant (for low-grade serous carcinoma)| ||Leuprolide acetate|• Immunotherapy$^{X}$| ||Megestrol acetate|Dostarlimab-gxly (for dMMR/MSI-H recurrent or advanced tumors)$^{44}$| ||Tamoxifen$^{1}$|Pembrolizumab (for MSI-H or dMMR solid tumors, or patients with TMB-H tumors ≥10 mutations/megabase)$^{45}$| |||• Vnsinabab (for dMMR/MSI-H recurrent or advanced tumors)$^{†}$| |||Tisleizumab (for dMMR/MSI-H recurrent or advanced tumors)$^{‡}$| |||Serpliulimab (for dMMR/MSI-H recurrent or advanced tumors)$^{§}$| |||Pucotenlimab (for dMMR/MSI-H recurrent or advanced tumors)$^{§}$|

[C] Major disagreement among Chinese editorial committee members

j Tamoxifen is not recommended for low-grade serous carcinoma.

$^{9}$ Chemotherapy has not been shown to be beneficial in ovarian border epithelial tumors (LMP).

$^{p}$ In general, the panel would recommend combination, platinum-based regimens for platinum-sensitive recurrent disease based on randomized trial data, especially in first relapses.

$^{9}$ Contraindicated for patients at increased risk of GI perforation.

$^{1}$ If response after chemotherapy, beacizumab can be continued as maintenance therapy until disease progression or unacceptable toxicity. Discontinue beacizumab before initiating maintenance therapy with a PARPi.

$^{5}$ Many of these single-agent cytotoxic therapy options have not been tested in patients who have been treated with modern chemotherapy regimens.

† For patients treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD defined by either: 1) a deleterious or suspected deleterious BRCA mutation; or 2) genomic instability and progression >6 months after response to the last platinum-based chemotherapy.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

$^{4}$ For patients with deleterious germline BRCA-mutated (as detected by an FDA-approved test or other validated test performed in a CLIA-approved facility) advanced ovarian cancer who have been treated with two or more lines of chemotherapy.

$^{5}$ For patients with deleterious germline and/or somatic BRCA mutated (as detected by an FDA-approved test or other validated test performed in a CLIA-approved facility) advanced ovarian cancer who have been treated with two or more lines of chemotherapy.

$^{5}$ For recommended dosing for individuals >70 years, see OV-C, 7 of 12.

× Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRa (FÖLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

$^{9}$ For patients treated with two prior lines of platinum-based therapy.

References on OV-C 10 of 12

Continued

OV-C

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PRINCIPLES OF SYSTEMIC THERAPY See Insights and Modifications (CHINA MS-2, MS-5, MS-6 to MS-10)

Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)°/Fallopian Tube/Primary Peritoneal Cancer

Recurrence Therapy for Platinum-Resistant Disease (alphabetical order)

|Preferred Regimens|Other Recommended Regimens|Useful in Certain Circumstances| |---|---|---| |Cytotoxic Therapy|Cytotoxic Therapys|Carboplatin/paclitaxel (for age >70)g,w,* Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)| |Cyclophosphamide (oral)/ bevacizumabq4,46|Capecitabine|Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)| |Docetaxel47|Carboplatin/docetaxel*|Immunotherapyx| |Etoposide (oral)48|Carboplatin/paclitaxel (weekly)q,9,*|Dostarlimab-gxly (for dMMR/MSI-H recurrent or advanced tumors)43| |Gemcitabine49,50|Carboplatin/gemcitabine14|Pembrolizumab (for patients with MSI-H or dMMR solid tumors, or TMB-H tumors ≥10 mutations/megabase)44| |Liposomal doxorubicin/ bevacizumabq5,41|± bevacizumabq,7,15,*|Envafolimab (for dMMR/MSI-H recurrent or advanced tumors)† Tisleizumab (for dMMR/MSI-H recurrent or advanced tumors)‡ Serplulimab (for dMMR/MSI-H recurrent or advanced tumors)§ Pucotlenimab (for dMMR/MSI-H recurrent or advanced tumors)¶| |Laiplasol doxorubicin/ bevacizumabq5,42|Carboplatin/paclitaxel, 58,59|Serplulimab (for dMMR/MSI-H recurrent or advanced tumors)§ Pucotlenimab (for dMMR/MSI-H recurrent or advanced tumors)¶| |Laiplasol doxorubicin/ bevacizumabq5,42|Ammotherapy|Hormone Therapy Fulvestrant (for low-grade serous carcinoma)| |Laiplasol doxorubicin/ bevacizumabq5,42|Ixabepilone/bevacizumab (category 2B)z,61|Targeted Therapyx Dabrafenib + trametinib (for BRAF V600E-positive tumors)32| |Laiplasol doxorubicin/ bevacizumabq5,42|Niraparib (category 3)z,27 Olaparib (category 3)z,28|Entrectinib33 or larrotectinib34 or raportectinib35 (for NTRK gene fusion-positive tumors)Fam-trastuzumab deruxtecan-nxki (for HER2-positive tumors [IHC 3+ or 2+])36 Mirvetuximab soravtansine-gynx/bevacizumab (for FRa-expressing tumors [≥25% positive tumor cells])q,38,62,83 Selpercatinib (for RET gene fusion-positive tumors)39 For low-grade serous carcinoma: Avutometinib/defactinib (for KRAS-mutated tumors)40 Trametinib41 Binimetinib (category 2B)42,43 For mucinous carcinoma: FOLFIRI ± bevacizumab (category 2B)64-67| |Laiplasol dotorubicin/ bevacizumabq5,42|||

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

Footnotes on OV-C 9A of 12 References on OV-C 10 of 12

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

OV-C 9A OF 12

PRINCIPLES OF SYSTEMIC THERAPY

Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)p/Fallopian Tube/Primary Peritoneal Cancerq

FOOTNOTES

[c] Major disagreement among Chinese editorial committee members.

g Albumin-bound paclitaxel may be substituted for those experiencing a hypersensitivity reaction to paclitaxel. However, albumin-bound paclitaxel will not overcome

infusion reactions in all patients.

j Tamoxifen is not recommended for low-grade serous carcinoma.

o Chemotherapy has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP).

q Contraindicated for patients at increased risk of GI perforation.

r If response after chemotherapy, bevacizumab can be continued as maintenance therapy until disease progression or unacceptable toxicity. Discontinue bevacizumab

before initiating maintenance therapy with a PARPi.

s Many of these single-agent cytotoxic therapy options have not been tested in patients who have been treated with modern chemotherapy regimens.

t For patients treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD defined by either: 1) a deleterious or suspected deleterious

BRCA mutation; or 2) genomic instability and progression >6 months after response to the last platinum-based chemotherapy.

u For patients with deleterious germline BRCA-mutated (as detected by an FDA-approved test or other validated test performed in a CLIA-approved facility) advanced

ovarian cancer who have been treated with two or more lines of chemotherapy.

v For patients with deleterious germline and/or somatic BRCA mutated (as detected by an FDA-approved test or other validated test performed in a CLIA-approved facility)

advanced ovarian cancer who have been treated with two or more lines of chemotherapy.

w For recommended dosing for individuals >70 years, see OV-C, 7 of 12.

x Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to

include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRg (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive

testing may be particularly important in LCOC with limited approved therapeutic options (OV-B).

z For those previously treated with taxanes.

References on OV-C 10 of 12

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PRINCIPLES OF SYSTEMIC THERAPY REFERENCES

$^{1}$ Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 2019;38:2416-2428. $^{2}$ Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Gynecol Oncol 2022;168:219-229. $^{3}$ González-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;38:231-2402. $^{4}$ Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154-2164. $^{5}$ Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495-2505. $^{6}$ Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274-1284. $^{7}$ Friedlander M, Matulonis U, Gourley C, et al. Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy. Br J Cancer 2018;119:1075-1085. $^{8}$ Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-1961. $^{9}$ Ledermann JA, Oza AM, Lorusso D, et al. Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:710-722. $^{10}$ McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6. $^{11}$ Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 2000;92:699-708.

12° Nagao S, Fujiwara K, Yamamoto K, et al. Intraperitoneal carboplatin for ovarian cancer – A phase 2/3 study. NEJM Evid 2023;2(5). 13° von Gruenigen VE, Huang HQ, Beumer JH, et al. Chemotherapy completion in elderly women with ovarian, primary peritoneal or fallopian tube cancer - An NRG oncology/Gynecologic Oncology Group study. Gynecol Oncol 2017;144:459-467.

elderly women with ovarian, primary peritoneal or fallopian tube cancer - An NRG oncology/Gynecologic Oncology Group study. Gynecol Oncol 2017;144:459-467.

14 Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006;24:4699-4707.

15 Aghajanian C, Blank SV, Goff BA, et al. OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30:2039-2045.

16 Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010;28:3323-3329.

17 Pfisterer J, Dean AP, Baumann K, et al. Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer. A prospective randomized phase III ENGOT/GCIG-Intergroup study (AGO Study Group, AGO-Austria, ANZGOG, GINECO, SGCTG). Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 9330.

18 Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361:2099-2106.

$^{9}$ Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779-791.

$^{0}$ Rose PG. Gemcitabine reverses platinum resistance in platinum-resistant ovarian compared with paclitaxel and peritoneal carcinoma. Int J Gynecol Cancer 2005;15:18-22.

$^{22}$ Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180-5186.

$^{2}$ Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180-5186.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SYSTEMIC THERAPY REFERENCES

23 Strauss HG, Henze A, Teichmann A, et al. Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Gynecol Oncol 2007;104:612-616.

$^{24}$ Kushner DM, Connor JP, Sanchez F, et al. Weekly docetaxel and carboplatin for recurrent ovarian and peritoneal cancer: a phase II trial. Gynecol Oncol 2007;105:358-364.

25. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374:1331-1338.

26 Mirza MR, Avall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol 2019;20:1409-1419.

27 Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019;20:636-648.

$^{28}$ Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244-250.

29 Friedlander M, Hancock KC, Rischin D, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 2010;119:32-37.

30 Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017;18:75-78.

31 Sugiyama T, Okamoto A, Enomoto T, et al. Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG Trial. J Clin Oncol 2016;34:2881-2887.

$^{32}$ Salama A, Li S, Macrae E, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: Results of the NCI-MATCH trial subprotocol H. J Clin Oncol 2020;38:3895-3904.

$^{33}$ Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2020;21:271–282.

$^{34}$ Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739.

$^{35}$ Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including non-small cell lung cancer: update from the phase 1/2 TRIDENT-1 trial. Ann Oncol. 2023;34:S787-S788.

36 Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol 2024;42:47-58.

37 Secord AA, Lewin SN, Murphy CG, Cecere SC, et al. The Efficacy and Safety of Mirvetuximab Soravtansine in FRalpha-Positive, Third-Line and Later, Recurrent Platinum-Sensitive Ovarian Cancer. The Single-Arm Phase 2 PICCOLO Trial. Ann Oncol. 2024:S0923-7534:04948-2.

38 Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol 2023;170:241:247.

39 Subbiah V, Wolf J, Konda B, et al. Tumour agnostic efficacy and safety of spercelpatinib in patients with RET fusion-positive solid tumors other than lung or thyroid: a global, phase 1/2, multicentre, open-label trial (LIBRETTO-001). Lancet Oncol 2022;23:1261-1273.

$^{40}$ Banerjee S, Nieuwenhuysen EV, Santin A, et al. Avutometinib plus defactinib in recurrent low-grade serous ovarian cancer: A subgroup analysis of ENGOT-OV60/GOG-3052/RAMP 201 Part A. Gyn Oncol 2024;190:S55-S56.

$^{41}$ Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer [abstract]. Ann Oncol 2019;30(Suppl):V897-V898.

42 Monk BJ, Grisham RN, Banerjee S, et al. MILO/ENGOT-ov11: Binimetinib versus physician's choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, Fallopian tube, or primary peritoneum. J Clin Oncol 2020;38:3753-3762.

43 Grisham RN, Vergote I, Banerjee SN, et al. Molecular results and potential biomarkers identified from MILO/ENGOT-ov11 phase 3 study of binimetinib versus physicians choice of chemotherapy (PCC) in recurrent low-grade serous ovarian cancer (LGSOC) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 5519.

$^{44}$ Berton D, Banerjee S, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair-deficient (dMMR) tumors: a combined analysis of 2 cohorts in the GARNET study [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 2564.

$^{45}$ Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.

46 Barber EL, Zsiros E, Lurain JR, et al. The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer. J Gynecol Oncol 2013;24:258-264.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SYSTEMIC THERAP REFERENCES

47 Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecologic Oncology Group

48 Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:405-410.

$^{49}$ Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007;25:2811-2818.

50 Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008;26:890-896.

51 Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-1308.

52 Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclaxel-resistant or primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol 2006;101:436-440.

53 Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topetecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 2004;95:1-8.

54 Seuholi J, Stengel D, Harter P, et al. Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: A randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2011;29:242-248.

55 Matulonis UA, Oaknin A, Pignata S, et al. Mirvetuximab soravtansine (MIRV) in patients with platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression: Characterization of antitumor activity in the SORAYA study. J Clin Oncol 2022;40:5512.

56 Moore KN, Angelergues A, Konecny GE, et al. Mirvetuximab Soravtansine in FRa-Positive, Platinum-Resistant Ovarian Cancer. N Engl J Med 2023;389:2162-2174.

57 Chekerov R, Hilpert F, Mahner S, et al. Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018;19:1247-1258.

58 Zsiros E, Lynam S, Attwood KM, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: A phase 2 nonrandomized clinical trial. JAMA Oncol 2021;7:78-85.

59 Poblete S, Caulkins M, Loecher C, et al. Pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer: Real-life clinical experience [abstract]. Ann Oncol 2022;33(Suppl): Abstract 569P.

60 Nagao S, Kogiku A, Suzuki K, et al. A phase II study of the combination chemotherapy of bevacizumab and gemcitabine in women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Ovarian Res 2020;13:14.

61 Roque DM, Siegel E, Buza N, et al. Randomised phase II trial of weekly ibabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian-fallopuan tube/primary peritoneal cancer. Br J Cancer 2022;126:1695-1703.

62' O'Malley D, Oaknin A, Matulonis U, et al. Mirvetuximab soravtansine and bevacizumab in folate receptor alpha-positive ovarian cancer: efficacy in patients with and without prior bevacizumab [abstract]. International Gynecologic Cancer Society Annual Meeting 2022; Abstract 496.

63' O'Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol 2020;157:379-385.

64 Kurnit CK, Sinno AK, Fellman BM, et al. Effects of gastrointestinal-type chemotherapy in women with ovarian mucinous carcinoma. Obstet Gyn 2019;134:1253-1259.

$^{65}$ André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated colorectal cancer. Eur J Canc 1999;35:1343-1347.

66 Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study. J Clin Oncol 2007;25:4779-4786.

$^{67}$ Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1065-1075.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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Note: All recommendations are category 2A unless otherwise indicated.

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OV-C 12A OF 12

REFERENCES

* Li N, Bu H, Liu J, et al. An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive

Recurrent Ovarian Cancer. Clin Cancer Res. 2021;27(9):2452-2458.

** Wu X, Zhu J, Wang J, et al. Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of

Chemotherapy: A Multicenter, Open-Label, Phase II Study. Clin Cancer Res. 2022;28(4):653-661.

† Li J,Deng Y,Zhang W,et al.Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors [J]. J Hematol Oncol. 2021,14(1):95.

‡ Li J, Xu Y, Zang A, et al. Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid

tumors. Chin J Cancer Res. 2024 Jun 30;36(3):257-269.

§ Li J,Qin SK,Zhong HJ,et al.Updated efficacy and safety results from the phase 2 study of serplulimab,a novel anti-PD-1 antibody,in patients with previously treated

unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors [J]. J Clin Oncol. 2022,40(16_suppl):2592.

¶ Zhang B, Song Y, Luo S, et al. Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study. Cell Rep Med. 2023 Dec 19;4(12):101301.

†† Guangwen Yuan, Qingshui Li, Ge Lou, et al. Final analysis of SCORES, a phase III randomized, double-blinded, placebo controlled study of suvemcitug combined

with chemotherapy for platinum resistant ovarian cancer. 2025 ASCO. Abstract 5554.

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Table of Contents Discussion

MANAGEMENT OF DRUG REACTIONS

Overview

$\bullet$ Virtually all drugs used in oncology have the potential to cause adverse drug reactions while being infused, which can be classified as either infusion or allergic reactions.$^{1}$

$\bullet$ Infusion reactions are often characterized by milder symptoms (eg, hot flushing, rash).

$\bullet$ Hypersensitivity (allergic) reactions are often characterized by more severe symptoms (eg, shortness of breath, generalized hives/itching, changes in blood pressure).

* Most adverse drug reactions that occur are mild reactions, but more severe reactions can occur.$^{2,3}$

$\bullet$ Anaphylaxis is a rare type of very severe allergic reaction that can occur with platinum and taxane agents (and others less commonly), can cause cardiovascular collapse, and can be life-threatening.$^{4-6}$

$\bullet$ Drug reactions can occur either during infusion or following completion of infusion (and can even occur days later).

$\bullet$ In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, and paclitaxel.$^{1}$

$\bullet$ Adverse reactions associated with biotherapeutic agents and taxane drugs (ie, docetaxel, paclitaxel) tend to be infusion-related and, in taxanes, are often attributed to the excipient (ie, Cremophor EL in paclitaxel, polysorbate 80 in docetaxel). These tend to occur during the first few cycles of treatment (although they can be seen during any infusion regardless of how many previous cycles were administered).

$\blacktriangleright$ Adverse reactions associated with platinum drugs (ie, carboplatin, cisplatin), a true allergy, tend to occur following re-exposure to the inciting drug or less commonly at the completion of initial chemotherapy (ie, cycle 6 of a planned 6 treatments).$^{3}$

* Preparation for a possible drug reaction

$\bullet$ Patients and their families should be counseled about the possibility of a drug reaction and the signs and symptoms of one. Patients should be told to report any signs and symptoms of a drug reaction, especially after they have left the clinic (ie, delayed rash).

* Clinicians and nursing staff should be prepared for the possibility of a drug reaction every time a patient is infused with a drug. Standing orders should be written for immediate intervention in case a severe drug reaction occurs and the treatment area should have appropriate medical equipment in case of a life-threatening reaction.$^{5}$

$\bullet$ Epinephrine (intramuscular [IM] 0.3 mL of 1 mg/mL solution/ Epen) should be used for any patient experiencing hypotension (systolic blood pressure of <90 mm Hg) with or without other symptoms of an allergic/hypersensitivity reaction during or shortly after any chemotherapy drug treatment. In the setting of acute cardiopulmonary arrest, standard resuscitation (advanced cardiovascular life support [ACLS]) procedures should be followed.

$\bullet$ Desensitization refers to a process of rendering the patient less likely to react in response to an allergen and can be considered an option for patients who have had drug reactions.$^{1,7-10}$

$\bullet$ If a patient has previously had a very severe life-threatening reaction, the implicated drug should not be used again unless under guidance of an allergist or specialist with desensitization experience.

Continued on OV-D, 2 of 7

References on OV-D, 3 of 7

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MANAGEMENT OF DRUG REACTIONS

Infusion Reactions

* Symptoms include: hot flushing, rash, fever, chest tightness, mild blood pressure changes, back pain, and chills.

$\bullet$ Symptoms usually can be treated by decreasing the infusion rate and resolve quickly after stopping the infusion. However, patients who have had mild reactions to carboplatin, cisplatin, or oxaliplatin may develop more serious reactions even when the platinum drug is slowly infused; therefore, consider consultation with an allergist.$^{11}$

* Infusion reactions are more common with paclitaxel (27% of patients); however, mild reactions can occur with liposomal doxorubicin.$^{11}$

* If an infusion reaction has previously occurred in response to a taxane:

$\bullet$ For mild infusion reactions (eg, flushing, rash, chills), patients may be rechallenged with the taxane if:

1) the patient, physician, and nursing staff are all comfortable with this plan;

2) the patient has been counseled appropriately; and

3) emergency equipment is available in the clinic area.

$\bullet$ Typically the taxane infusion can be restarted at a much slower rate, and the rate can be slowly increased as tolerated as per the treating clinician's judgment.$^{7,12}$ Note that this slow infusion is different from desensitization.

$\bullet$ Many institutions have nursing policies that stipulate how to reinforce the drug if the patient has had a prior infusion reaction.

Allergic Reactions (ie, True Drug Allergies)

$\bullet$ Symptoms include: rash, edema, shortness of breath (bronchospasm), syncope or pre-syncope, chest pain, tachycardia, hives/itching, changes in blood pressure, nausea, vomiting, chills, changes in bowel function, and occasionally feeling of impending doom.

$\bullet$ Symptoms may continue to persist after stopping infusion and/or after treatment interventions.

$\bullet$ Allergic reactions are more common with platinum drugs such as carboplatin (16% of patients), cisplatin, and oxaliplatin.$^{12}$ Mild reactions can occur with platinum agents.$^{12}$

$\bullet$ Patients who are at higher risk of developing a hypersensitivity (allergic reaction include those in the following settings:

$\bullet$ Re-introduction of the drug after a period of no exposure and following multiple cycles of the drug during the first and subsequent exposures

$\bullet$ IV administration of the drug rather than oral or IP administration

* Those with allergies to other drugs

$\bullet$ Those who have previously had a reaction

$\bullet$ If an allergic reaction has previously occurred:

$\bullet$ Consider consultation with an allergist (or qualified medical or gynecologic oncologist) and skin testing for patients who have experienced a platinum reaction (eg, carboplatin-hypersensitivity reaction).$^{12-14}$

$\bullet$ Patients who have had mild reactions may develop more serious reactions even when the platinum drug is slowly infused.$^{12}$

For more severe or life-threatening reactions—such as those involving blood pressure changes, dyspnea, tachycardia, widespread urticaria, anaphylaxis, or hypoxia—the implicated drug should not be used again unless under guidance of a specialist with desensitization experience.

$\bullet$ If it is appropriate to give the drug again, patients should be desensitized prior to resuming chemotherapy even if the symptoms have resolved. Patients must be desensitized with each infusion if they previously had a drug reaction.$^{1}$,$^{7}$⁻$^{10}$

References on OV-D, 3 of 7

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OV-D 2 OF 7

NCCN Guidelines for China Version 3.2025

Abstract

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

References

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NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF DRUG REACTIONS

![DRUG REACTION TO PLATINUM AGENTS\n\nREACTION\n\n| | | | | |\n|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|--\n](1/parseimages/figuredd24ae6ac3e34e73b8b0456fa907f529_0_6.png) Drug Reaction to Taxane, Liposomal Doxorubicin, or Biotherapeutic Agents (OV-D, 6 of 7)

ª Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin).

b Most severe reactions are allergic reactions and more commonly are caused by platinum agents.

c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).

d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed.

e Mild reactions can progress to severe reactions by re-exposure. An allergy consultation may provide skin testing and evaluate sensitization and the risk for further, more severe reactions.

f Referral to an academic center with expertise in desensitization is preferred.

$^{1}$ Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574-580.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF DRUG REACTIONS

![DRUG REACTION TO PLATINUM AGENTS\n\nREACTION\n\nMild $reaction^{a}$ (hot flushing, rash, pruritus) → OV-D, 4 of 7\n\nIV or IP drug reaction to platinum agents\n\nSevere $reaction^{b}$ (shortness of breath, changes in blood pressure requiring treatment, dyspnea, Gl symptoms [nausea, vomiting])\n\nStop infusion\nAdminister oxygen, nebulized bronchodilators, H1 blocker antihistamine, H2 blockers, corticosteroid$^{c}$; IM epinephrine$^{d}$ if needed\n\nConsider allergy consultation\nDo not rechallenge/readminister drug until evaluated by allergist or specialist with desensitization expertise\nPotential candidate for desensitization$^{f,1}$ with each infusion\nLife-threatening $reaction^{b}$ (ie, anaphylaxis) (acute onset, generalized hives, respiratory compromise, severe hypotension, Gl symptoms [nausea, vomiting�])\nStop infusion\nAdminister IM epinephrine,$^{d}$ oxygen, nebulized bronchodilators, H1 blocker antihistamine, H2 blockers, corticosteroid$^{c}$ as a group, vomiting)\n\nDisgaller allergy consultation\nDo not rechallenge/readminister drug until evaluated by allergist or specialist with desensitization expertise\nConsider allergy consultation\nDo not re challenge/readminister drug until evaluated by allergist or specialist with desensitization expertise\nLife-threatening $reaction^{b}$ (ie, anaphylaxis) (acute onset, oxygen, nebulized bronchodilators, H1 blocker antihistamine, H2 blockers, corticosteroid$^{c}$ as a group, vomiting)\n\nLife-threatening $reaction^{b}$ (ie, anaphylaxis) (acute onset, generalized hives, respiratory compromise, severe hypotension, Gl symptoms [nausea, vomiting])\n\nDisgaller allergy consultation\nDo not re challenge/readminister drug until evaluated by allergist or specialist with desensitization expertise\nTo! All recommendations are category 2A unless otherwise indicated.\n](1/parseimages/figure676e706daf65441196689397996d92f8_0_5.png)

Drug Reaction to Taxane, Liposomal Doxorubicin, or Biotherapeutic Agents (OV-D, 6 of 7)

a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin).

b Most severe reactions are allergic reactions and more commonly are caused by platinum agents.

c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).

d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed.

f Referral to an academic center with expertise in desensitization is preferred.

$^{9}$ For both taxanes and platinum analogues, it is preferred that anyone with a life-threatening reaction be evaluated and referred to an academic center if the drug is still considered first line.

$^{1}$ Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574-580.

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NCCN Guidelines Index Table of Contents Discussion

![MANAGEMENT OF DRUG REACTIONS\nDRUG REACTION TO TAXANE, LIPOSOMAL DOXORUBICIN, OR BIOTHERAPEUTIC AGENTS\n\nMIDRACTAEN (hot flushing, rash, pruritus, pain in chest/abdomen/pelvis/back)\n\nStoff infusion to Symptoms often resolve quickly after stopping infusion\nAdminister H1 blocker antihistamine to treat symptoms\n\nIV or IP drug reaction to taxane, liposomal doxorubicin, or biotherapeutic agents\n\nSevere $reaction^{b}$ (shortness of breath, changes in blood pressure requiring treatment, dyspnea, GI symptoms [nausea, vomiting], pain in chest/abdomen/pelvis/back, feeling of impending doom/anxiety/something wrong)\n\nStoff infusion to Symptoms often resolve quickly after stopping infusion\nAdminister H1 blocker antihistamine to treat symptoms\n\nIV or IP drug reaction to taxane, liposomal doxorubicin, or biotherapeutic agents\n\nStoff infusion to Symptoms often resolve quickly after stopping infusion\nAdminister H1 blocker antihistamine to treat symptoms\n\nStoff infusion to Symptoms been threshold, rechallenge with drug at slower infusion rate$^{h}$ Administer premedication with H1 blocker antihistamine, corticosteroids, H2 blockers$^{c}$\n\nStoff infusion to Symptoms [nausea, disentihocrithamine and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesin and chesi\n](1/parseimages/figure7fccee7be2154525a8d14f3243dd9853_0_5.png) a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin).

b Most severe reactions are allergic reactions and more commonly are caused by platinum agents.

c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).

h Consider switching to albumin-bound paclitaxel due to medical necessity (ie, hypersensitivity reaction), or consider switching to docetaxel; however, there are no data to support switching taxanes. Cross reactions have occurred and have been life-threatening. Some reactions to paclitaxel may occur because of the diluent.

$^{1}$ Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574-580.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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MANAGEMENT OF DRUG REACTIONS

![DRUG REACTION TO TAXANE, LIPOSOMAL DOXORUBICIN, OR BIOTHERAPEUTIC AGENTS\n\nMild reaction$^{a}$ (hot flushing, rash, pruritus, pain in chest/abdomen/pelvis/back)\n\nIV or IP drug reaction to taxane, liposomal doxorubicin, or biotherapeutic agents\n\nSevere $reaction^{b}$ (shortness of breath, changes in blood pressure requiring treatment, dyspnea, Gl symptoms [nausea, vomiting], pain in chest/abdomen/pelvis/back), feeling of impending doom/anxiety/ something wrong)\n\nStip infusion\n- Do not rechallenge/readminister drug until evaluated by allergist or specialist with desensitization expertise\n- Potential candidate for desensitization$^{f,1}$ with each infusion\n###########################################################################################################################################\n](1/parseimages/figure6b0a010ed2f94608a15261cdca0c8d91_0_6.png)

Drug Reaction to Platinum Agents (OV-D, 4 of 7)

d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed.

f Referral to academic center with expertise in desensitization is preferred.

$^{1}$ Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574-580.

ª Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin).

b Most severe reactions are allergic reactions and more commonly are caused by platinum agents.

c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

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WHO HISTOLOGIC CLASSIFICATION$^{1,2}$

|Serous Tumors|| |---|---| |• Serous cystadenoma NOS|0| |• Serous surface papilloma|0| |• Serous adenofibroma NOS|0| |• Serous cystadenofibroma NOS|0| |• Serous borderline tumor NOS|1| |• Serous borderline tumor, micropapillary variant|2| |• Serous carcinoma, non-invasive, low-grade|2| |• Low-grade serous carcinoma|3| |• High-grade serous carcinoma|3| |Mucinous Tumors|| |• Mucinous cystadenoma NOS|0| |• Mucinous adenofibroma NOS|0| |• Mucinous borderline tumor|1| |• Mucinous adenocarcinoma|3| |Endometrioid Tumors|| |• Endometrioid cystadenoma NOS|0| |• Endometrioid adenofibroma NOS|0| |• Endometrioid tumor, borderline|1| |• Endometrioid adenocarcinoma NOS|3| |• Seromucinous carcinoma|3| |Clear Cell Tumors|| |• Clear cell cystadenoma|0| |• Clear cell cystadenofibroma|0| |• Clear cell borderline tumor|1| |• Clear cell adenocarcinoma NOS|3|

|Brenner Tumors|| |---|---| |Brenner tumor, NOS|0| |Brenner tumor, borderline malignancy|1| |Brenner tumor, malignant|3| |Seromucinous Tumors|| |Seromucinous cystadenoma|0| |Seromucinous adenofibroma|0| |Seromucinous borderline tumor|1| |Other carcinomas|| |Mesonephric-like adenocarcinoma|3| |Carcinoma, undifferentiated, NOS|3| |Dedifferentiated carcinoma|3| |Carcinosarcoma NOS|3| |Mixed cell adenocarcinoma|3| |Mesenchymal Tumors|| |Endometrioid stromal sarcoma, low-grade|3| |Endometrioid stromal sarcoma, high-grade|3| |Leiomyoma NOS|0| |Leiomyosarcoma NOS|3| |Smooth muscle tumor of uncertain malignant potential|1| |Myxoma NOS|0| |Mixed Epithelial & Mesenchymal TumorsAdenosarcoma|3|

$^{1}$ Reproduced with permission from Adhikari L, Hassell LA. World Health Organization Classification of Female Genital Tumours, 5th edition. IARC, 2020.

$^{2}$ Behavior is coded 0 for benign tumors; 1 for unspecified, borderline, or uncertain behavior; 2 for carcinoma in situ and grade III intraepithelial neoplasia; 3 for malignant tumors, primary site.

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WHO HISTOLOGIC CLASSIFICATION$^{1,2}$

|Sex Cord-Stromal Tumors: Pure Stromal Tumors|0| |---|---| |• Fibroma NOS|0| |• Cellular fibroma|1| |• Thecoma NOS|0| |• Thecoma, luteinized|0| |• Sclerosing stromal tumor|0| |• Microcystic stromal tumor|0| |• Signet-ring stromal tumor|0| |• Leydig cell tumor of the ovary NOS|0| |• Steroid cell tumor NOS|0| |• Steroid cell tumor, malignant|3| |• Fibrosarcoma NOS|3| |Sex Cord-Stromal Tumors: Pure Sex Cord Tumors|0| |• Adult granulosa cell tumor of the ovary|3| |• Granulosa cell tumor, juvenile|1| |• Sertoli cell tumor NOS|1| |• Sex cord tumor with annular tubules|1| |Mixed Sex Cord-Stromal Tumors|1| |• Sertoli-Leydig cell tumor NOS|1| |• Sertoli-Leydig cell tumor, well differentiated|0| |• Sertoli-Leydig cell tumor, moderately differentiated|1| |• Sertoli-Leydig cell tumor, moderately differentiated|1| |• Sertoli-Leydig cell tumor, retiform|1| |• Sex cord tumor NOS|1| |• Gynandroblastoma|1|

|Germ Cell Tumors|0| |---|---| |• Teratoma, benign|0| |• Immature teratoma NOS|3| |• Dysgerminoma|3| |• Yolk sac tumor NOS|3| |• Embryonal carcinoma NOS|3| |• Choriocarcinoma NOS|3| |• Mixed germ cell tumor|3| |Monodermal Teratoma & Somatic-type|| |Tumors from Dermoid Cyst|| |• Struma ovarii, NOS|0| |• Struma ovarii, malignant|3| |• Struma carcinoid|1| |• Teratoma with malignant|3| |• transformation|| |• Cystic teratoma NOS|0| |Germ Cell- Sex Cord-Stromal Tumors|| |• Gonadoblastoma|1| |• Dissecting gonadoblastoma|| |• Undifferentiated gonadal tissue|| |• Mixed germ cell- sex cord-stromal tumor, NOS|1| |Metastases to the ovary||

|Miscellaneous Tumors|| |---|---| |• Adenoma of rete ovarii|0| |• Adenocarcinoma of rete ovarii|3| |• Wolffian tumor|1| |• Solid pseudopapillary tumor of ovary|1| |• Small cell carcinoma, hypercalcaemic type|3| |• Small cell carcinoma, large cell variant|| |• Wilms tumor|3| |Tumor-like Lesions|| |• Follicle cyst|0| |• Corpus luteum cyst|0| |• Large solitary luteinized follicle cyst|0| |• Hyperreactio luteinalis|0| |• Pregnancy luteoma|0| |• Stromal hyperplasia and hyperthecosis|0| |• Fibromatosis and massive oedema|0| |• Leydig cell hyperplasia|0| |Metastases to the ovary||

$^{1}$ Reproduced with permission from Adhikari L, Hassell LA. World Health Organization Classification of Female Genital Tumours, 5th edition. IARC, 2020.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Authors

Abstract

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

• The phase 3 PRIMA study demonstrated that niraparib signiicantly prolonged PFS vs placebo in the irst-line maintenance setting regardless of HRD status. CI, ), in the overall population. 5 • Furthermore, niraparib maintenance therapy for newly diagnosed advanced ovarian cancer patients and the PSR all-comer population are covered by medical insurance and highly accessible. -3012 trial. Ann Oncol. 2 24;35(11):981-992. 3. Li N, Zhu J, Yin R, et al. Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023;9(9):1230-1237.

References

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-2

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

Inclusion of Fuzuloparib (OV-5, OV-8, Footnote ll; OV-C 3 of 12; OV-C 8 of 12; and OV-C 9 of 12):

• Fuzuloparib is a PARP inhibitor developed independently in China. It was approved in China in 2020 and 2021 for the treatment of PSR ovarian cancer with germline BRCA mutation and for the maintenance treatment of PSR ovarian cancer respectively. Its e吊cacy and safety have been conirmed

through large-scale Phase 3 clinical trials, and it is covered by medical insurance.1,2 Additionally, fuzuloparib has shown some beneits in the treatment of patients with platinum-resistant recurrent ovarian cancer (PROC) in later lines of therapy.2

• The FZOCUS-1 phase III trial assessed the e吊cacy and safety of fuzuloparib as monotherapy in the irst-line maintenance setting for advanced ovarian cancer. A total of 674 patients were randomly assigned and treated, this randomized clinical trial found that BIRC-assessed PFS was signiicantly

prolonged with fuzuloparib versus placebo in the overall population (median, not reached [NR] vs 11.1 months; HR: 0.49; 95% CI: 0.37-0.67; 1-sided

P<0.0001). Median PFS by BIRC was NR with fuzuloparib versus 14.9 months with placebo in patients with gBRCA1/2 mutation (HR: 0.40; 95% CI:

0.22-0.73; 1-sided P<0.0001), and 25.5 months versus 8.4 months in patients without gBRCA1/2 mutation (HR: 0.53; 95% CI: 0.37-0.75; 1-sided

P=0.0001).The data support fuzuloparib as a new treatment option in this setting.3

• Therefore, fuzuloparib is included in the treatment recommendations for the following populations: maintenance treatment for patients with advanced

ovarian cancer who are in a complete or partial response to irst-line platinum-based chemotherapy, maintenance treatment for PSR ovarian cancer,

and treatment of PSROC or PROC with germline BRCA mutations.

1. Li N, Zhang Y, Wang J, et al. Fuzuloparib Maintenance Therapy in Patients With Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial. J Clin Oncol. 2022;40(22):2436-2446.

2. Li N, Bu H, Liu J, et al. An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer. Clin Cancer Res. 2021;27(9):2452-2458.

3. Wu LY,Li N,Wang J, et al. Fuzuloparib as maintenance therapy among patients with advanced ovarian cancer after a response to first-line platinum-based

chemotherapy: Results from a randomized, placebo-controlled, phase III trial [J]. Gynecol Oncol. 2024;190:S74-S75.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Inclusion of Senaparib (OV-5, OV-C 3 of 12):

• Senaparib is a novel PARP inhibitor and developed independently in China. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1)

404 females with advanced ovarian cancer and response to irst-line platinum-based chemotherapy to senaparib or placebo. The primary endpoint was PFS assessed by blinded independent central review. At the prespeciied interim analysis, the median PFS was not reached with senaparib and was

13.6 months with placebo (hazard ratio 0.43, 95% CI 0.32-0.58; P<0.0001). The beneit with senaparib over placebo was consistent in the subgroups deined by BRCA1/2 mutation or homologous recombination status and senaparib was well tolerated. Based on these results, the NMPA granted full

approval for senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to irst-line chemotherapy.

Wu XH,Liu JH,Wang J, et al. Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial. Nat Med 2024;30:1612-1621.

CHINA-MS-3

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-4

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

Qing-lei Gao, Jianqing Zhu, Weidong Zhao, et al. Overall survival (OS) in patients with PSR ovarian cancer treated with olaparib maintenance monotherapy: Update from the L-MOCA trial [J]. J Clin Oncol. 2024;42(16-Suppl):5559.

Inclusion of Olaparib (OV-8, Footnote ll):

• The L-MOCA study is the irst phase 3 trial to evaluate olaparib e吊cacy and tolerability exclusively in Asian patients with PSR ovarian cancer.

225 patients were enrolled and received olaparib, overall median PFS was 16.1 months; median PFS was 21.2 and 11.0 months in BRCA-mutated

and wild-type BRCA subgroups, respectively.

• Therefore, olaparib maintenance therapy was highly e爪ective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. The indication for olaparib maintenance therapy in all-comer PSR ovarian cancer patients has not been withdrawn in China.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-5

Inclusion of Pamiparib (OV-C 8 of 12 and OV-C 9 of 12):

• Pamiparib is a PARP inhibitor developed independently in China. It was approved in April 2021 for the treatment of patients with recurrent advanced

ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have received at least second-line or subsequent chemotherapy and have

germline BRCA (gBRCA) mutations. In its pivotal Phase 2 studies, pamiparib demonstrated certain activity in patients with advanced epithelial ovarian cancer (including fallopian tube cancer or primary peritoneal cancer) who had received at least two lines of chemotherapy and had gBRCA mutations (a total of 101 patients, including 82 with PSR ovarian cancer and 19 with PROC.

• Among the PSR ovarian cancer patients, the objective response rate (ORR) was 68.3% (95% CI, 57.1–78.1), the median PFS was 15.2 months (95% CI, 10.35–20.63), and the median duration of response (DoR) was 13.8 months (95% CI, 10.97–20.73). Among the PROC patients, the ORR was

31.6% (95% CI, 12.6–56.6), the median PFS was 6.2 months (95% CI, 4.21–16.59), and the mDoR was 11.1 months (95% CI, 4.21–16.59). Currently,

pamiparib is covered by medical insurance.

• Therefore, pamiparib is included in the treatment recommendations for the following population: patients with advanced ovarian cancer (regardless of platinum sensitivity or resistance) who have received at least second-line or subsequent chemotherapy and carry germline BRCA1/2 gene mutations.

Wu X, Zhu J, Wang J, et al. Pamiparib Monotherapy for Patients with Germline BRCA1/2-Mutated Ovarian Cancer Previously Treated with at Least Two Lines of Chemotherapy: A Multicenter, Open-Label, Phase II Study. Clin Cancer Res. 2022;28(4):653-661.

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-6

Inclusion of Suvemcitug/paclitaxel (weekly) or Suvemcitug/topotecan or Suvemcitug/liposomal doxorubicin (OV-C 9 of 12):

• Suvemcitug, a novel recombinant humanized anti-VEGF antibody developed in China.

• A randomized, double-blind, placebo-controlled, phase 3 trial (SCORES) conducted at 55 centers in China enrolled patients with PROC. At the data cuto爪 for the inal analysis (October 11, 2024), 421 patients were enrolled. A total of 279 OS events (66.3%) occurred, the median OS was 15.31

months versus 14.03 months (stratiied hazard ratio, 0.768; 95% CI, 0.595-0.991; P = 0.0304). Suvemcitug plus chemotherapy led to a signiicant

improvement of OS versus placebo plus chemotherapy, with a 23% reduction in the risk of death and a more than 10% improvement of the 24-month OS rate (33.0% vs 22.3%). The addition of suvemcitug to chemotherapy signiicantly improved the outcomes of patients with PROC with manageable toxicities. This is the irst phase III study demonstrated a signiicant OS beneit of anti-angiogenic agent in patients with PROC.

• Therefore, Suvemcitug in combination with paclitaxel, liposomal doxorubicin, or topotecan has been approved by the NMPA in 2025 for the treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer in adults with platinum-resistant disease who have received no more than one line of

systemic therapy.

Guangwen Yuan, Qingshui Li, Ge Lou, et al. Final analysis of SCORES, a phase III randomized, double-blinded, placebo controlled study of suvemcitug combined with chemotherapy for platinum resistant ovarian cancer. 2025 ASCO Abstract 5554.

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

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NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-7

Inclusion of Envafolimab (OV-C 8 of 12 and OV-C 9 of 12):

• Envafolimab is an innovative PD-L1 antibody drug developed independently in China and the world's irst subcutaneously administered PD-L1 antibody drug. The drug has demonstrated good e吊cacy and acceptable safety in patients with advanced solid tumors who have failed irst-line standard

treatment and have dMMR/MSI-H (mismatch repair deiciency/microsatellite instability-high).

• The NMPA has approved its use in the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch

repair-deicient (dMMR) advanced solid tumors. Therefore, envafolimab is included in the treatment recommendations for the following population:

patients with MSI-H or dMMR, platinum-sensitive or platinum-resistant recurrent or metastatic ovarian cancer.

Li J, Deng Y, Zhang W, et al. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol. 2021;14(1):95.

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-8

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

Jian Li, Ye Xu, Aimin Zang et al. A Phase 2 study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable or metastatic

microsatellite instability-high/mismatch repair deficient solid tumors. J Clin Oncol 2021;39(15_suppl):Abstract 2569.

Dong Wang, Naiyi Zhang, Aimin Zang, et al. Phase 2 study of tislelizumab monotherapy in previously treated, locally advanced, unresectable or metastatic microsatellite instability-high/mismatch repair-deficient solid tumors: Gynecological cancer subgroup. Gynecologic Oncology 2022;166(Suppl 1):S80-S81.

Inclusion of Tislelizumab (OV-C 8 of 12 and OV-C 9 of 12):

• Tislelizumab is a humanized monoclonal antibody (IgG4 variant) targeting programmed cell death protein 1 (PD-1). It has been approved for 13 indications in China, including its approval on March 11, 2022, for the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deicient (dMMR) advanced solid tumors.

• Therefore, tislelizumab is included in the treatment recommendations for the following population: patients with MSI-H or dMMR, platinum-sensitive or platinum-resistant recurrent or metastatic ovarian cancer.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-9

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

Li J,Qin SK,Zhong HJ,et al.Updated efficacy and safety results from the phase 2 study of serplulimab,a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors [J] .J Clin Oncol. 2022;40(16_suppl):2592.

Inclusion of Serplulimab (OV-C 8 of 12 and OV-C 9 of 12):

• Serplulimab is a novel humanized monoclonal antibody against programmed cell death protein 1 (PD-1). On March 24, 2022, the National Medical

Products Administration (NMPA) approved its use in the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deicient (dMMR) advanced solid tumors.

• The phase 2 serplulimab clinical study (NCT03941574) in patients with unresectable/metastatic MSI-H/dMMR solid tumors who have progressed on or

been intolerant to standard therapies with a median follow-up of 7.7 months was presented at ASCO 2021. An updated e吊cacy and safety results from

sensitivity analysis after another 6-month follow-up enrolled 108 patients, including 68 patients with conirmed MSI-H (by local sites or central lab) in

the main e吊cacy analysis population (MEAP), 58 patients with conirmed MSI-H (by central lab) and had no major protocol deviations in the sensitivity

analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. The independent radiological

review committee (IRRC)-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI

30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median duration of response (DoR), progression-free survival (PFS), overall survival (OS) were not reached; 12-month OS rate was

74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the safety set (SS), 57 (52.8%) patients had grade ≥3 treatmentemergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported.

• This study demonstrated antitumor activity and the manageable safety proile sustained after a longer duration of follow-up, supporting serplulimab as a

potential tissue-agnostic antitumor treatment. Therefore, serplulimab is included as a recommendation for patients with MSI-H or dMMR, platinum-sensitive or platinum-resistant recurrent or metastatic ovarian cancer.

NCCN Guidelines Index Table of Contents Discussion

Note: This is the NCCN Guidelines for China. For deinitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines for China Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

CHINA-MS-10

CHINESE EDITORIAL COMMITTEE INSIGHTS AND MODIFICATIONS

The contents of this page are provided by the Chinese Editorial Committee — Ovarian Cancer Expert Panel Members.

Zhang B, Song Y, Luo S, et al. Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study. Cell Rep Med. 2023;4(12):101301.

Inclusion of Pucotenlimab (OV-C 8 of 12 and OV-C 9 of 12):

• Pucotenlimab is a humanized anti-PD-1 monoclonal antibody (IgG4 variant) with an engineered Fc domain. It has been approved for the treatment of patients with unresectable or advanced microsatellite instability-high (MSI-H) /mismatch repair-deicient (dMMR) solid tumors, who have experienced

disease progression after at least one prior line of therapy and have no satisfactory alternative treatment options in China.

• This multicenter, single-arm, phase II study (NCT03704246) evaluated pucotenlimab in patients with previously treated, advanced mismatch repairdeicient (dMMR) or microsatellite instability-high (MSI-H) solid tumors. The cohort included 100 patients, with a median follow-up of 22.5 months.

The enrolled patients included 71 patients with colorectal cancer, 10 patients with gastric cancer, 7 patients with endometrial cancer, 4 patients with

neuroendocrine tumor, 3 patients with ovarian cancer, 2 patients with cervical cancer(CC), 2 patients with esophageal cancer, and 1 patients with anal

cancer.

• Based on the assessment by an independent review committee (IRC), the objective response rate (ORR) was 49.0% (95% CI, 38.86%–59.20%) for

the entire cohort. The median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 56.1%, and the 24-month OS rate was 68.9%.

• Treatment-related adverse events (TRAEs) occurred in 83% of patients, with Grade ≥3 TRAEs observed in 18% of patients. One fatal case of Grade 5

myocarditis was reported. Immune-related adverse events (irAEs) occurred in 29% of patients, with the most common being hypothyroidism (12.0%).

• Biomarker analysis suggested that KMT2D mutations were associated with a signiicantly higher ORR (69.8% vs. 15.0% in wild-type; adjusted p=0.009), independent of tumor mutational burden (TMB). A neutrophil-to-lymphocyte ratio (NLR) <4 at the second treatment cycle was also associated with

improved ORR and survival outcomes. PD-L1 expression was not predictive of response.

• Although the number of patients with ovarian cancer in this study was small (n=3), the demonstrated e吊cacy and manageable safety proile of

pucotenlimab in advanced dMMR/MSI-H solid tumors support its consideration as a treatment option. Therefore, pucotenlimab is included as a treatment recommendation for is included in the treatment recommendations for the following population: patients with MSI-H or dMMR, platinum-sensitive or

platinum-resistant recurrent or metastatic ovarian cancer.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

Staging

Table 1

American Joint Committee on Cancer (AJCC)

TNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017)

Primary Tumor (T)

|TNM|FIGO|TNM|FIGO|| |---|---|---|---|---| |TX|Primary tumor cannot be assessed|T2|II|| |T0|No evidence of primary tumor|||| |T1|I|Tumor limited to ovaries (one or both) or fallopian tube(s)|T2a|IIA Extension and/or implants on the uterus and/or fallopian tube(s) and/or ovaries| |T1a|IA|Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings|T2b|IIB Extension to and/or implants on other pelvic tissues| |T1b|IB|Tumor limited to both ovaries; (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings|T3|Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes| |T1c|IC|Tumor limited to one or both ovaries or fallopian tubes, with any of the following:|T3a|| |T1c1|IC1|Surgical spill|T3b IIIB|| |T1c2|IC2|Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface|T3c IIIC Macroscopic peritoneal metastasis beyond pelvis|| |T1c3|IC3|Malignant cells in ascites or peritoneal washings|T3c IIIC Macroscopic peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)||

Used with the permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1.

Note: All recommendations are category 2A unless otherwise indicated.

Continued

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

Staging

Table 1 (Continued)

American Joint Committee on Cancer (AJCC)

TNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017)

Regional Lymph Nodes (N)

|TNM|FIGO| |---|---| |NX|Regional lymph nodes cannot be assessed| |N0|No regional lymph node metastasis| |N0(i+)|Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm| |N1|IIIA1 Positive retroperitoneal lymph nodes only (histologically confirmed)| |N1a|IIIA1 Metastasis up to and including 10 mm in greatest dimension| |N1b|IIIA1ii Metastasis more than 10 mm in greatest dimension|

Distant Metastasis (M)

TNM FIGO

M0 No distant metastasis

M1 IV Distant metastasis, including pleural effusion with positive cytology: liver or splenic parenchymal metastasis; metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestine

M1a IVA Pleural effusion with positive cytology

M1b IVB Liver or splenic parenchymal metastases; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

Continued

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

NCCN Guidelines Index Table of Contents Discussion

Staging

Table 2. AJCC Prognostic Groups

TNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017)

||T|N|M| |---|---|---|---| |Stage I|T1|N0|M0| |Stage IA|T1a|N0|M0| |Stage IB|T1b|N0|M0| |Stage IC|T1c|N0|M0| |Stage II|T2|N0|M0| |Stage IIA|T2a|N0|M0| |Stage IIB|T2b|N0|M0| |Stage IIIA1|T1/T2|N1|M0| |Stage IIIA2|T3a|NX/N0/N1|M0| |Stage IIIB|T3b|NX/N0/N1|M0| |Stage IIIC|T3c|NX/N0/N1|M0| |Stage IV|Any T|Any N|M1| |Stage IVA|Any T|Any N|M1a| |Stage IVB|Any T|Any N|M1b|

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

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Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

NCCN Guidelines Index

Table of Contents Discussion

ABBREVIATIONS

|ACLS|advanced cardiovascular life support|HCT|hematopoietic cell transplant|PARPi|PARP inhibitor| |---|---|---|---|---|---| |AUC|area under the curve|HIPEC|hyperthermic intraperitoneal chemotherapy|PCS|primary cytoreductive surgery| |BSO|bilateral salpingo-oophorectomy|HR|homologous recombination|PR|partial response| |β-hCG|beta-human chorionic gonadotropin|HRD|homologous recombination deficiency|REI|reproductive endocrinology and infertility| |CAP|College of American Pathologists|IDS|interval debulking surgery|RRSO|risk-reducing salpingo-oophorectomy| |CBC|complete blood count|IHC|immunohistochemistry||| |CEA|carcinoembryonic antigen|IM|intramuscular|SEE-FIM|sectioning and extensively examining the fimbriated end| |CLIA|Clinical Laboratory Improvement Amendments|IP|intraperitoneal|STIC|serous tubal intraepithelial carcinoma| |CR|complete response|LCOC|less common ovarian cancers||| |ctDNA|circulating tumor DNA|LDH|lactate dehydrogenase||| |C/A/P|chest/abdomen/pelvis|LFT|liver function test|TMB|tumor mutational burden| |dMMR|mismatch repair deficient|LMP|low malignant potential|TMB-H|tumor mutational burden-high tumor node metastasis| |FIGO|International Federation of Gynecology and Obstetrics|LOH|loss of heterozygosity||USO| |FNA|fine-needle aspiration|MMMT|malignant mixed Müllerian tumor|USO|unilateral salpingo-oophorectomy| |GI|gastrointestinal|MSI|mismatch repair||| |||MSI-H|microsatellite instability||| ||||microsatellite instability-high|||

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

NCCN Guidelines Index

Table of Contents

Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated.

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Ovarian Cancer

Discussion

This discussion corresponds to the NCCN Guidelines for Ovarian Cancer. The following pages were updated on July 25, 2022: MS-2, MS-17, MS-35, MS-36, MS-92, MS-93, MS-94. Other sections up to MS-82 were last updated on January 12, 2021. The remaining text (Follow-up Recommendations and subsequent sections) last updated November 11, 2017. Topotecan dosing on MS-28 was changed August 17, 2021.

Overview... MS-2

Interval Debulking Surgery After Neoadjuvant Chemotherapy of

Literature Search Criteria and Guidelines Update Methodology ... MS-3

Invasive Epithelial Ovarian Cancer .................................................... MS-58

Risk Factors for Ovarian Cancer .................................................... MS-3

Monitoring Response to Adjuvant Systemic Therapy .................................... MS-62

Reproductive Risk Factors .................................................... MS-3

Options After First-Line Chemotherapy

Obesity, Smoking, and Lifestyle and Environmental Risk Factors MS-3

Drug Reactions . MS-78

Family History and Genetic Risk Factors .MS-3

Radiation Therapy .................................................... MS-81

Risk-Reducing Surgery for High-Risk Patients ...MS-4

Follow-up Recommendations... MS-82

Serous Tubal Intraepithelial Carcinoma (STIC)

Management of an Increasing CA-125 Level .................................... MS-82

Screening.................................................. MS-4

Recurrent Disease .................................................... MS-83

Symptoms of Ovarian Cancer . MS-4

Acceptable Recurrence Modalities

Screening with Ultrasound and/or Serum CA-125 . MS-5

Less Common Ovarian Cancers . MS-88

Screening with Other Biomarker Tests .MS-7

Recommended Workup .................................................... MS-88

Risk-Reducing Salpingo Oophorectomy (RRSO) Protocol . . . MS-7

Surgery .................................................. MS-89

Recommended Workup $\ldots$ MS-9

Clear Cell Carcinoma 59

Patients Presenting with Clinical Symptoms/Signs...MS-9

Mucinous Carcinomas .................................................... MS-90

Workup for Patients Referred with Diagnosis by Previous Surgery

Low-Grade Serous Carcinoma MS-92

MS-13

Endometrial Epithelial Carcinoma . MS-94

Diagnosis, Pathology, and Staging .MS-14

Malignant Germ Cell Tumors . MS-95

Histologic Subtypes .................................................... MS-15

Malignant Sex Cord-Stromal Tumors . MS-96

Staging . MS-16

Carcinosarcomas (Malignant Mixed Müllerian Tumors) . MS-97

Molecular Testing . MS-17

Borderline Epithelial Tumors (Low Malignant Potential)

Primary Treatment.................................................. MS-18

Summary. MS-99

Primary Surgery .................................................... MS-18

NCCN Guidelines Version 3.2025

Ovarian Cancer

Overview

Ovarian neoplasms consist of several histopathologic entities, with epithelial ovarian cancer accounting for the majority of malignant ovarian neoplasms (about 90%).$^{1}$⁻$^{4}$ Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in females.$^{5}$ In 2022 it is estimated that 19,880 new diagnoses and 12,810 deaths from this malignancy will occur in the United States.$^{5}$ Five-year survival is about 49%, although survival is longer for select patients with early stage disease and certain histological subtypes.$^{5}$⁻$^{8}$ Approximately half of patients present with distant disease; however, certain uncommon subtypes, such as clear cell and endometrioid cancer, are more likely to be diagnosed at earlier stages.$^{5}$⁻$^{7}$,$^{9}$

These NCCN Guidelines for Ovarian Cancer discuss cancers originating in the ovary, fallopian tube, or peritoneum and include recommendations for epithelial subtypes, including serous, endometrioid, carcinosarcoma (malignant mixed Müllerian tumors [MMMTs] of the ovary), clear cell, mucinous, and borderline epithelial tumors (also known as low malignant potential [LMP] tumors). The recommendations are primarily based on data from patients with the most common subtypes—high-grade serous and grade 2 and 3 endometrioid carcinoma. Also included in the guidelines are recommendations for less common ovarian cancers (LCOC), specifically carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous carcinoma, grade 1 endometrioid carcinoma, borderline epithelial tumors, and non-epithelial subtypes including malignant sex cord-stromal tumors and germ cell tumors.

By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Exceptions to the rule were discussed among panel members during the process of developing these guidelines.

A 5% rule (omitting clinical scenarios that comprise less than 5% of all cases) was used to eliminate uncommon clinical occurrences or conditions from these guidelines.

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Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Guidelines for Ovarian Cancer, an electronic search of the PubMed database was performed to obtain key literature in ovarian cancer published since the previous Guidelines update, using the following search terms: ((ovarian OR fallopian OR (primary and peritoneal) OR ovary OR (sex and cord-stromal) or mullerian) AND (carcinoma OR cancer OR malignancy OR malignancies OR lesion OR tumor). The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.$^{10}$ The search results were narrowed by selecting studies in humans published in English. Articles were also excluded if they: 1) involved investigational agents that have not yet received FDA approval; 2) did not pertain to the disease site; 3) were clinical trial protocols; or 4) were reviews that were not systematic reviews. The search results were further narrowed by selecting publications reporting clinical data, meta-analyses and systematic reviews of clinical studies, and treatment guidelines developed by other organizations.

The potential relevance of the PubMed search results was examined by the oncology scientist and panel chairs, and a list of selected articles was sent to the panel for their review and discussion at the panel meeting. The panel also reviewed and discussed published materials referenced in Institutional Review Comments or provided with Submission Requests. The data from key PubMed articles, as well as articles from additional sources deemed as relevant to these Guidelines and discussed by the panel, have been included in this version of the Discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the panel's review of lower-level evidence and expert opinion. The complete details of the Development and Update of the NCCN Guidelines are at www.NCCN.org.

Risk Factors for Ovarian Cancer

Reproductive Risk Factors

Epidemiologic studies have identified risk factors in the etiology of ovarian cancer.$^{4,11,12}$ A 30% to 60% decreased risk for cancer is associated with 1 or more pregnancies/births, the use of oral contraceptives, and/or breastfeeding.$^{11,13-26}$ Conversely, nulliparity confers an increased risk for ovarian cancer. Data suggest that postmenopausal hormone therapy and pelvic inflammatory disease may increase the risk for ovarian cancer,$^{11,27-37}$ although results vary across studies.$^{38-41}$ The risk for ovarian borderline epithelial tumors (also known as LMP tumors) may be increased after ovarian stimulation for in vitro fertilization.$^{32,42-46}$

Obesity, Smoking, and Lifestyle and Environmental Risk Factors

Studies evaluating obesity as a risk factor for ovarian cancer have yielded inconsistent results,$^{47}$ which may be due to associations between obesity and other ovarian cancer risk factors (eg, parity, oral contraceptive use, menopausal status).$^{23}$,$^{48}$,$^{49}$ The risk associated with obesity may differ across ovarian cancer subtypes, and depend on the timing and reason for weight gain.$^{39}$,$^{48}$-$^{50}$ Smoking is associated with an increased risk for mucinous carcinomas but a decreased risk for clear cell carcinomas.$^{11,51}$-$^{55}$ $^{11}$,$^{55}$ $^{66}$ but so far Environmental factors have been investigated, such as talc,$^{56}$-$^{66}$ but so far they have not been conclusively associated with the development of this neoplasm.

Family History and Genetic Risk Factors

Family history (primarily patients having two or more first-degree relatives with ovarian cancer)—including linkage with BRCA1 and BRCA2 genotypes (hereditary breast and ovarian cancer [HBOC] syndrome) or families affected by Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC] syndrome)—is associated with increased risk of ovarian cancer, particularly early-onset disease.$^{11,67-88}$ In addition to mutations in

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BRCA1/2 and the genes associated with Lynch syndrome (eg, MLH1, MSH2, MSH6, PMS2),$^{74,86,87,89-92}$ germline mutations in a variety of other genes have been associated with increased risk of ovarian cancer (eg, ATM, BRIP1, NBN, PALB2, STK11, RAD51C, RAD51D).$^{73,74,89,92-105}$ Patients with mutations in BRCA1/2 account for only approximately 15% (range, 7%-21%) of those who have ovarian cancer.$^{73,89,95,106-114}$ Studies testing large panels of genes have found that 3% to 8% of patients with ovarian cancer carry mutations in genes other than BRCA1 and BRCA2 known to be associated with ovarian cancer susceptibility.$^{73,74,95,108,112,113}$

Risk-Reducing Surgery for High-Risk Patients

In those at high risk (with either BRCA1 or BRCA2 mutations), risk-reducing bilateral salpingo-oophorectomy (BSO) is associated with a reduced risk for breast, ovarian, fallopian tube, and primary peritoneal cancers.$^{115-119}$ Prospective studies have shown that among patients at high risk due to BRCA1 or BRCA2 mutation, occult ovarian, fallopian tube, or primary peritoneal cancer is found in up to 5% of patients undergoing risk-reducing salpingo-oophorectomy (RRSO),$^{118,120-125}$ enabling them to be diagnosed at an earlier and possibly more treatable stage. However, there is a residual risk for primary peritoneal cancer after risk-reducing BSO in individuals at high risk for ovarian cancer.$^{118,121,123,126,127}$ 128Additional considerations and recommended procedures for risk reduction surgery are described in the Risk-Reducing Salpingo-Oophorectomy (RRSO) Protocol section below.

Serous Tubal Intraepithelial Carcinoma (STIC)

It is now generally accepted that the fallopian tube is the origin of many serous ovarian and primary peritoneal cancers, and that serous intraepithelial carcinoma of the fallopian tube (also known as serous tubal intraepithelial carcinoma [STIC]) is a precursor of most high-grade serous ovarian or peritoneal cancer.$^{1,127,129-139}$ A referral to a gynecologic oncologist/comprehensive cancer center is recommended for

management of occult STIC. At present, management options consist of: 1) observation alone with or without CA-125 testing when no evidence of invasive cancer is noted; and 2) surgical staging with observation or chemotherapy based on NCCN Guidelines if invasive cancer is noted. For those without prior genetic counseling and/or testing, discovery of a STIC should prompt a genetics evaluation. Nonetheless, it is not clear whether surgical staging and/or adjuvant chemotherapy is beneficial for those with STIC. An ongoing clinical trial (NCT04251052) sponsored by the National Cancer Institute (NCI) will prospectively track the incidence of STIC lesions as well as outcomes in those with pathogenic variants of BRCA1 that elected to undergo RRSO or risk-reducing salpingectomy with possible delayed oophorectomy.$^{140}$

Screening

Symptoms of Ovarian Cancer

Because of the location of the ovaries and the biology of most epithelial cancers, it has been difficult to diagnose ovarian cancer at an earlier, more curable stage. Evaluations of patients with newly diagnosed ovarian cancer have resulted in consensus guidelines for ovarian cancer symptoms,$^{139,141-143}$ which may enable earlier identification of patients who may be at an increased risk of having developed early-stage ovarian cancer.$^{144,145}$ Symptoms suggestive of ovarian cancer include: bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary symptoms (urgency or frequency), especially if these symptoms are new and frequent (>12 d/mo),$^{144}$ and cannot be attributed to any known (previously identified) malignancy or cause. Physicians evaluating those with this constellation of symptoms must be cognizant of the possibility that ovarian pathology may be causing these symptoms.$^{146,147}$ Studies testing proposed symptom indices have found that these are not as sensitive or specific as necessary, especially in those with early-stage disease.$^{145,148-154}$

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Screening with Ultrasound and/or Serum CA-125

The literature does not support routine screening for ovarian cancer in the (asymptomatic) general population,$^{155,156}$ and routine screening is not currently recommended by any professional society.$^{146,147,155,157-164}$ Several large prospective randomized trials have evaluated screening for ovarian cancer with serum CA-125 and/or ultrasound (US) compared with "usual care" or no screening in the general population of postmenopausal individuals with intact ovaries (Table 1). Primary analysis results and meta analyses of data from these randomized studies suggest that screening may increase the likelihood of diagnosis at an early disease stage,$^{165-167}$ and may slightly lengthen survival in those diagnosed with ovarian cancer.$^{156,166,168}$ However, screening did not improve ovarian cancer-related mortality overall.$^{156,165,167,168}$ U.S. Preventative Services Task Force assessment of these randomized trials concluded that in average-risk individuals aged 45 years or older, ovarian cancer-related mortality was not improved by annual screening with transvaginal US (TVUS) alone, CA-125 alone, or both.$^{159}$ Results from these randomized prospective trials and from single-arm prospective trials suggest that the positive predictive value was low (<50%) for the screening methods tested (serum CA-125)

and/or US).$^{169-172}$ Harms of screening included false positives in up to 44% of patients (over the course of multiple rounds of screening), which may have caused unnecessary stress and resulted in unnecessary surgery in up to 3.2%, with complications in up to 15% of false-positive surgeries.$^{155,159,165,173-175}$ A number of analyses have aimed to determine methods to improve the utility of US- and CA-125 based screening in postmenopausal individuals at average risk.$^{166,172,176-188}$ Several have found that compared with a single CA-125 serum concentration threshold for further testing/surgery, using the risk of ovarian cancer algorithm (ROCA) to determine CA-125-based thresholds may enable earlier detection of ovarian cancer and improve the sensitivity of CA-125-based screening.$^{166,176,178}$ In the UKCTOCS trial, ROCA was used prospectively in the multimodality screening arm as criteria for further testing (CA-125 at 3 months and/or TVUS), but nonetheless ovarian cancer-related mortality was not significantly different from the unscreened population.$^{165}$ Data from large population-based studies have shown that a variety of other conditions not related to cancer may impact CA-125 levels,$^{189}$ which may explain the poor positive predictive value of CA-125 screening observed in prospective trials.

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|Trial, Primary Report|Patients|Arms|Follow-up, Median| |---|---|---|---| |UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) NCT00058032 Jacobs et al, 2016$^{165}$|Age: 50-74 yearsNo prior bilateral oophorectomyPersonal cancer history: no history of ovarian cancer, no active non-ovarian malignancyFamily cancer history of breast or ovarian cancer: 6.4%breast, 1.6%; excluded if elevated risk of familial breast or ovarian cancer|Annual screening with CA-125, with TVUS as a second-line test (n=50,640)Annual screening with TVUS (n=50,359)No screening (n=101,359)|11.1 years| |Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial NCT00002540 Pinsky et al, 2016$^{156}$|Age: 55-74 yearsNo prior bilateral oophorectomyPersonal cancer history: no prior lung, colorectal, or ovarian; 3.6% had prior breast cancer; no current treatment for other cancer (except nonmelanoma skin cancer)Family cancer history of breast or ovarian cancer: ~17%|Screening: annual TVUS and CA-125; bimanual palpitation offered (n=39,105)Usual care (n=39,111)|14.7 years| |Jacobs et al, 1999$^{168}$|Age: ≥45 yearsNo prior bilateral oophorectomyPersonal cancer history: no history of ovarian cancer, no active malignancyFamily cancer history: NR|Screening: offered 3 annual CA-125, with pelvic US as second-line test (n=10,977)No screening (n=10,958)|6.8 years|

CA-125, cancer antigen 125; NR, not reported; TVUS, transvaginal ultrasound; US, ultrasound.

For those with high-risk factors (eg, BRCA mutations, family history of breast or ovarian cancer), RRSO is generally preferred over screening as it reduces the likelihood of breast, ovarian, fallopian tube, and primary peritoneal cancers.$^{115-119}$ For those who choose to defer or decline RRSO, some physicians use CA-125 monitoring and endovaginal US.$^{120,157,158,162}$ Strong supportive evidence for this approach is lacking, however, as several large prospective studies in high-risk patients have shown that these methods have low positive predictive value and do not improve ovarian cancer-related mortality.$^{190-194}$ However, prospective studies in high-risk patients have also shown that screening with CA-125 and TVUS may improve the likelihood of diagnosis at an earlier stage,$^{190,191,193}$ and

may improve survival of the patients who develop ovarian cancer.$^{192}$ As in average-risk patients, analyses of data from high-risk patients suggests that interpretation of CA-125 using ROCA rather than a single concentration threshold improves screen sensitivity and the likelihood of ovarian cancer detection at an earlier stage.$^{190}$ In high-risk patients the appropriate CA-125 cut-point may depend on menopausal status.$^{195}$ Recommendations for screening for ovarian cancer in patients with genetic risk factors can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org).

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Screening with Other Biomarker Tests

In addition to CA-125, there are a number of biomarkers that have been explored as possible screening tools for early detection of ovarian cancer.$^{18,196-209}$ Data for most of these proposed biomarkers is limited to retrospective analyses comparing biomarker levels in patients with known ovarian cancer versus healthy controls. Very few biomarkers have been tested prospectively to determine whether they can detect ovarian cancer or predict development of ovarian cancer in those who have no other signs or symptoms of cancer. Data show that several markers (including CA-125, HE4, mesothelin, B7-H4, decoy receptor 3 [DcR3], and spondin-2) do not increase early enough to be useful in detecting early-stage ovarian cancer.$^{182,210,211}$

There are a number of biomarker tests and prediction algorithms (based on a variety factors, such as symptoms, imaging results, biomarkers, and patient characteristics) that have been developed for assessing the likelihood of malignancy among patients who have an adnexal mass (and have not yet had surgery). It is important to note that these tests are for preoperative assessment only, and none is suitable for ovarian cancer screening prior to detection of an adnexal mass; they are also not for use as stand-alone diagnostic tests. For example, the OVA1 test is a multivariate index assay (MIA) that uses five markers (including transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA-125) in preoperative serum to assess the likelihood of malignancy in patients with an adnexal mass for which surgery is planned, with the aim of helping community practitioners determine which patients to refer to a gynecologic oncologist for evaluation and surgery.$^{212-216}$ The Society of Gynecologic Oncology (SGO) and the FDA have stated that the OVA1 test should not be used as a screening tool to detect ovarian cancer in patients without any other signs of cancer, or as a stand-alone diagnostic tool.$^{146,161,217}$ Moreover, based on data documenting an increased survival, the NCCN Guidelines Panel recommends that all patients with suspected

ovarian malignancies (especially those with an adnexal mass) should undergo evaluation by an experienced gynecologic oncologist prior to surgery.$^{147,218-221}$ For discussion of preoperative tests recommended by NCCN for patients with an undiagnosed adnexal mass, see the section below entitled Recommended Workup, Patients Presenting with Clinical Symptoms/Signs.

Risk-Reducing Salpingo Oophorectomy (RRSO) Protocol

The RRSO protocol is recommended for patients at risk for HBOC and is described in detail in the algorithm (see the Principles of Surgery in the algorithm). Selection of patients appropriate for this procedure is described in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org). In addition to reducing the risk of breast, ovarian, fallopian tube, and primary peritoneal cancers in patients at high risk,$^{115-119}$ RRSO can also result in early diagnosis of gynecologic cancer. Occult ovarian, fallopian tube, and primary peritoneal cancer is sometimes found by RRSO (in 3.5%–4.6% of patients with BRCA1/2 mutations),$^{118,120-125}$ and in some cases only detected by pathologic examination of specimens.$^{120,222-227}$ This emphasizes the need for well-tested protocols that include careful pathologic review of the ovaries and tubes.$^{123,128}$

This protocol recommends minimally invasive laparoscopic surgery. This procedure should include a survey of the upper abdomen, bowel surfaces, omentum, appendix (if present), and pelvic organs. Any abnormal peritoneal findings should be biopsied. Pelvic washing for cytology should be obtained, using approximately 55 cc normal saline instilled and aspirated immediately. The procedure should include total BSO, removing 2 cm of proximal ovarian vasculature or IP ligament, all of the fallopian tube up to the cornua, and all of the peritoneum surrounding the ovaries and fallopian tubes, especially the peritoneum underlying areas of adhesion between the fallopian tube and/or ovary and the pelvic

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sidewall.$^{123}$ It is recommended to engage in minimal instrument handling of the tubes and ovaries to avoid traumatic exfoliation of cells.$^{123}$ Both ovaries and tubes should be placed in an endobag for retrieval from the pelvis. Complete evaluation of the fallopian tubes is important, as prospective studies have found that roughly a half of the cases of occult disease identified by RRSO in BRCA1/2 mutation carriers were tubal neoplasms.$^{118,120,122-124}$ For pathologic assessment, fallopian tubes should be processed by sectioning and extensively examining the fimbriated end (SEE-Fim) of the tubes and then assessed to determine whether any evidence of cancer is present.$^{128,228,229}$ The ovaries should also be carefully sectioned, processed, and assessed.$^{128}$ The CAP protocol describes the process for sectioning the fallopian tubes and ovaries.$^{230,232}$ If occult malignancy or STIC is identified, the patient should be referred to a gynecologic oncologist.

Note that it is controversial whether a hysterectomy should also be done in patients undergoing RRSO. Some patients with elevated risk of ovarian cancer due to genetic risk factors or family history may also have elevated risk of endometrial cancer.$^{233-237}$ The relationship between BRCA mutations and uterine cancer has been evaluated in multiple studies, with some studies showing that BRCA mutation carriers are at higher risk of uterine/endometrial cancer compared with the general population or compared with those without BRCA mutations;$^{238-242}$ other studies showing no linkage$^{243,244}$ or a lower risk of uterine cancer among BRCA mutation carriers;$^{245}$ and some studies suggesting that increased risk is largely due to tamoxifen exposure.$^{240,246}$ In a few studies of BRCA mutation carriers who underwent RRSO without hysterectomy and had no evidence of disease at the time of surgery, the post-surgery incidence of uterine cancer was higher compared with the general population,$^{247-249}$ but in other studies it was not elevated.$^{250}$ Several studies found that BRCA1 mutations were linked to endometrial or uterine cancer, but BRCA2 mutations either were not associated with increased risk or were not

analyzed.$^{240-242-247-249}$ However, there are also studies showing no significant association between uterine cancer and BRCA1 mutations,$^{243,245}$ so further research on this topic is needed.

Certain pathogenic variants associated with Lynch syndrome have been linked to increased risk of endometrial and ovarian cancers, and associated with cases where both types of cancer develop in an individual patient or family.$^{83,86-88,90,251-255}$ Certain reproductive factors, such as infertility, parity, and exposure to contraceptives, fertility drugs, and postmenopausal hormone therapy, are known to increase or decrease the risk of both ovarian and endometrial cancers.$^{15,16,19,30,45,256-258}$ Among patients with who underwent RRSO due to BRCA mutation, diagnosis of breast cancer, or family history of breast/ovarian cancer, and elected to have hysterectomy at the time of RRSO, several studies reported finding occult uterine disease, although the frequency varied.$^{120,259-262}$ Based on studies specifically focusing on patients with mutations associated with Lynch syndrome, however, discovery of occult endometrial cancer may be as frequent as occult ovarian/fallopian tube lesions, and the incidence of endometrial cancer may be significantly reduced by prophylactic hysterectomy.$^{263,264}$ One large population-based study of individuals with premenopausal primary breast cancer showed that prophylactic BSO plus hysterectomy reduced the risk of new primary breast cancer and improved breast-cancer associated mortality; neither procedure alone significantly modified these risks, and the effect was not seen in those with postmenopausal breast cancer.$^{265}$ See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org) for further discussion of selection of patients who may benefit from hysterectomy at the time of RRSO.

The prevention benefits of salpingectomy alone are not yet proven.$^{266-276}$ If salpingectomy alone is considered, the fallopian tube from the fimbria to its insertion into the uterus should be removed; the fallopian tubes should

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also be carefully processed and assessed as described above for BSO.$^{123,128}$ The concern for risk-reducing salpingectomy alone is that the individuals are still at risk for developing ovarian cancer. In addition, in premenopausal individuals, oophorectomy reduces the risk of developing breast cancer but the magnitude is uncertain.$^{277}$ For further discussion of residual risks of cancer, see the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org).

The risks of surgery include injury to the bowel, bladder, ureter, and vessels.$^{122,261,278-280}$ For both patients who are premenopausal and those who are postmenopausal at time of RRSO, menopause symptoms may emerge, re-emerge, or worsen.$^{281-287}$ RRSO may also have long-term impacts on sexual functioning and quality of life (QOL).$^{281,282,285,286,288-297}$ Although the existing limited data suggest that management with hormone replacement therapy (HRT) likely does not increase risk of breast cancer in BRCA mutation carriers undergoing RRSO,$^{288,298-303}$ the efficacy of HRT for symptom management in this population is debated.$^{281-285,293,294,296,300-302}$ RRSO in premenopausal individuals increases risk of certain cardiovascular conditions (eg, coronary heart disease, cardiac arrhythmias, hyperlipidemia), chronic obstructive pulmonary disease, arthritis, asthma, osteoporosis, and mental health conditions (cognitive dysfunction, depression, anxiety).$^{284,304-310}$

Recommended Workup

Patients with ovarian cancer may present in several different ways. Some present with clinical signs and/or symptoms, which upon imaging reveal a pelvic mass and potentially evidence of metastasis. For other patients, ovarian cancer is an incidental finding during a surgery or other procedure. Recommended workup for each of these presentations is described below.

Patients Presenting with Clinical Symptoms/Signs

Clinical symptoms that warrant further workup for possible ovarian cancer include suspicious/palpable pelvic mass found on an abdominal/pelvic exam, ascites, abdominal distention, and/or symptoms (ie, bloating, pelvic/abdominal pain, difficulty eating for feeling full quickly, and urinary symptoms, such as increased urgency or frequency).$^{144}$ Clinical signs might include abdominal distension/ascites and a mass noted on abdominal/pelvic examination. Further workup for these patients should include imaging, laboratory studies, evaluation of nutritional status, GI evaluation if indicated, and family history. Each of these elements of workup is described in greater detail below.

Imaging

The primary workup for patients with clinical signs or symptoms of ovarian cancer should include an abdominal/pelvic US and/or abdominal/pelvic CT/MRI scan. US is typically used for initial evaluation, as it has been shown to be effective at triaging the majority of adnexal masses into benign or malignant categories.$^{311-313}$ Other imaging modalities may be helpful when the results of US are indeterminate (ie, either the organ of origin or malignant potential is unclear), and may improve assessment of metastases, staging, and preoperative planning.$^{311,313,314}$ Abdominal/pelvic MRI may be useful for determining malignant potential of adnexal masses if US is not reliable or results are indeterminate.$^{311-313,315-319}$ FDG-PET/CT scan may also be useful for indeterminate lesions.$^{320-322}$ The NCCN Panel recommends PET/CT or MRI for indeterminate lesions if they will alter management.

Various imaging methods and algorithms for evaluating imaging results have been proposed for preoperatively distinguishing benign from malignant adnexal masses, with the goal of determining which patients should have surgery and/or be referred to a gynecologic oncologist for further evaluation and surgery. Multiple US-based imaging algorithms for

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predicting malignancy have been developed and tested prospective studies comparing preoperative US results to final diagnosis after surgery.$^{323-327}$ The most thoroughly tested of these are the International Ovarian Tumor Analysis (IOTA) Simple Rules algorithm, based on five US features;$^{188,328-337}$ and the IOTA logistic regression model (LR2), which combines five US variables with age.$^{186,338-341}$ A variety of MRI-based approaches for distinguishing benign from malignant masses have been explored in prospective trials comparing preoperative MRI results to final postoperative diagnosis, although these approaches have been less thoroughly tested than the US techniques. Examples include proton MR spectroscopy,$^{342}$ diffusion-weighted imaging (DWI),$^{343-345}$ apparent diffusion coefficient (ADC) maps,$^{346}$ 3.0 Tesla (3T) MRI,$^{347}$ and dynamic contrast-enhanced (DCE) MRI.$^{348}$ Although both US and MRI are recommended options for preoperative imaging, the NCCN Guidelines are silent regarding the exact techniques used for each, and do not endorse any specific model for preoperative triage.

For assessment of abdominopelvic metastases for preoperative staging, estimation of resectability, and surgical planning, abdominal/pelvic CT or MRI are generally more useful than US.$^{314,315,318,349-351}$ Although CT is preferred in some circles, MRI has been shown to provide equivalent accuracy for staging and comparable accuracy for predicting peritoneal tumor volume, and can be useful if CT results are inconclusive.$^{314}$ For assessing advanced disease, FDG-PET/CT may also be useful if CT results are indeterminate, and has been shown to have higher accuracy than CT for detection of metastases.$^{314,321,352-355}$

Although there is no direct evidence that chest x-ray or chest CT is necessary, panel members felt that it should be part of the overall evaluation of a patient before surgical staging if clinically indicated. CT of the chest can detect pleural or pulmonary metastases, as well as pleural

effusion, which may help with treatment planning.$^{314}$ All CT/MRI imaging should be performed with contrast unless contraindicated.

Laboratory Studies and Biomarker Tests

Appropriate laboratory studies for patients presenting with clinical symptoms/signs of ovarian cancer include CBC and chemistry profile with liver function test.

A number of specific biomarkers and algorithms using multiple biomarker test results have been proposed for preoperatively distinguishing benign from malignant tumors in patients who have an undiagnosed adnexal/pelvic mass. Biomarker tests developed and evaluated in prospective trials comparing preoperative serum levels to postoperative final diagnosis include serum HE4 and CA-125, either alone or combined using the Risk of Ovarian Malignancy Algorithm [ROMA] algorithm;$^{185,187,356-371}$ the MIA (brand name OVA1) based on serum levels of five markers: transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA-125$^{154,212-216,372}$; and the second-generation MIA (MIA2G, branded name OVERA) based on CA-125, transferrin, apolipoprotein A1, follicle-stimulating hormone [FSH], and HE4.$^{184,373}$ The FDA has approved the use of ROMA, OVA1, or OVERA for estimating the risk for ovarian cancer in those with an adnexal mass for which surgery is planned, and have not yet been referred to an oncologist.$^{217,374,375}$ Although the American Congress of Obstetricians and Gynecologists (ACOG) has suggested that ROMA and OVA1 may be useful for deciding which patients to refer to a gynecologic oncologist,$^{376}$ other professional organizations have been non-committal.$^{161,312,377}$ Not all studies have found that multi-biomarker assays improve all metrics (ie, sensitivity, specificity, positive predictive value, negative predictive value) for prediction of malignancy compared with other methods (eg, imaging, single-biomarker tests, symptom index/clinical assessment).$^{185,215,357,378-380}$ Currently, the NCCN Panel does not recommend the use of these

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biomarker tests for determining the status of an undiagnosed adnexal/pelvic mass.

Nonetheless, the NCCN Guidelines do include CA-125 testing as a possible element of preoperative workup, if clinically indicated. This recommendation is based on data showing that serum CA-125 levels correlate with extent of disease, and may have prognostic value, so may help in treatment planning.$^{381-385}$ Serum CA-125 levels tend to correlate with the clinical course of disease, especially in those with elevated pretreatment levels, so can be useful for monitoring response to therapy and surveillance for recurrence.$^{4,382,384-396}$

Some evidence suggests that HE4 may be a useful prognostic marker in patients with ovarian cancer, decreases during response to treatment, and may improve early detection of recurrence relative to CA-125 alone.$^{397-424}$ NCCN Panel members sometimes test HE4 in patients who do not have elevated CA-125, as HE4 can be useful for future monitoring in such patients. However, because results vary across studies,$^{425-427}$ the NCCN Guidelines currently do not recommend routine HE4 as part of preoperative workup.

In addition to CA-125, the NCCN Guidelines mention that other tumor markers may be used as part of preoperative workup, if clinically indicated: inhibin, alpha-fetoprotein [AFP], beta-human chorionic gonadotropin [beta-hCG], lactate dehydrogenase [LDH], carcinoembryonic antigen [CEA], and CA19-9. Serum levels of these markers can be elevated in patients with certain LCOCs, and correlate with disease course in some of these patients. Measurement of these markers prior to surgery can help to assess for LCOC (see Less Common Ovarian Cancers), and facilitate future monitoring during surveillance after treatment, especially in patients who do not have elevated serum CA-125 at baseline and/or have tumor types in which CA-125 level is less likely to be informative.$^{395}$

For example, AFP, beta-hCG, and LDH are markers for malignant germ cell tumors that can be helpful in intraoperative diagnosis, preoperative planning, and post-treatment monitoring for recurrence.$^{376,395,428-436}$ AFP can be produced by endodermal sinus (yolk sac) tumors, embryonal carcinomas, polyembryomas, and immature teratomas; beta-hCG can be produced by choriocarcinomas, embryonal carcinomas, polyembryomas, and, in low levels, in some dysgerminomas; and LDH can be a marker for dysgerminoma.$^{428,429}$ Some studies in young patients presenting with an ovarian mass have found that high levels of AFP and beta-hCG were correlated with higher likelihood of malignancy,$^{436,437}$ or linked to specific subtypes,$^{431,438,439}$ suggesting that these markers may help with intraoperative diagnosis to determine whether fertility-sparing surgery is an option. High serum AFP levels and poor decline in serum AFP levels after treatment appear to be associated with worse outcomes in patients with germ cell tumors.$^{432,438-443}$ High serum beta-CG may also be correlated with poorer prognosis.$^{432,444}$ High levels of serum LDH have been correlated with more extensive disease and poor outcomes in some patients with ovarian germ cell tumors.$^{443,445-447}$ If a patient with a germ cell tumor or sex chord stromal tumor has elevated levels of one or more of these markers at baseline, and levels decline after treatment, then the marker(s) is more likely to be useful for follow-up for recurrence.$^{448}$ AFP and hCG are commonly used to monitor for recurrence in patients with germ cell tumors (GCTs), and have included clinical trials for detection of recurrence.$^{448-451}$

Sex cord-stromal tumors of the ovary, particularly granulosa cell tumors, can produce inhibin, and inhibin expression level in tumor tissue and serum have been proposed as diagnostic markers.$^{395,452-461}$ Some studies have shown that serum levels of inhibin A and B, particularly inhibin B, correlate with extent of disease in patients with granulosa cell tumors, decreasing during treatment and then increasing again prior to relapse, leading to the proposal that serum inhibin monitoring may be helpful for

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long-term follow-up.$^{462-467}$ In some cases of ovarian stromal tumor inhibin levels are not elevated, however, so this marker is not useful for monitoring response to treatment.$^{468}$

Elevated serum CEA is a marker associated with gastrointestinal (GI) primary cancers, but can also occur in patients with ovarian malignancies, particularly mucinous tumors.$^{4,469-477}$ Because of its association with GI cancers, some advocate for further GI imaging in patients with high serum CEA.$^{142,469}$ A ratio of serum CA-125 to CEA >25 has been proposed for differentiating ovarian cancer from colorectal cancer,$^{478,479}$ particularly for confirming ovarian cancer diagnosis in patients considering neoadjuvant therapy (and biopsy results are not available).$^{469,480}$ CA-125:CEA ratio has been incorporated into entry criteria in trials testing neoadjuvant therapies.$^{481-483}$ For patients with mucinous ovarian cancer, it has been proposed that CEA may be useful for monitoring for recurrent disease.$^{146,476,484}$ CA19-9 is another marker that is elevated more often in mucinous tumors compared with other ovarian cancer types.$^{477,485-492}$ Results from some studies suggest that serum CA19-9 may be useful for monitoring for recurrence, especially in patients with mucinous ovarian cancers, and in those with high CA19-9 levels prior to treatment.$^{395,488,493,494}$

Evaluation of Nutritional Status and Gastrointestinal (GI) Evaluation

Workup should also include evaluation of the patient's nutritional status, and GI evaluation if clinically indicated. Patients with ovarian cancer often present with bloating, pelvic or abdominal pain, difficulty eating, or feeling full quickly,$^{144}$ which can lead to changes in dietary habits that result in poor nutritional status. Poor nutritional status has been linked to higher risk of suboptimal surgery, surgical complications, and poor survival, especially in older patients.$^{495-501}$ There are a variety of ways to assess nutritional status, including body weight, body mass index, anthropometrics, serum protein, serum albumin, transferrin, lymphocyte

count, bioelectrical impedance analysis, and body composition measures (adipose and lean tissues, skeletal muscle index).$^{495}$-498,500,502-516 Two commonly used metrics are the prognostic nutritional index (PNI) and subjective global assessment (SGA).$^{496,504,517-523}$ Evaluation of nutritional status is recommended as part of baseline workup as it is important for determining whether a patient is a good surgical candidate, and for preoperative planning.$^{480,524}$ For those who are not good surgical candidates, NACT may be a better option versus upfront debulking surgery. However, poor nutritional status in the context of a GI mass may be an indication for prioritizing surgery to remove or reduce the GI mass,$^{525,526}$ especially if the patient is otherwise a relatively fit surgical candidate.

Given that GI cancers and primary mucinous carcinoma of the ovary can both cause serum CEA elevation,$^{4,469-477}$ and can both present with adnexal masses, GI tract evaluation is especially important in these patients to determine whether patients have metastases to the ovary or primary mucinous carcinoma of the ovary (see Mucinous Carcinomas).$^{527}$ The presence of a pancreatic mass or widespread abdominal disease should also increase suspicion for primary GI cancer.

Family History and Genetic Testing

Obtaining a family history and referral to a genetic counselor is an important part of workup, as some patients may have hereditary traits that may inform future treatment and determine whether family members should be screened. Primary treatment (surgery and chemotherapy) should not be delayed for a genetic counselling referral, however, as genetic test results are not needed for selection of primary surgery and/or chemotherapy, and delay in treatment is associated with poorer outcomes.$^{528,529}$ Recommendations regarding genetic testing can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and the NCCN Guidelines for

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Genetic/Familial High-Risk Assessment: Colorectal (available at www.NCCN.org).

Although germline and/or somatic BRCA1 and BRCA2 status may inform future options for maintenance therapy, BRCA testing for the purpose of informing treatment is not needed until after there is histologic confirmation of ovarian, fallopian tube, or primary peritoneal cancer (eg, after primary surgery or confirmation by biopsy). See Molecular Testing section below.

Prediction of Malignancy, Referral to a Gynecologic Oncologist

There are a number of prediction algorithms that combine multiple factors, such as symptoms, imaging results, biomarkers, and patient characteristics, to predict the likelihood of malignancy among patients who have an undiagnosed adnexal mass (ie, a mass detected by clinical exam or imaging that has not yet been resected and definitively diagnosed by pathology).$^{316,338,351,371,530}$ These algorithms were developed with the goal of reducing the number and/or extent of unnecessary surgeries by using the likelihood of malignancy to determine which patients are most likely to benefit from surgery, and/or identify cases to be referred to a gynecologic oncologist for further testing and surgery. Many of these algorithms have been tested in prospective trials comparing préoperative prediction to postoperative histologically confirmed diagnosis, including IOTA Assessment of Different NEoplasias in the adneXa (ADNEX), which uses patient age, type of center (oncology referral vs other), serum CA-125, and six US variables;$^{316,330,531,532}$ Risk of Malignancy Indexes (RMI-1 through 4), which use US features, patient menopausal status, and serum CA-125;$^{339,358,359,533-539}$ combining symptom index (SI) with CA-125 and HE4 results;$^{153}$ and the (early) ACOG/SGO referral guidelines based on patient age, CA-125 level, physical findings, imaging results, and family history.$^{351,371,540}$ Several prospective studies have compared multiple algorithms or algorithms versus other metrics to determine which most accurately predicts malignancy.$^{212,214,215,338,357-359,378,379}$

Currently the NCCN Guidelines do not endorse any of these methods. Because primary assessment and debulking by a gynecologic oncologist is associated with improved survival, all patients with lesions suspected to be ovarian malignancies (based on clinical evidence) should be referred to an experienced gynecologic oncologist for evaluation—both to assess suitability for different primary surgical options and to select the best method for obtaining the material needed for definitive diagnosis.$^{147,218-221}$ A gynecologic oncologist should be involved in assessing whether a patient is a suitable surgical candidate and/or an appropriate candidate for neoadjuvant therapy, and consideration of laparoscopic evaluation to determine feasibility of debulking surgery. A gynecologic oncologist should also be consulted for management of occult STICs.

Workup for Patients Referred with Diagnosis by Previous Surgery

Patients are on occasion referred to NCCN Member Institutions after having a previous diagnosis of ovarian cancer by surgery or tissue biopsy (cytopathology). At times, patients with newly diagnosed ovarian cancer have had cytoreductive surgery and comprehensive staging procedures (ie, having met the standards for surgical staging of the Gynecologic Oncology Group [GOG]).$^{541}$ In some instances, referral occurs after incomplete surgery and/or staging (eg, uterus and/or adnexa intact, omentum not removed, incomplete lymph node dissection, residual disease that is potentially resectable, surgical stage not completely documented, occult invasive carcinoma found at time of risk reduction surgery). The components of surgical staging are listed in the algorithm (see Principles of Surgery in the algorithm).

Workup procedures are very similar for patients having undiagnosed or diagnosed pelvic masses at the time of referral. In these cases, evaluation by a gynecologic oncologist is important for determining whether the previous surgery was adequate or an additional surgery is needed. Prior imaging studies and operative notes should be reviewed to determine

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additional workup needed and to inform treatment approach. Additional imaging may be needed to screen for distant disease and evaluate for residual disease not removed during the previous surgery. Imaging options include chest/abdominal/pelvic CT or MRI, PET/CT, and/or US. All imaging should be performed with contrast unless contraindicated. Pathology review of tissue from the previous surgery is important for confirming diagnosis and cancer type. CBC and chemistry profile with LFTs should be obtained, and CA-125 or other tumor markers should be measured if indicated to corroborate likely diagnosis and to serve as baseline for future follow-up. See section above on Laboratory Studies and Biomarker Tests. If not previously done, workup should include obtaining a family history, genetic risk evaluation, and germline and somatic testing, if not previously done. Recommendations regarding genetic testing can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal (available at www.NCCN.org). As described in the Molecular Testing section below, germline and/or somatic BRCA1/2 testing informs selection of maintenance therapy (after first-line platinum-based chemotherapy). Molecular analysis of tumor tissue from the previous surgery may be warranted. In the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy (category 2B).

Diagnosis, Pathology, and Staging

Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen, which may occur preoperatively, intraoperatively, or postoperatively. If possible, fine-needle aspiration (FNA) should be avoided for diagnosis of ovarian cancer in patients with presumed early-stage disease to prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity; however, FNA may be necessary in patients who are not candidates for primary debulking, such as those

with bulky disease, older patients, or patients in poor health.$^{542,543}$ Both primary peritoneal and fallopian tube cancers are usually diagnosed postoperatively (if there is no major involvement of the ovary) or preoperatively (if there is a biopsy and the patient has already had a bilateral oophorectomy). Patients who have equivocal pathologic findings or who are referred to NCCN Member Institutions after having a previous diagnosis of ovarian cancer should have their pathology reviewed by pathologists at NCCN Member Institutions.

Primary peritoneal and fallopian tube cancers are treated in the same manner as epithelial ovarian cancer, so distinguishing these three possible primary sites is less crucial than ruling out other cancers that commonly involve the adnexa, such as uterine, cervical, gastro intestinal (small and large bowel, pancreatic) cancers or lymphoma;$^{544,545}$ benign ovarian and non-ovarian conditions also need to be ruled out (eg, serous cystadenoma).$^{546}$ In addition, metastases to the ovaries need to be ruled out (see Mucinous Carcinomas).

The CAP protocol is a useful tool for pathology reports, and has been updated for consistency with the AJCC Cancer Staging Manual, 8th edition.$^{230,547}$ Based on the CAP protocol (Version 1.1.1.0; Feb 2020)$^{230}$ and panel consensus, the NCCN Guidelines recommend that pathologic assessment should include the following elements: all tumor site(s) (eg, ovary, fallopian tube, pelvic/abdominal peritoneum, uterus, cervix, omentum); all tumor size(s); for ovarian/fallopian tumors, surface involvement (present/absent/cannot determine), specimen integrity (capsule/serosa intact/fractured/fragmented); histologic type and grade; extension and/or implants (if sampled/identified); cytology results from peritoneal/ascitic fluid/washings and pleural fluid; the number and location of lymph nodes examined, and size of largest lymph node metastatic deposits; and evidence of STIC, endometriosis [particularly if in continuity with endometrioid or clear cell carcinoma], and endosalpingiosis.

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The complete histologic classification from the WHO is included in the NCCN Guidelines.$^{1}$ The WHO pathology manual is also a useful resource.$^{1,548}$

Histologic Subtypes

Epithelial ovarian cancer has four main subtypes, including serous, endometrioid, mucinous, and clear cell; most patients (about 70%) have serous cancers.$^{3,549-552}$ Molecular characterization of clear cell, mucinous, or low-grade (grade 1) serous tumors suggests that mutations in these cancer types are different from those in higher grade tumors.$^{553-555}$ Ovarian cancer can be divided into Types 1 and 2 based on these molecular alterations. Data suggest that serous tumors can be categorized as either low grade (grade 1) or high grade (grade 2 or 3).$^{549,556-561}$

Ovarian borderline epithelial tumors, also called LMP tumors or atypical proliferative tumors, are another type of primary epithelial lesions. The terms for borderline epithelial tumors have changed over the years, and recent CAP protocols do not use "LMP."$^{230,562}$ Borderline tumors have cytologic characteristics suggesting malignancy, and may grossly resemble an invasive cancer, but microscopic evaluation shows no evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the diagnosis of borderline epithelial lesions) can be identified microscopically by the pathologist. The characteristic pathologic hallmark of typical epithelial ovarian cancer is the identification of peritoneal implants, which microscopically and/or macroscopically invade the peritoneum. Borderline epithelial tumors are typically serous or mucinous; but other histologic subtypes can also occur (see WHO Histologic Classification in the algorithm).$^{1}$,$^{230}$

Carcinosarcomas arising in the ovary, fallopian tubes, or peritoneum, also called carcinomas of Müllerian origin or MMMTs, are biphasic, with both malignant epithelial and sarcomatous elements. Clonality studies suggest

that this is a metaplastic carcinoma, with both components arising from an epithelial precursor, and the sarcomatous component resulting from transdifferentiation (epithelial-mesenchymal transition).$^{563-570}$

Germ cell tumors are a non-epithelial subtype, and include dysgerminomas, immature teratomas, embryonal tumors, and endodermal sinus (yolk sac) tumors.$^{1}$ Malignant sex cord-stromal tumors, another non-epithelial subtype, are rare and include granulosa cell tumors (most common) and Sertoli-Leydig cell tumors.$^{1}$

In some cases, it can be difficult to distinguish between cancer subtypes. For example, high-grade endometrioid tumors can be difficult to distinguish from high-grade serous tumors.$^{549}$ Some endometrioid tumors look similar to clear cell tumors, while others may resemble sex cord-stromal tumors.$^{549}$ Immunohistochemistry (IHC) with certain markers may help with differential diagnosis. Whereas most (80%–90%) of serous carcinomas are positive for WT1, endometrioid and clear cell carcinomas are usually negative.$^{562,571,572}$ Endometrioid adenocarcinomas are usually positive for cytokeratin 7 (CK7), PAX8, CA-125, and estrogen receptors. The presence of endometriosis can sometimes help to distinguish subtypes, as clear cell carcinomas and endometrioid tumors can be associated with endometriosis, whereas other subtypes are less likely to be.$^{562}$ Endometrioid carcinomas are also very similar in appearance to sex cord-stromal tumors.$^{562}$ Most clear cell carcinomas express Napsin A, a marker that is specific to this subtype.$^{573}$ It is difficult to distinguish based on histology between primary mucinous ovarian carcinomas and GI metastases.$^{574-576}$ PAX8 immunostaining is typical of primary tumors,$^{572}$ although absence of PAX8 does not rule out ovary as the primary site. SATB2 is consistent with colonic origin.$^{577}$ Metastatic colorectal adenocarcinomas also usually are positive for CK20 and CEA.

Stage at diagnosis, prognosis, the typical course of disease, and responsiveness to specific therapies vary across cancer

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subtypes.$^{6,549,551,552,578,579}$ In the NCCN Guidelines, most of the recommendations are based on data from patients with the most common subtypes—high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers (LCOC), which in the Guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors.

A pathology and staging cancer protocol is available from the College of American Pathologists (CAP) for examination of specimens from patients with primary tumors of the ovary, fallopian tube, or peritoneum, including pTNM requirements from the AJCC Staging Manual 8th edition and FIGO Staging.$^{230}$

Staging

The NCCN Guidelines for Ovarian Cancer reflect the importance of stage and grade of disease on prognosis and treatment recommendations. Ovarian cancer is classified primarily as stages I to IV using the FIGO (International Federation of Gynecology and Obstetrics) staging system, which was approved by the AJCC and incorporated into the AJCC Cancer Staging Manual 8th Edition staging system, which was published in late 2016 and was effective for all cancer cases recorded on or after January 1, 2018 (see Staging section of the algorithm).547,557 More than half of patients present with distant disease, although certain LCOC are more likely to be diagnosed at earlier stages 7,9,580 Serous ovarian cancer is now often referred to as either low grade (most grade 1 serous tumors) or high grade (most grade 2 or 3 serous tumors).230,549,556,557,559,560 Pathologists may use histologic grades 1, 2, or 3 for endometrioid carcinomas, mucinous carcinomas, and stage IC tumors.230 Primary peritoneal adenocarcinoma, fallopian tube carcinoma, and LCOC are also staged using the FIGO/AJCC (8th edition) ovarian cancer staging system.547,556,557 Except for select individuals with stage I, grade 1 tumors (in whom survival is greater than 95% after comprehensive laparotomy), patients in all other stages of ovarian cancer are likely to require treatment after surgical staging. All patients with ovarian cancer, particularly those requiring additional treatment, should be encouraged to participate in a relevant clinical trial.

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Molecular Testing

Upon pathologic confirmation of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, patients should be referred for a genetic risk evaluation and germline and somatic testing (if not previously done). This recommendation for germline and somatic testing is intentionally broad so that the genetic counselor and treating oncologist have the latitude to order whichever molecular tests they consider necessary based on evaluation of the individual patient and their cancer family history. Since germline and/or somatic BRCA1/2 testing informs selection of maintenance therapy for those with stage II-IV disease who are in complete response (CR) or partial response (PR) after first-line platinum-based chemotherapy, NCCN Panel members agree that it is important to establish BRCA1/2 mutation status for patients who may be eligible for maintenance therapy following completion of platinum-based first-line chemotherapy. Homologous recombination status (e.g., homologous recombination deficient [HRD] vs. homologous recombination proficient [HRP]) may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy for those without a BRCA1/2 mutation. For additional recommendations on workup, staging and primary treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, please refer to OV-1 in the guidelines on http://www.NCCN.org.

With the availability of next-generation sequencing technology, the panel discussed whether comprehensive tumor molecular analysis should be recommended for all patients. Some panel members stated that comprehensive tumor testing may not be necessary for certain patients in the upfront setting, specifically those with a germline mutation in BRCA1/2 or other homologous recombination/DNA repair pathway genes. However, some patients (such as those who lack a BRCA1/2 mutation or experience disease recurrence) may benefit from a more thorough tumor molecular analysis to inform additional targeted therapy options. The panel agreed

that tumor testing may be beneficial at multiple points throughout the evolution of the disease.

Therefore, the current guidelines recommend tumor molecular analysis both in the upfront setting and upon recurrence (OV-B 1 of 3). The goal of tumor testing in the upfront setting is to optimize identification of molecular alterations that can inform the use of interventions with demonstrated benefit in this setting, such as PARP inhibitors. Molecular alterations that should be probed for in this setting include BRCA1/2 status, loss of heterozygosity, or homologous recombination status, in the absence of a germline BRCA mutation.

Other tumor tissue molecular markers may inform selection of treatment for persistent or recurrent disease but testing for these is not needed until the disease has proven to be refractory or at time of relapse. The panel recommends that tumor molecular analysis in the recurrence setting should include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit. These include (but are not limited to): BRCA1/2, HR status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, and NTRK, if prior testing did not include these markers. The panel emphasizes that more comprehensive tumor analysis may be particularly important for less common histologies with limited approved treatment options. Prior to selection of systemic therapy for refractory or recurrent disease, validated tumor molecular testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-approved facility using the most recent available tumor tissue.

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Primary Treatment

Primary treatment for presumed ovarian, fallopian tube, or primary peritoneal cancer usually consists of appropriate surgical staging and debulking surgery, followed in most (but not all) patients by systemic chemotherapy.$^{13,142,218,581,582}$ However, for some patients with early-stage disease, surgery alone (followed by observation) may be sufficient as primary treatment. In addition, for certain histologic subtypes, adjuvant therapy with hormonal agents are options that may be considered. NACT with interval debulking surgery (IDS) should be considered in patients with advanced-stage ovarian cancer who are not good candidates for upfront primary debulking surgery (PDS) due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.$^{48,583}$ Emerging data support an increasing role of PARP inhibitors in the management of ovarian cancer.$^{584}$ In the primary treatment setting, PARP inhibitors have been incorporated as NCCN-recommended maintenance therapy options for select patients after first-line chemotherapy. Each of these primary treatment options, including maintenance therapy options after first-line chemotherapy, are described in more detail below. As described above, for all patients with suspected or confirmed ovarian cancer a gynecologic oncologist should be involved in assessing whether a patient is a suitable surgical candidate and/or an appropriate candidate for neoadjuvant therapy, and consideration of laparoscopic evaluation to determine feasibility of debulking surgery. The NCCN Guidelines recommend symptom management and best supportive care for all patients; individuals should be referred for palliative care assessment if appropriate (see the NCCN Guidelines for Palliative Care, available at www.NCCN.org).$^{161,585,586}$

Primary Surgery

Based on published improved outcomes, it is recommended that a gynecologic oncologist be the provider to determine the best surgical approach and perform the appropriate primary surgery.$^{219-221}$ An open

laparotomy is recommended for most patients, but minimally invasive techniques may be appropriate in certain circumstances (See Open Laparotomy Versus Minimally Invasive Techniques). Prior to surgery, patients with advanced disease should be counseled about port placement if intraperitoneal (IP) chemotherapy is being considered. Intraoperative pathologic evaluation with frozen sections may assist in management by providing confirmation of diagnosis and cancer type and providing information about the extent of disease. For all procedures, the surgeon should describe the following in the operative report: 1) the extent of initial disease in the pelvis, mid abdomen, and upper abdomen before debulking; 2) whether a complete or incomplete resection was achieved; and 3) if resection was incomplete, the amount and size of residual disease in the aforementioned areas after debulking.$^{587}$

For most patients presenting with suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, initial surgery should include a hysterectomy (if uterus present) and BSO with comprehensive staging and debulking as indicated.$^{13,588,589}$ This is the recommended approach for stage IA-IV if optimal cytoreduction appears feasible, the patient is a surgical candidate, and fertility is not a concern. It is described in greater detail below in the section entitled Debulking Surgery for Newly Diagnosed Disease.

For patients with early-stage disease who wish to preserve fertility, less extensive surgery may be an option, as described in the section entitled Fertility-Sparing Options for Stage I Disease.

NACT with IDS should be considered for patients with advanced-stage ovarian cancer who are not good candidates for PDS due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.$^{480,583}$ The anticipated benefit from NACT therapy is to allow for medical improvement of the patient and/or clinical response that would increase the likelihood of optimal

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cytoreduction at IDS. Patients treated with NACT and IDS should also receive postoperative adjuvant chemotherapy. See sections entitled Neoadjuvant Chemotherapy and Interval Debuking Surgery. As described in the section entitled Laparoscopic Evaluation Prior to Resection, for certain patients with bulky disease, a minimally invasive procedure may be appropriate for obtaining biopsy material to confirm diagnosis and/or for molecular testing, and for determining whether optimal cytoreduction is possible.

Open Laparotomy Versus Minimally Invasive Techniques

In most cases where surgery is recommended as part of primary treatment for suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, it should be performed by open laparotomy including a vertical midline abdominal incision. The surgical guidelines emphasize that an open laparotomy should be used for most patients undergoing surgical staging, primary debulking, interval debulking, or secondary cytoreduction.

Improvement of minimally invasive methods and selection of appropriate patients are the topics of much study and debate.$^{590-620}$ Minimally invasive techniques are commonly used for early-stage disease (or presumed early-stage disease), and some studies have shown no difference in surgical outcomes, recurrence rates, or survival for those who received minimally invasive versus open surgical staging.$^{591,593-595,598-600,604,611-614,621-625}$

$^{625}$ If signs of lymph node metastasis or localized carcinomatosis are found, lymphadenectomy and complete pelvic peritonectomy may be feasible using minimally invasive techniques.$^{608}$ The NCCN Guidelines indicate that in early-stage disease, minimally invasive techniques to achieve the surgical goals may be considered in selected patients if performed by an experienced gynecologic oncologist.$^{315,588,601,626,627}$

Studies in patients undergoing PDS for advanced disease have shown that debulking and surgical staging is technically feasible using minimally invasive techniques, and hysterectomy and unilateral salpingo-

oophorectomy (USO) or BSO can be achieved using a minimally invasive approach.$^{597,602}$ Several studies have reported results for patients who received IDS via minimally invasive techniques, following NACT.$^{603,606,607,609,619}$ These studies have shown that for patients undergoing IDS, minimally invasive approaches are safe, technically feasible, and can achieve optimal cytoreduction; cancer-specific survival may be worse (than with laparotomy) if patients are not carefully selected; and patients with extensive disease will likely need to be converted to open laparotomy.$^{603,606,607,609,619}$ The NCCN Guidelines recommend that in select patients (who have undergone NACT), minimally invasive procedures may be used for IDS, provided that optimal debulking can be achieved. If the patient cannot be optimally debulked using minimally invasive techniques, either in the PDS or IDS setting, then they should be converted to an open procedure.

Laparoscopic Evaluation Prior To Resection

In select patients with advanced-stage disease, minimally invasive procedures (assessment laparoscopy) may be used to assess whether optimal cytoreduction is likely to be achieved by PDS, in order to determine whether NACT may be a better initial treatment option.$^{628-639}$ A randomized trial assessed whether laparoscopy would be useful to predict the ability to achieve optimal cytoreduction (<1 cm residual disease).

Optimal cytoreduction was achieved in 90% (92/102) of patients randomized to the assessment laparoscopy arm compared to 61% (60/99) of patients who were randomized to the laparotomy without assessment laparoscopy arm (relative risk [RR], 0.25; 95% CI, 0.13-0.47; P < .001).$^{634}$ Assessment laparoscopy to evaluate extent of disease and feasibility of resection was used frequently in the large prospective trials validating NACT and IDS and was required in one of these trials (SCORPION).$^{481-}$

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Ovarian Cancer

Fertility-Sparing Options for Stage I Disease

Fertility preservation is an evolving field and area of active research, with many approaches being explored, and many patient- and case-specific factors to consider, especially for those with malignancies.$^{641-643}$ Patients who wish to retain fertility options should be referred to a reproductive endocrinologist for preoperative evaluation and consultation. Large retrospective studies and meta-analyses have found that for stage I epithelial ovarian cancer, fertility-sparing surgery did not appear to compromise disease-free survival (DFS) or overall survival (OS) compared with radical surgery.$^{644-653}$ Although clear cell histology is associated with increased risk of poor outcomes,$^{651}$ some studies have shown that even among patients with stage I clear cell, fertility-sparing surgery does not increase risk of relapse or shorten survival compared with radical surgery.$^{645,646,649,650,653}$ Large retrospective studies among patients with stage I borderline ovarian tumors have found that recurrence rate and survival is similar for those treated with fertility-sparing versus radical surgery.$^{654-657}$ In retrospective studies, including multivariate analyses, fertility-sparing surgery does not appear to be associated with poorer outcomes (DFS, progression-free survival [PFS], OS) compared with more extensive surgery in patients with stage I germ cell tumors and sex cordstromal tumors.$^{658-673}$ Fertility-sparing surgery may be considered for patients who wish to preserve fertility and have apparent early-stage disease and/or low-risk tumors, such as early-stage invasive epithelial tumors, LMP lesions, malignant germ cell tumors, or malignant sex cordstromal tumors. Even if the contralateral ovary cannot be spared, uterine preservation can be considered as it allows for potential future assisted reproductive approaches. A USO (preserving the uterus and contralateral ovary/falopian tube) and comprehensive surgical staging may be adequate for select patients who wish to preserve fertility and appear to have stage IA unilateral tumors.$^{674-679}$ For those with bilateral stage IB tumors who wish to maintain fertility, a BSO (preserving the uterus) and comprehensive surgical staging can be considered. In patients undergoing

USO or BSO, comprehensive surgical staging should still be performed in most patients to rule out occult higher-stage disease, because data show that approximately 30% of patients (with presumed early-stage disease) are upstaged after undergoing complete staging surgery.$^{595,599,600,680-684}$ Comprehensive surgical staging may be omitted in pediatric/adolescent patients with clinically apparent early-stage malignant germ cell tumors based on the pediatric surgical literature suggesting that incomplete staging does not result in poorer outcomes (OS).$^{685}$ For adults with apparent stage I malignant ovarian germ cell tumors, comprehensive staging is recommended based on results from retrospective studies suggesting that incomplete surgical staging may be associated with increased risk of recurrence;$^{686,687}$ although others found no relationship between incomplete staging and DFS.$^{688}$

Debulking Surgery for Newly Diagnosed Disease

Debulking surgery is widely accepted as an important component of initial treatment for patients with clinical stage II, III, or IV disease, and multiple retrospective studies have contributed to the understanding of the extent of debulking needed to achieve maximal cytoreduction.142,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676,680,689-691.242,218,221,676

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For patients with newly diagnosed epithelial ovarian cancer apparently confined to an ovary or to the pelvis, the goal of surgery is to achieve complete cytoreduction of all pelvic disease and to evaluate for occult disease in the upper abdomen or retroperitoneum. For patients with newly diagnosed invasive epithelial ovarian cancer involving the pelvis and upper abdomen, the goal is to achieve optimal cytoreduction of all abdominal, pelvic, and retroperitoneal disease.

On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations. For obvious disease beyond the ovaries, cytologic assessment of ascites and/or lavage specimens will not alter stage or management. For patients with disease apparently confined to an ovary or to the pelvis, all peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied. In the absence of any suspicious areas, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm.

Hysterectomy and BSO should be performed. Although hysterectomy is recommended for most patients, USO or BSO with uterine preservation may be considered for selected patients with apparent stage I/IB disease desiring to preserve fertility (See Fertility-Sparing Options for Stage I Disease). Every effort should be made to keep an encapsulated ovarian mass intact during removal.$^{543,598}$ For young patients who will abruptly enter menopause after surgery, various supportive care measures may be used to help decrease hot flashes and other symptoms, and potentially reduce the risk of other systemic comorbidities that are more likely with surgical menopause.$^{699-702}$ HRT has not been shown to worsen survival in premenopausal patients with gynecologic cancers, but limited perspective data exist.$^{703,704}$

For patients with disease apparently confined to an ovary or to the pelvis (presumed stage I/II), omentectomy should be performed to rule out higher-stage disease. For patients with disease involving the pelvis and upper abdomen (stage III/IV), all involved omentum should be removed.

The use of systematic lymphadenectomy is an area of controversy. For patients with presumed early stage, a randomized trial showed that systematic aortic and pelvic lymphadenectomy improved detection of metastatic nodes compared with node sampling (positive nodes found in 9 vs. 22%; P = .007), but was not associated with improved PFS or OS.$^{705}$ Operating time and the proportion of patients requiring blood transfusions was significantly higher for those who underwent systematic lymphadenectomy.$^{705}$ However, meta-analyses that included retrospective or observational studies have reported that systematic lymphadenectomy improves OS in patients with early-stage disease, even though it does not improve PFS.$^{706,707}$ Similar to this randomized controlled trial, other prospective studies using systematic lymphadenectomy have found 3% to 14% of patients had positive lymph nodes.$^{708-712}$

For patients with advanced ovarian cancer, some early prospective studies suggested that systematic lymphadenectomy improved survival.$^{713,714}$ An early international randomized trial in patients with stage IIIB-IV (optimally debulked) epithelial ovarian cancer found that systematic lymphadenectomy improved PFS compared with resection of bulky nodes only, although OS was not improved, operating times were longer, and more patients required blood transfusions.$^{715}$ A randomized study of patients with stage IA-IV disease undergoing second look surgery found that although systematic lymphadenectomy increased detection of nodal metastases compared with resection of bulky nodes only (positive nodes found in 24% vs. 13%; P = .02), this did not translate into improved PFS or OS in the whole population or in subpopulations based on stage or extent of resection.$^{716}$ As in other studies, systematic lymphadenectomy was

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associated with longer operating times, more blood loss and transfusions, and longer hospital stays.$^{716}$ More recently, a large randomized trial (LION, NCT00712218) found that in patients with stage IIB-IV ovarian cancer who had macroscopically complete resection and normal nodes both before and during surgery, lymphadenectomy did not improve PFS or OS, and was associated with increased rates of serious postoperative complications and mortality within 60 days after surgery.$^{717}$ However, meta-analyses that included data from retrospective and observational studies have found that systematic lymphadenectomy improves OS in patients with advanced disease, even though PFS is not improved.$^{706,707,718-720}$

Pelvic and para-aortic lymph node dissection is recommended for patients with disease confined to affected ovaries or to the pelvis, and for those with more extensive disease who have tumor nodules outside the pelvis that are 2 cm or less (presumed stage IIIB). Para-aortic lymph node dissection should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels. The preferred method of dissecting pelvic lymph nodes is removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve.$^{541}$

For those with more extensive disease outside of the pelvis (nodules >2 cm), suspicious and/or enlarged nodes should be resected, if possible.$^{715}$,$^{721}$ Systematic lymph node dissection and resection of clinically negative nodes is not required for these patients because results will not change staging and the procedure does not appear to impact OS, based on results from randomized trials (described above).$^{715}$⁻$^{717}$

Some surgeons classify debulking based on the number of procedures. Procedures that may be considered for optimal surgical cytoreduction (in all stages) include: bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.$^{690,695,722}$

Extensive resection of upper abdominal metastases is recommended as part of debulking for patients who can tolerate this surgery, as it is associated with improved PFS and OS.$^{690,695}$

Select patients with low-volume residual disease after surgical cytoreduction for stage II or III invasive epithelial ovarian or peritoneal cancer are potential candidates for IP therapy.$^{723,724}$ In these patients, consideration should be given to placement of an IP catheter with initial surgery.$^{588}$

Surgical Considerations for Mucinous Tumors

Since primary invasive mucinous tumors of the ovary are uncommon, it is important to establish the primary site in patients with these tumors. Thus, the upper and lower GI tract should be carefully evaluated to rule out an occult GI primary with ovarian metastases, and an appendectomy need only be performed in patients with a suspected or confirmed mucinous ovarian neoplasm if it appears to be abnormal.$^{725-727}$ A normal appendix does not require surgical resection in this setting.

> Surgical Considerations for Ovarian Borderline Epithelial (LMP) Tumors Although data show upstaging with lymphadenectomy, other data show that lymphadenectomy does not affect OS.$^{723}$,$^{724}$ However, omentectomy and multiple biopsies of peritoneum (the most common sites of peritoneal implants) may upstage patients and may affect prognosis,$^{734}$,$^{736}$,$^{741}$ although some retrospective studies did not find association with prognosis.$^{729}$,$^{742}$,$^{744}$

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Ancillary Palliative Surgical Procedures

Patients presenting with symptoms may benefit from ancillary palliative procedures performed during primary or secondary cytoreductive surgery. Decisions on the use of ancillary procedures should be made in conjunction with a gynecologic oncology surgeon or a practitioner familiar with ovarian cancer patterns of recurrence. Palliative surgical procedures that may be appropriate in select patients include paracentesis or insertion of an indwelling peritoneal catheter, thoracentesis, pleurodesis, video-assisted thoracoscopy, or insertion of a pleural catheter, nephrostomy, or use of ureteral stents, gastrostomy tube, intestinal stents, or surgical relief of intestinal obstruction.

Analysis of Surgical Specimens

As described in the section entitled Diagnosis, Pathology, and Staging, surgical specimens should undergo pathology assessment to determine/confirm diagnosis, determine histologic subtype, and determine stage. Molecular testing is also appropriate for most patients; see Molecular Testing section above for detailed recommendations.

Primary Treatment for Patients Referred with Diagnoses by Previous Surgery

For patients referred with newly diagnosed ovarian cancer after a recent surgical procedure, primary treatment depends on the findings noted during the workup and evaluation performed by a gynecologic oncologist, including the type of cancer, apparent stage, and the extent of residual disease. For those with an epithelial cancer and no evidence of residual disease on workup, further surgical staging is not needed if adjuvant chemotherapy is planned. For select subtypes, observation is an alternative to adjuvant chemotherapy in patients with stage IA/IB (Table 2). For patients with these subtypes and presumed stage IA/IB (and no evidence of residual disease), surgical staging can be considered if the patient would be a candidate for observation or reduced number of cycles

of adjuvant chemotherapy. In these cases, observation after complete surgical staging is an option as long as the results confirm stage IA/IB disease. If surgical staging indicates higher-stage disease, however, adjuvant chemotherapy is usually recommended, depending on the specific cancer type. In some cases with presumed stage IA-IC and no signs of residual disease detected by workup, patients may opt for surgical staging to confirm whether they will be eligible for maintenance therapy following adjuvant chemotherapy. As discussed below, bevacizumab and PARP inhibitor maintenance options are only recommended for patients with stage II-IV disease, so those with presumed stage IA-IC disease may be particularly interested in surgical staging to determine whether they should be upstaged and thus eligible and/or needing maintenance therapy.

For patients who have an epithelial cancer and evidence of residual disease on workup, tumor cytoreductive surgery is recommended if the residual disease appears resectable. Following cytoreductive surgery, adjuvant treatment recommendations depend on cancer type and stage. If the residual disease appears unresectable, patients should be treated with NACT and IDS, and postoperative adjuvant chemotherapy could be considered (see sections on Neoadjuvant Chemotherapy and Interval Debulking Surgery).

Management After Primary Surgery

In the NCCN Guidelines for Ovarian Cancer, adjuvant therapy is defined as drugs or other forms of supplemental treatment following cancer surgery intended to decrease the risk of disease recurrence or to primarily treat residual disease, whether gross or microscopic, following surgical cytoreduction. Most patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer should receive adjuvant systemic chemotherapy after primary surgery. Postoperative observation is an option for select patients with stage I disease, depending on cancer histologic type and

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substage, as shown in Table 2. Observation is considered an option in these select groups of stage I patients either because survival is greater than 90% with surgical treatment alone, or because for low-risk disease in certain cancer types it has not been demonstrated that adjuvant chemotherapy provides clear clinical benefit compared with observation alone for those who have had complete surgical staging.$^{745-751}$ Furthermore, postoperative observation should generally only be considered for patients who have had resection of all disease and complete surgical staging to rule out the possibility of clinically occult disease that would result in upstaging. For some of the less common epithelial cancer types (eg, mucinous, grade 1 endometrioid, low-grade serous), the benefit of adjuvant systemic therapy has not been demonstrated and observation is an option (Table 2). If analysis of a biopsy or surgical specimen shows a non-epithelial cancer type, such as sex cord-stromal or germ cell tumors, a patient should be treated according to separate pathways specific for non-epithelial cancers (see Less Common Ovarian Cancers: Malignant Sex Cord-Stromal Tumors and Malignant Germ Cell Tumors in the algorithm). See sections below on these less common cancer types.

A large variety of regimens and approaches have been tested in prospective randomized trials as postoperative therapy for patients with newly diagnosed ovarian cancer. Most of these regimens have included intravenous (IV) chemotherapy, but IP administration of chemotherapy has also been tested, as have targeted agents and drugs from other classes.

Recent trials have shown that maintenance therapy after postoperative platinum-based chemotherapy can have a positive impact on PFS in patients with advanced disease, so integration of maintenance therapy as part of postoperative management is increasing in prevalence and importance.$^{752-755}$ Selection of immediate postoperative treatment should be informed by eligibility criteria for maintenance therapy. This is discussed in greater detail in the section entitled Options After First-Line Chemotherapy.

Based on results of phase III randomized trials, the NCCN Guidelines include several options for postoperative treatment (within 6 weeks) in patients with advanced epithelial cancers: platinum-based IV chemotherapy, platinum-based IV/IP chemotherapy, and platinum-based IP chemotherapy plus bevacizumab, as outlined in Table 3. Specific options and supporting data for each of these categories of treatment are described in greater detail in the sections below. For stage I disease, data are more limited, and while the NCCN Guidelines include some platinum-based IV chemotherapy options, IP/IV chemotherapy and use of bevacizumab are not recommended approaches for stage I disease (Table 2). Specific options for stage I disease are also discussed in a subsequent section. For certain rarer cancer types, there are additional recommended adjuvant treatment options, including additional chemotherapy options, chemotherapy/bevacizumab regimens (stage II–IV only), and hormonal therapies (Table 2 and Table 3). More information on these options can be found in subsequent sections for specific LCOCs.

|Cancer Type|Pathologic Staginga|Recommended Options (category 2A unless otherwise noted)||| |---|---|---|---|---| |Cancer Type|Pathologic Staginga|Observation|Standard IV Platinum-Based $Chemotherapy^{b}$|Other Adjuvant Systemic Therapy| |High-grade serous carcinoma|Stage IA/B/C|--|Yes|--| |Grade 2 endometrioid|Stage IA/IB|Yes|Yes|--| |Grade 3 endometrioid|Stage IA/B/C|--|Yes|--|

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|Carcinosarcoma|Stage IA/B/C|--|Yes|Carboplatin/ifosfamide Cisplatin/ifosfamide Paclitaxel/ifosfamide (category 2B)| |---|---|---|---|---| |Clear cell carcinoma|Stage IA|Yes|Yes|--| |Clear cell carcinoma|Stage IB/IC|--|Yes|--| |Mucinous carcinoma|Stage IA/IB|Yes|--|--| |Mucinous carcinoma|Stage IC|Yes|Yes|5-FU/leucovorin/oxaliplatin Capecitabine/oxaliplatin| |Grade 1 endometrioid|Stage IA/IB|Yes|--|--| |Grade 1 endometrioid|Stage IC|Yes (category 2B)|Yes|Hormone therapy (category 2B)$^{c}$| |Low-grade serous carcinoma|Stage IA/IB|Yes|--|--| |Low-grade serous carcinoma|Stage IC|Yes (category 2B)|Yes|Hormone therapy (category 2B)$^{c}$|

--, not recommended; FU, fluorouracil; IV, intravenous

ª Stage confirmed by a complete surgical staging procedure and pathologic analysis.

b Regimen options for all cancer types include Paclitaxel 175/carboplatin, Docetaxel/carboplatin, Carboplatin/liposomal doxorubicin, as shown in Table 8. Not including options for those who are over the age of 70 years, have poor performance score, or have comorbidities.

c Hormone therapy options include aromatase inhibitors [anastrozole, lerozole, exemestane], leuprolide acetate, or tamoxifen.

|Cancer Type|Recommended Options (category 2A unless otherwise noted)||| |---|---|---|---| |Cancer Type|Standard IV Platinum-based Chemotherapy ± Bevacizumab|Other|Other| |High-grade serous|Yes|IP/IV paclitaxel/cisplatin (optimally debulked stage III only)|| |Grade 2/3 endometrioid|Yes|IP/IV paclitaxel/cisplatin (optimally debulked stage III only)|| |Carcinosarcoma|Yes|IP/IV paclitaxel/cisplatin (optimally debulked stage III only) Carboplatin/ifosfamide Cisplatin/ifosfamide Paclitaxel/ifosfamide (category 2B)|| |Clear cell carcinoma|Yes|IP/IV paclitaxel/cisplatin (optimally debulked stage III only)|| |Mucinous carcinoma|Yes|5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab) Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab)|| |Low-grade serous|Yes|Hormone therapy (aromatase inhibitors [anastrozole, letrozole, exemestane], leuprolide acetate, tamoxifen) (category 2B)|| |Grade 1 endometrioid|Yes|Hormone therapy (aromatase inhibitors [anastrozole, letrozole, exemestane], leuprolide acetate, tamoxifen) (category 2B)||

FU, fluorouracil; IP, intraperitoneal; IV, intravenous.

ª Not including options for those who are over the age of 70 years, have poor performance score, or have comorbidities.

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ᵇ Paclitaxel 175/carboplatin, Paclitaxel weekly/carboplatin weekly, Docetaxel/carboplatin, Carboplatin/liposomal doxorubicin, Paclitaxel weekly/carboplatin every 3 weeks (q3weeks), Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab (ICON-7 & GOG-218), as shown in Table 4 and Table 11.

For all patients, the goals of postoperative therapy and considerations for selection and management during therapy should be discussed prior to the initiation of therapy. As for all aspects of their diagnosis and treatment of ovarian, fallopian tube, or peritoneal cancer, patients should be encouraged to participate in clinical trials. Chemosensitivity/resistance and/or other biomarker assays have been proposed for informing decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available, but the current level of evidence is not sufficient to supplant standard-of-care chemotherapy (category 3). Prior to recommending chemotherapy, requirements for adequate organ function and performance status should be met.

During drug-based therapy, patients should be observed closely and treated for any complications. Appropriate blood chemistry tests should be monitored. Appropriate dose reductions and modifications of chemotherapy should be performed depending on toxicities experienced and goals of therapy. Consider scalp cooling to reduce incidence of alopecia for patients receiving chemotherapy with high rates of alopecia.$^{756}$

Options for IV Chemotherapy

Comparison of IV chemotherapy regimens for postoperative treatment of newly diagnosed ovarian cancer has been the subject of many prospective randomized trials. Most of these trials have failed to show significant differences between regimens in efficacy outcomes (eg, PFS, OS), but many have shown differences in toxicity profile, ability to complete the planned therapy, and QOL. For this reason, the NCCN Guidelines include a number of recommended options for postoperative IV chemotherapy in patients with newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer. The NCCN-recommended options for platinum-based IV chemotherapy to treat stage II–IV epithelial disease are summarized in Table 4, along with the list of trials that tested these regimens (last column). Table 5, Table 6, and Table 7 summarize the results of randomized trials that tested these recommended regimens. The most commonly used regimen, paclitaxel 175/carboplatin, has been considered the standard postoperative chemotherapy for ovarian cancer for many years, so there are many studies in which it has been tested (Table 5, Table 6, and Table 7). The history supporting these options is summarized below.

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|Paclitaxel weekly/ carboplatin q3weeks|Dose-dense paclitaxel, 80 mg/m² IV over 1 hour on days 1, 8, and 15 followed by carboplatin AUC 5-6° IV over 30-60 minutes on Day 1|3|6|2A|Other Recommended|$ICON8^{758,759}$ $JGOG-3016^{760-762}$ $GOG-0262^{763}$| |---|---|---|---|---|---|---| |Carboplatin/ liposomal doxorubicin|Carboplatin AUC 5 IV over 30-60 minutes + pegylated liposomal doxorubicin 30 mg/m² IV over 1 hourf|4|6|2A|Other Recommended|$MITO-2^{764}$| |Docetaxel/ carboplatin|Docetaxel 60-75 mg/m² IV over 1 hour followed by carboplatin AUC 5-6 IV over 30-60 minutes on Day 1|3|6|2A|Other Recommended|$SCOTROC1^{765}$|

AUC, area under the curve; IV, intravenous; q3weeks, every 3 weeks.

a Includes high-grade serous, grade 2/3 endometrioid, clear cell carcinoma; stage IC only for mucinous, low-grade serous, and grade 1 endometrioid.

b These options are primarily for patients aged ≤70 years, with good performance status, and without comorbidities. For patients who are >70 years, have poor performance score, or have comorbidities, see alternate treatment options discussed in the section entitled Options for Patients Who Are >70 years or Have Comorbidities or Poor Performance Score.

c Infusion times may need to be adjusted for patients with prior hypersensitivity reaction(s). See Management of Drug Reactions in the algorithm.

d NCCN Category of Evidence and Consensus.

e Note that carboplatin dosing may be revised based on changes in serum creatinine methodology (see FDA carboplatin dosing statement). The AUC of 5 to 6 for carboplatin reflects contemporary treatment.

$^{f}$ For the first cycle of pegylated liposomal doxorubicin, infuse at 1 mg/min and make sure that the patient does not have a reaction.

|Trial|Stage|$N^{c}$|First-Line Systemic $Therapy^{d}$|Efficacy^{e}|Safety/QOL^{f}||| |---|---|---|---|---|---|---|---| |Trial|Stage|$N^{c}$|Dosing per Cycle|Efficacy^{e}|Safety/QOL^{f}|Cycle Length Weeks|# Cycles| |Dutch/Danish $RCT^{766,767}$|IIB-IV|208|Paclitaxel 175 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1|3|6|NS|More nausea, vomiting, peripheral neurotoxicityLess granulocytopenia and thrombocytopenia| |$GOG-158^{f},$ 768|III|792|Paclitaxel 135 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1|3|6|NS|More GI, renal, and metabolic toxicity;Less thrombocytopenia| |AGO-OVAR-3769-771|IIB-IV|798|Paclitaxel 185 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1|3|6|NS|More nausea/vomiting, appetite loss, fatigue, and neurotoxicityLess hematologic toxicityWorse overall QOL, physical functioning, role functioning, cognitive functioning| |ChiCTR-TRC-11001333772|II-IV|182|Paclitaxel 175 mg/$m^{2}$ D1 + nedaplatin 80 mg/$m^{2}$ D1|3|6|ITT: NS Stage III-IV: better PFS (P = .02); NS OS|Less grade 3-4 leukopenia|

D, day (of cycle); GI, gastrointestinal; ITT, intent-to-treat population; NS, no significant difference between arms; QOL, quality of life; RCT, randomized controlled trial.

a Each of the trials used the following regimen as comparator: Paclitaxel 175 mg/m$^{2}$ + carboplatin AUC 5-6, both D1, every 3 weeks (q3weeks) x 6 cycles.

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b Doublets not recommended in the NCCN Guidelines.

c N shows total number of patients randomized, including those in the Paclitaxel 175/carboplatin control arm.

cTest regimen compared with Paclitaxel 175/carboplatin

e Efficacy outcomes compared with Paclitaxel 175/carboplatin; NS indicates no significant difference between regimens for PFS and/or OS.

f* Toxicity or QOL compared with Paclitaxel 175/carboplatin.

|Trial|Stage|$N^{b}$|First-Line Systemic Therapy^{c}$|Efficacy^{d}|Safety/$QOL^{e}$||| |---|---|---|---|---|---|---|---| |Trial|Stage|$N^{b}$|Dosing per Cycle|Efficacy^{d}|Safety/$QOL^{e}$|Cycle Length, Weeks|# Cycles| |$ICON3^{773}$|IC-IV|653|Cyclophosphamide 500 mg/m² D1 + doxorubicin 50 mg/m² D1 + cisplatin 50 mg/m² D1|3|6|NS|More nausea/vomiting, feverLess sensory neuropathy| |HeCOG $RCT^{774}$|IIC-IV|247|Paclitaxel 175 mg/m² D1 + carboplatin AUC 7 D1 cycles 1, 3, $5^{h}$ + cisplatin at 75 mg/m² D1 cycles 2, 4, 6|3|6|NS|More severe nausea/vomiting| |AGO-OCSG $RCT^{775}$|IIB-IV|1282|Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + epirubicin 60 mg/m² D1|3|6|NS|More nausea/emesis, mucositis, infections, and grade 3-4 hematologic toxicitiesWorse QOL| |NCT00102375776|IIB-IV|1308|Paclitaxel 175 mg/m² D1 cycles 1-6 + carboplatin AUC 5 D1 cycles 1-6 + topotecan 1.25 mg/m² D1-5 cycles 7-10|3|≤10|NS|More grade 3-4 hematologic toxicities and grade 3-4 infections| |GOG-0182- $ICON5^{777,778}$|III-IV|4312|Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + gemcitabine 800 mg/m² D1|3|8i|NS|More neutropenia, thrombocytopenia, anemia, fever/infection, hepatic toxicity, peripheral neuropathy, GI toxicity| |GOG-0182- $ICON5^{777,778}$|III-IV|4312|Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + pegylated liposomal doxorubicin 30 mg/m² D1 cycles 1, 3, 5, 7|3|8i|NS|More neutropenia, thrombocytopenia, anemia, fever/infection, GI toxicity| |GOG-0182- $ICON5^{777,778}$|III-IV|4312|Paclitaxel 175 mg/m² D1 cycles 5-8 + carboplatin AUC 5 D3 cycles 1-4, AUC 6 D1 cycles 5-8 + topotecan 1.25 mg/m²/d D1-3 cycles 1-4|3|8i|NS|More anemia, hepatic toxicityLess peripheral neuropathy| |GOG-0182- $ICON5^{777,778}$|III-IV|4312|Paclitaxel 175 mg/m² D1 cycles 5-8 + carboplatin AUC 6 D8 cycles 1-4, D1 cycles 5-8 + gemcitabine 1000 mg/m²/d D1,8 cycles 1-4|3|8i|NS|More thrombocytopenia, anemia, hepatic toxicity, pulmonary toxicityLess peripheral neuropathy| |Bolis et al, $2010^{779}$|III-IV|326|Topotecan 1.0 mg/m² D1-3 + paclitaxel 175 mg/m² D3 + carboplatin AUC 5 D3|3|6|NS|More fatigue, anemia, leukopenia, neutropenia|

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|Trial|Stage|$N^{b}$|First-Line Systemic Therapy $^{c}$|Efficacy $^{d}$|Safety/$QOL^{e}$|||| |---|---|---|---|---|---|---|---|---| |Trial|Stage|$N^{b}$|Dosing per Cycle|Efficacy $^{d}$|Safety/$QOL^{e}$|Cycle Length, Weeks|# Cycles|| |du Bois et al, $2010^{780}$|I-IV|1742|Paclitaxel 175 mg/$m^{2}$ D1+ carboplatin AUC 5 D1+ gemcitabine 800 mg/$m^{2}$ D1, D8|3|6|Worse PFS (P=.0044) NS OS|• More grade 3-4 hematologic toxicity, fatigue • Worse QOL|| |OV-16/ EORTC-55012/ GEICO-0101781|IIB-IV|819|Cisplatin 50 mg/$m^{2}$ D1 cycles 1-4+ topotecan 0.75 mg/$m^{2}$ D 1-5 cycles 1-4+ paclitaxel 175 mg/$m^{2}$ D1 cycles 5-8+ carboplatin AUC 5 D1 cycles 5-8+ epirubicin 75 mg/$m^{2}$|3|8j|NS|• More hematologic toxicities, thromboembolic events, nausea, vomiting, and hospitalizations • Less neurosensory effects and allergic reactions|| |NSGO, EORTC GCG and NCIC CTG782|IIB-IV|887|Paclitaxel 175 mg/$m^{2}$ D1+ carboplatin AUC 5 D1+ epirubicin 75 mg/$m^{2}$|3|6-9|NS|• More anemia, febrile neutropenia, use of G- SCF, nausea, vomiting, mucositis • Less allergic reactions, arthralgia, myalgia • Worse QOL||

AUC, area under the curve; D, day (of cycle); NS, no significant difference between arms; QOL, quality of life.

ª Each of the trials used the following regimen as comparator: Paclitaxel 175 mg/m$^{2}$ + carboplatin AUC 5-6, both D1, every 3 weeks (q3weeks) x 6 cycles.

$^{b}$N shows total number of patients randomized, including those in the Paclitaxel 175/carboplatin

c Test regimen compared with Paclitaxel 175/carboplatin

* Efficacy outcomes compared with Paclitaxel 175/carboplatin; NS indicates no significant difference between regimens for PFS and/or OS.

e Toxicity or QOL compared with Paclitaxel 175/carboplatin.

† Carboplatin dosing in the control arm of GOG-158 was AUC 7.5 (instead of AUC 5-6).

$^{9}$ Paclitaxel dosing in the control arm of AGO-OVAR-3 was 185 mg/m$^{2}$ (instead of 175 mg/m$^{2}$).

$^{e}$ Carboplatin dosing in the control arm of HeCOG was AUC 7 (instead of AUC 5-6).

i In GOG-0182-ICON5, 8 cycles was also used for the carboplatin/paclitaxel control arm.

* In OV-16, 8 cycles was also used for the paclitaxel/carboplatin control arm.

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|Trial|Stage|$N^{b}$|First-Line Systemic $Therapy^{c}$|Efficacy^{d}$ HR [95% CI]|Safety/QOL^{e}$||| |---|---|---|---|---|---|---|---| |Trial|Stage|$N^{b}$|Dosing per Cycle|Efficacy^{d}$ HR [95% CI]|Safety/QOL^{e}$|Cycle Length, Weeks|# Cycles| |$ICON3^{773}$|IC-IV|943|Carboplatin AUC ≥$5^{f}$ D1|3|6|NS|• Less alopecia grade 3-4, fever grade 3-4, sensory neuropathy grade 2-3, motor neuropathy grade 3-4| |SCOTROC1765|IC-IV|1077|Docetaxel 75 mg/m² D1 + carboplatin AUC 5 D1|3|$6^{g}$|NS|• More GI, peripheral edema, allergic reactions, nail changes • Less neurosensory and neuromotor toxicity, arthralgia, alopecia, abdominal pain • QOL: Global NS| |MITO-2 NCT00326456764|IC-IV|820|Carboplatin AUC 5 D1 + pegylated liposomal doxorubicin 30 mg/m² D1|3|$3-6^{i}$|NS|• More anemia, thrombocytopenia, skin toxicity, stomatitis • Less neuropathy, alopecia, diarrhea • QOL: less diarrhea after 3 cycles and loss of appetite after 3 cycles| |MITO-7 NCT00660842757|IC-IV|822|Paclitaxel 60 mg/m² D1, D8, D15 + carboplatin AUC 2 D1, D8, D15|3|6|NS|• More pulmonary toxicity • Less neutropenia, febrile neutropenia, thrombocytopenia, neuropathy, hair loss, vomiting • Better QOL| |JGOG-3016 NCT00226915760,761|II-IV|637|Paclitaxel 80 mg/m² D1, 8, $15^{h}$ + carboplatin AUC 6 D1|3|6|Better PFS: 0.76 [0.62-0.91]; P=.0037 Better OS: 0.79, [0.63-0.99]; P=.039|• More grade 3-4 anemia • Global QOL NS; worse QOL on FACT-T subscale| |GOG-0262 NCT01167712763|II-IV|112|Paclitaxel 80 mg/m² D1, 8, 15 + carboplatin AUC 6 D1|3|6|Better PFS: 0.62 [0.40-0.95]; P=.03|• More anemia and sensory neuropathy • Less neutropenia • Worse QOL on FACT-O TOI| |GOG-0262 NCT01167712763|II-IV|580|Paclitaxel 80 mg/m² D1, 8, 15 + carboplatin AUC 6 D1 + bevacizumab 15 m/kg D1 cycles 2-6|3|6|NS|• More grade 3-4 AEs, including uncomplicated neutropenia, anemia • Worse Global QOL| |ICON8 NCT01654146758,759|IC-IV|1566|Paclitaxel IV 80 mg/m² D1, D8, D15 + carboplatin IV AUC 5-6 D1|3|6|NS|• More grade 3-4 AEs, including uncomplicated neutropenia, anemia • Worse Global QOL| |ICON8 NCT01654146758,759|IC-IV|1566|Paclitaxel IV 80 mg/m² D1, D8, D15 + carboplatin IV AUC 2 D1, D8, D15|3|6|NS|• More grade 3-4 AEs, including uncomplicated neutropenia, carboplatin hypersensitivity reaction • Worse Global QOL|

AE, adverse event; AUC, area under the curve; D, day (of cycle); NS, no significant difference between arms; QOL, quality of life.ª Unless otherwise noted, each of the trials listed used the following regimen as comparator: Paclitaxel 175 mg/m$^{2}$ D1 + carboplatin AUC 5-6 D1, every 3 weeks (q3weeks) x 6 cycles.

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$^{e}$ N shows total number of patients randomized, including those in the Paclitaxel 175/carboplatin control arm.

c Regimen compared with Paclitaxel 175/carboplatin

$^{e}$ Efficacy outcomes compared with Paclitaxel 175/carboplatin; NS indicates no significant difference between regimens for PFS and/or OS. Hazard ratio (HR) with 95% confidence interval (CI) and P-value are provided if statistically significant.

e Toxicity or QOL compared with paclitaxel 175/carboplatin regimen.

$^{1}$ Both arms in ICON3 used carboplatin AUC ≥5.

$^{9}$ In SCOTROC1, patients whose disease responded after 6 cycles were allowed to continue on carboplatin alone for another 3 cycles.

$^{h}$ JGOG-3016, the paclitaxel dosage in the control arm was 180 mg/m$^{2}$ (instead of 175 mg/m$^{2}$ as in the other trials).

$^{1}$ For those with good response after 3 cycles, MITO-2 allowed an additional 3 cycles.

In GOG-0262, those who opted to have bevacizumab and were undergoing NACT (3 cycles) + IDS + adjuvant chemotherapy (3 cycles), bevacizumab was administered for cycles 2, 5, and 6.

Results from multiple early trials suggested that regimens that included a platinum agent resulted in better response rates and PFS (compared with other chemotherapy options).$^{783,784}$ Subsequent trials aimed at determining which platinum-based combinations are the most effective and safe.

Selecting a Platinum Agent

Multiple randomized trials compared carboplatin versus cisplatin, either alone or in combination with other agents (examples in Table 5 and 6).$^{767-770}$.

$^{770,785-790}$ All of these trials showed equivalent efficacy, but differences in toxicity profiles and QOL. Cisplatin was associated with higher rates of neurotoxicity, GI toxicities (eg, nausea, emesis), renal toxicity, metabolic toxicities, anemia, and alopecia, while carbóplatin was associated with higher rates of thrombocytopenia and granulocytopenia.$^{767-770,785-790}$ The AGO-OVAR-3 study found that QOL was significantly better with carboplatin/paclitaxel versus cisplatin/paclitaxel, both in global QOL metrics and on various subscales.$^{769,770}$ Several randomized studies tested alternating carboplatin and cisplatin every other course, but found that efficacy was similar and toxicity somewhat worse than using carboplatin for every course.$^{774,790}$ Based on results from all these studies carboplatin is the recommended platinum agent for postoperative IV chemotherapy in patients with newly diagnosed ovarian, fallopian tube, and primary peritoneal cancers.

Selecting a Non-Platinum Agent (for Use in Combination with a Platinum Agent)

Many different chemotherapy agents have been tested in combination with platinum agents as options for IV chemotherapy in newly diagnosed ovarian cancer. Large randomized trials have compared various platinum-based doublet, triplet, and quadruplet combinations with cyclophosphamide, paclitaxel, docetaxel, topotecan, doxorubicin, epirubicin, gemcitabine, topotecan, and melphalan.764,765,773,775-777,779-782,791-797 Trials that compared platinum-based doublets with cyclophosphamide versus paclitaxel showed that paclitaxel was associated with significantly better response rate, PFS and OS.791-793 Thus, paclitaxel is preferred over cyclophosphamide for platinum-based combination therapy in the first-line setting. Based on results from randomized trials showing improved safety and QOL with carboplatin/paclitaxel versus cisplatin/paclitaxel (Table 5),767-770 carboplatin/paclitaxel became the "standard" combination therapy option for postoperative first-line IV chemotherapy in patients with ovarian, fallopian tube, or primary peritoneal cancer. Most subsequent trials used this doublet, usually paclitaxel 175 mg/m$^{2}$ plus carboplatin AUC 5-6, given on day 1 of a 21-day cycle, as the control arm (see examples in Table 5, Table 6, and Table 7). This regimen is also a recommended option in the NCCN Guidelines (Table 4).

$^{797}$ Trials that compared platinum-based doublets with cyclophosphamide versus paclitaxel showed that paclitaxel was associated with significantly better response rate, PFS and OS.$^{791-793}$ Thus, paclitaxel is preferred over cyclophosphamide for platinum-based combination therapy in the first-line setting. Based on results from randomized trials showing improved safety and QOL with carboplatin/paclitaxel versus cisplatin/paclitaxel (Table 5),$^{767-770}$ carboplatin/paclitaxel became the “standard” combination therapy option for postoperative first-line IV chemotherapy in patients with ovarian, fallopian tube, or primary peritoneal cancer. Most subsequent trials used this doublet, usually paclitaxel 175 mg/m$^{2}$ plus carboplatin AUC 5–6, given on day 1 of a 21-day cycle, as the control arm (see examples in Table 5, Table 6, and Table 7). This regimen is also a recommended option in the NCCN Guidelines (Table 4).

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Two other platinum-based doublets have shown similar efficacy to carboplatin/paclitaxel, but with different safety profiles.$^{764,765}$ The SCOTROC1 study found that docetaxel/carboplatin resulted in similar PFS, OS, and global QOL scores as paclitaxel/carboplatin, and was associated with lower rates of neurotoxicity, arthralgia, myalgia, alopecia, and abdominal pain, but higher rates of other adverse events (AEs) (GL peripheral edema, allergic reactions, and nail changes [Table 7]).$^{765}$ The MITO-2 trial found that pegylated liposomal doxorubicin/carboplatin was associated with a higher response rate but similar PFS and OS as paclitaxel/carboplatin (Table 7).$^{764}$ pegylated liposomal doxorubicin/carboplatin was associated with higher rates of certain hematologic toxicities, skin toxicity, and stomatitis, but lower rates of neurotoxicity and alopecia than the paclitaxel/carboplatin control.$^{764}$ Global QOL and most functional domains and symptom scales were the same across treatment arms, and pegylated liposomal doxorubicin/carboplatin was associated with worse scores for certain patient-reported toxicities.$^{764}$ Therefore, this regimen may be useful in select patients at high risk for neurotoxicity or those who would like to avoid alopecia. The docetaxel/carboplatin and liposomal doxorubicin/carboplatin regimens are both recommended options in the NCCN Guidelines (Table 4), and may be considered for patients who are at high risk for neuropathy (eg, patients with diabetes).$^{798}$

Randomized trials testing platinum-based triplet or quadruplet regimens have generally found that these do not improve efficacy but are associated with worse toxicity when compared with platinum-based doublets$^{773,775-777,779-782}$ or single-agent platinum regimens.$^{794,795}$ Examples of platinum-based triplet and quadruplet regimens that have been compared with the standard paclitaxel/carboplatin regimen are in Table 5 and 6. One study showed that adding gemcitabine to carboplatin/paclitaxel actually resulted in worse PFS compared with carboplatin/paclitaxel alone (Table 5 and 6).$^{780}$

Carboplatin/Paclitaxel Dosing Options

As noted above, for postoperative first-line treatment of ovarian cancer, the most commonly used dosing for IV carboplatin/paclitaxel combination therapy is paclitaxel 175 mg/m$^{2}$ + carboplatin AUC 5–6, both given on day 1 of a 3-week cycle. As summarized in Table 7, multiple randomized studies have compared different dosing schedules for IV carboplatin and paclitaxel regimens as first-line postoperative therapy for ovarian cancer.$^{757-761,763,799,800}$ Three different randomized trials (JGOG-3016, GOG-0262, and ICON8) tested “dose-dense” weekly paclitaxel dosing of 80 mg/m$^{2}$ combined with the standard carboplatin dosing (AUC 6, day 1, every 3 weeks).$^{758,760,761,763}$ JGOG-3016 results showed that this regimen improved PFS and OS, GOG-0262 showed that this regimen improved PFS (in the subset of patients who were not receiving concurrent bevacizumab), and ICON8 found no significant improvements in PFS or OS (Table 7). All three trials reported increased rates of neutropenia and signs of worse QOL among patients treated with the dose-dense regimen.

Two randomized trials (MITO-7 and ICON8) compared standard paclitaxel/carboplatin dosing with weekly paclitaxel (60 or 80 mg/m$^{2}$) plus weekly carboplatin (AUC 2), and found no significant differences in efficacy outcomes.$^{757-759}$ MITO-7, which tested 60 mg/m$^{2}$ paclitaxel, showed higher rates of pulmonary toxicity, but lower rates of neutropenia, febrile neutropenia, thrombocytopenia, neuropathy, hair loss, and vomiting, and significant improvement in QOL.$^{757}$ ICON8, which tested 80 mg/m$^{2}$ paclitaxel, showed higher rates of neutropenia and carboplatin hypersensitivity reaction, and worse global QOL compared with standard carboplatin/paclitaxel dosing.$^{758,759}$ Based on these results, if a weekly regimen is used, the paclitaxel weekly/carboplatin weekly regimen using 60 mg/m$^{2}$ paclitaxel is the recommended option (for stage II–IV disease; Table 4).

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Options for Stage I, Epithelial Cancer Types

Most of the patients had stage III-IV disease in randomized trials testing IV chemotherapy as postoperative first-line treatment for ovarian cancer. More recent trials allowed patients with stage II-IV disease, but only some included patients with select stage I disease (Table 5, Table 6, and Table 7). Therefore, the list of recommended options is much shorter for patients with stage I disease, as summarized in Table 8, which also shows trials that tested the recommended regimens (last column). Patients with stage I disease were included in randomized trials comparing IV paclitaxel/carboplatin (standard dosing) with single-agent carboplatin (ICON3),$^{773}$ docetaxel/carboplatin (SCOTROC1),$^{765}$ pegylated liposomal

doxorubicin/carboplatin (MITO-2),$^{764}$ and weekly paclitaxel/weekly carboplatin (MITO-7 and ICON8).$^{757-759}$ Of these, the first three are recommended options for stage I disease in epithelial cancer types. Paclitaxel weekly/carboplatin weekly is more logistically challenging to administer and is therefore not often used in the setting of stage I disease, given the lower risk of recurrence (compared with more advanced disease). Patients with stage I disease have also been included in some randomized trials testing triplet or quadruplet regimens,$^{773,780,795,796}$ but the added toxicity of these regimens with no clear impact on efficacy makes options inappropriate for stage I.

|Regimen Short Name|Detailed Dosing per $Cycle^{c}$|Cycle Length, Weeks|# Cycles|$Category^{d}$|Preference Category|Randomized Trials| |---|---|---|---|---|---|---| |Paclitaxel 175/ carboplatin|Paclitaxel 175 mg/$m^{2}$ IV over 3 hours followed by carboplatin AUC 5–6° IV over 30–60 minutes on Day 1|3|High-grade serous: 6 All other: 3|2A|Preferred|$ICON3^{773}$ GOG-$157^{801,802}$ du Bois, $2010^{780}$ SCOTROC1765 MITO-$2764$ MITO-$757$ MITO-$758,759$ ICON$8^{758,759}$| |Carboplatin/ liposomal doxorubicin|Carboplatin AUC 5 IV over 30–60 minutes + pegylated liposomal doxorubicin 30 mg/$m^{2}$ IV over 1 $hour^{f}$|4|High-grade serous: 6 All other: 3|2A|Other Recommended|$MITO-2^{764}$| |Docetaxel/ carboplatin|Docetaxel 60–75 mg/$m^{2}$ IV over 1 hour followed by carboplatin AUC 5–6 IV over 30–60 minutes on Day 1|3|High-grade serous: 6 All other: 3|2A|Other Recommended|$SCOTROC1^{765}$|

AUC, area under the curve; IV, intravenous.

ª Includes high-grade serous, grade 2/3 endometrioid, clear cell carcinoma; stage IC only for mucinous, low-grade serous, and grade 1 endometrioid.

b These options are primarily for patients aged ≤70 years, with good performance status, and without comorbidities. For patients who are >70 years, have poor performance score, or have comorbidities, see alternate treatment options discussed in the section entitled Options for Patients Who Are >70 years or Have Comorbidities or Poor Performance Score.

c Infusion times may need to be adjusted for patients with prior hypersensitivity reaction(s). See Management of Drug Reactions in the algorithm.

d NCCN Category of Evidence and Consensus.

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f For the first cycle of pegylated liposomal doxorubicin, infuse at 1 mg/min and make sure that the patient does not have a reaction.

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Adjuvant Chemotherapy Options for Patients with Advanced Age and/or Comorbidities

Adjuvant systemic chemotherapy is considered an essential component of care for patients with ovarian, fallopian tube, or primary peritoneal cancers. For most patients with epithelial cancer types and stage I disease, first-line systemic therapy generally consists of intravenous (IV) platinum-based chemotherapy, with paclitaxel 175 mg/m$^{2}$ and carboplatin area under the curve (AUC) 5-6 every 3 weeks recommended in the guidelines as a preferred regimen. IV platinum-based chemotherapy with or without bevacizumab is also a recommended option for first-line systemic therapy for those with stage II–IV disease. Additionally, alternate regimens (such as platinum-based IV/intraperitoneal [IP] chemotherapy or hormone therapy) are recommended as options, depending on cancer subtype, completeness of the initial surgery, and stage of disease. Please refer to OV-C 5 of 11, OV-C 6 of 11, and OV-C 7 of 11 in the Principles of Systemic Therapy section of the guidelines on http://www.NCCN.org for a complete list of primary systemic therapy options recommended for epithelial ovarian, fallopian tube, or primary peritoneal cancers.

Unfortunately, patients with advanced age (≥70 years) and/or comorbidities may be less likely to tolerate certain combination chemotherapy regimens, leading to discontinuation before the regimen is completed.$^{771,798,803-805}$ For example, patients aged 70 years or older undergoing paclitaxel/carboplatin-based therapy may be at higher risk of febrile neutropenia, anemia, diarrhea, asthenia, thromboembolic events, or hypertension (associated with bevacizumab).$^{771,803}$ Studies have suggested that risk of severe toxicity, discontinuation of adjuvant chemotherapy, and even worse overall survival (OS) may be correlated with increased age (even among older patients); functional status or depression at baseline (as quantified by the Hospital Anxiety and Depression Scale [HADS]), Activities of Daily Living (ADL) score, Instrumental Activities of Daily Living (IADL) score, and social activities

score); lymphopenia, hypoalbuminemia, and a number of co-medications.$^{806-811}$

As patients >70 years and those with comorbidities may be intolerant to the combination chemotherapy regimens, alternate combination therapy dosing (see OV-C 7 of 11) may be appropriate for these patients. For example, the dose of paclitaxel and carboplatin can be reduced. For guidance on how potential chemotherapy toxicity can be assessed, please refer to the NCCN Guidelines for Older Adult Oncology (available at http://www.NCCN.org).

Prior versions of the guidelines recommended carboplatin monotherapy as an option for patients >70 years and/or those with comorbidities. Although this recommendation was based on clinical evidence from several studies,$^{773,795,808-810}$ none of the studies were randomized trials specifically designed to evaluate single-agent carboplatin in patients >70 years and/or patients with comorbidities.

More recently, Elderly Women with Ovarian Cancer (EWOC)-1, an open-label, phase 2 randomized trial, evaluated carboplatin monotherapy (AUC 5-6, every 3 weeks [q3w]) alongside two other carboplatin combination regimens (weekly paclitaxel 60 mg/m$^{2}$ + carboplatin AUC 2 or standard paclitaxel 175 mg/m$^{2}$/carboplatin q3w) in 120 patients aged 70 years or older with stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer.$^{812}$ A Geriatric Vulnerability Score (GVS) of 3 or higher was also required for eligibility in this study; GVS is a tool that was developed to identify vulnerable patients ≥70 years with advanced ovarian cancer.$^{808}$ Patients with a GVS score of 3 or higher are likely to experience worse survival, lower treatment completion, and toxicity.

Data from this study suggested that carboplatin monotherapy was associated with significantly worse outcomes than the carboplatin-combination therapy regimens in this patient population.$^{812}$ The median

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OS was 7.4 months (95% CI, 5.3–32.2) in the carboplatin monotherapy

group, whereas the median OS was 17.3 months (95% CI, 10.8–32.2) in the weekly carboplatin-paclitaxel group and not reached in the carboplatinpaclitaxel every 3 weeks group. The hazard ratio (HR) for inferior overall survival of the carboplatin monotherapy group versus the carboplatinpaclitaxel q3w group was 2.79 (95% CI, 1.57–4.96; P < .001). Higher

incidences of grade 3 or higher thrombocytopenia and anemia were

reported in the carboplatin monotherapy group than the carboplatin

combination therapy groups. In contrast, higher rates of low-grade

gastrointestinal adverse events, neuropathy, and alopecia were reported in the two carboplatin combination groups.

Due to the worse survival outcomes associated with carboplatin

monotherapy compared with the carboplatin-combination regimens, the

trial was prematurely terminated on the recommendation of the

independent data monitoring committee.812 Therefore, based on these

data, the NCCN panel no longer recommends carboplatin monotherapy as an option for patients who are >70 years and/or those with comorbidities, as carboplatin-combination therapy is considered the standard-of-care

first-line chemotherapy regimen for this population.

The following regimens are recommended in the guidelines as options for those >70 years and/or those with comorbidities (OV-C 7 of 11):

• Paclitaxel 135 mg/m2 IV + carboplatin AUC 5 IV given every 21 days for 3 to 6 cycles, depending on stage and cancer subtype810

• Paclitaxel 60 mg/m2 IV, followed by carboplatin AUC 2 IV on days 1, 8, and 15, repeated every 21 days for 6 cycles757,812,813

The latter option can also be considered for patients with poor

performance status. Please refer to the Principles of Systemic Therapy

section in the guidelines for a complete list of recommended primary

therapy regimens and dosing recommendations for ovarian, fallopian tube, and primary peritoneal cancers.

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Number of Cycles

Recommendations for the number of cycles of treatment vary with the stage of the disease. Panel members had an extensive discussion about the number of cycles of chemotherapy that should be recommended for patients with advanced-stage disease. There is no evidence confirming that more than 6 cycles of combination chemotherapy are required for initial chemotherapy. Early randomized studies showed that patients treated with 8 or 10 cycles of adjuvant first-line platinum-based IV chemotherapy had similar survival but experienced worse toxicity than those treated with only 5 cycles.$^{814,815}$ For the regimens recommended in the NCCN Guidelines (for postoperative first-line IV chemotherapy), most of the supporting phase III randomized trials tested 6 cycles of therapy (see Table 5, Table 6, and Table 7). Although cross-trial comparisons should be interpreted with caution, the few trials that used greater than 6 cycles,$^{776,777,781,782}$ did not appear to show better outcomes than those that used 6 cycles. Also, it has been noted that among the two trials showing improved efficacy with first-line cisplatin/paclitaxel versus cisplatin/cyclophosphamide in patients with advanced ovarian cancer, the later trial that allowed continuation beyond 6 cycles, up to 9 cycles reported a smaller treatment effect (on PFS and OS) and had higher rates of neurotoxicity, suggesting that treatment beyond 6 cycles is unlikely to provide additional clinical benefit.$^{791,792}$ One randomized trial (NCT00102375) showed that adding 4 cycles of topotecan after 6 cycles of carboplatin/paclitaxel did not improve PFS or OS, or even response among those with measurable disease (Table 6).$^{776}$ The phase III randomized trial GOG-157 compared 3 versus 6 cycles of paclitaxel/carboplatin as postoperative first-line IV chemotherapy for patients with stage I-II epithelial ovarian cancer at high risk, defined as stage IA/IB with grade 3 or clear cell, or stage IC/II with any grade.$^{801,802}$ For the intent-to-treat (ITT) population, the number of cycles did not have

a significant impact on relapse-free survival (RFS) or OS, whereas 6 cycles was associated with higher rates of grade 3–4 neurotoxicity, grade 4 granulocytopenia, and grade 2–4 anemia.$^{801,802}$ After a median of 91 months of follow-up, exploratory analysis by cancer type showed that 6 cycles (vs. 3) was associated with significant improvement in RFS for patients with serous histology (HR, 0.30; 95% CI, 0.13-0.72; P = .007), but this effect was not seen for any other cancer subtypes (ie, endometrioid, clear cell, mucinous), and the number of cycles did not significantly impact OS for any subgroup.$^{802}$ Based on these data the NCCN Guidelines recommend 6 cycles adjuvant IV chemotherapy for stage I high-grade serous carcinoma, 3 cycles for other stage I epithelial cancers, and 6 cycles for stage II–IV epithelial disease (regardless of tumor type).

Toxicity

All of these regimens have different toxicity profiles. The docetaxel/carboplatin regimen is associated with increased risk for neutropenia; the IV paclitaxel/carboplatin regimen is associated with increased risk of sensory peripheral neuropathy; and dose-dense paclitaxel is associated with increased risk of anemia and decreased QOL.$^{760,762,764,765}$ Note that there are no agents to prevent chemotherapy-induced peripheral neuropathy.$^{816}$

Targeted Agents

Bevacizumab in the First-Line Setting

Two phase 3 randomized trials, GOG-0218 and ICON7, tested the effects of adding bevacizumab during first-line platinum-based combination chemotherapy and as single-agent maintenance therapy after first-line chemotherapy (for patients who had not progressed during initial treatment with chemotherapy + bevacizumab).$^{817-819}$ The study design and results from these trials are summarized in Table 10.

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|A. Summary of Results|||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---| |Trial|$Patients^{a}$|First-Line Chemotherapy^{b}$ → Maintenance|n|F/u, $mo^{c}$|PFS Median (months), HR [95% CI], P-$value^{d}$|OS Median (months), HR [95% CI], P-$value^{d}$|AEs G3-4|AEs G5|Dc'd $AE_{s}^{e}$||| |GOG-0218 NCT00262847 Burger $2011^{817}$|Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%|Arm 1: carbo/pac/placebo → placebo|625|19.$4^{f}$|10.3|39.3|NR|1.0%|12%||| |GOG-0218 NCT00262847 Burger $2011^{817}$|Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%|Arm 2: carbo/pac/bev → placebo|623|11.2 [0.795-1.040]|0.908 [0.795-1.040]|38.7 [0.827-1.297]|NR|1.6%|15%||| |GOG-0218 NCT00262847 Burger $2011^{817}$|Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%|Arm 3: carbo/pac/bev → bev|625|11.2 [0.795-1.040]|14.1 [0.625-0.824]|39.7 [0.727-1.152]|NR|2.2%|17%||| |GCIG ICON7 Perren $2011^{818}$ Oza $2015^{819}$|High-risk early stage (I-IIA and clear cell or Grade 3; 9%), IIB-IIIB (21%) or IIIC-IV (70%) Residual disease, R0/>0-≤1 cm/>1 cm: 48%/24%/26% Cancer type: 69% serous Tumor grade 3: 72%|Arm 1: carbo/pac → none|Arm 1: carbo/pac → none|764|48.6|17.5|58.6|54%|1%||| |GCIG ICON7 Perren $2011^{818}$ Oza $2015^{819}$|High-risk early stage (I-IIA and clear cell or Grade 3; 9%), IIB-IIIB (21%) or IIIC-IV (70%) Residual disease, R0/>0-≤1 cm/>1 cm: 48%/24%/26% Cancer type: 69% serous Tumor grade 3: 72%|Arm 2: carbo/pac/bev → bev|764|48.8|19.9 [0.83-1.05]|0.$93^{g}$ P=.25|58.0 [0.85-1.14]|65%|1%|||

|B. Treatment Regimens|| |---|---| |Trial|Treatments| |GOG-0218|Arm 1: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 Arm 2: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 + bevacizumab 15 mg/kg q3weeks x cycles 2-6 Arm 3h: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 + bevacizumab 15 mg/kg q3weeks x cycles 2-6 → maintenance bevacizumab 15 mg/kg q3weeks x cycles 7-22| |GCIG ICON7|Arm 1: Carboplatin AUC 5-6 + paclitaxel 175 mg/m², q3weeks x 6 cycles Arm 2h: Carboplatin AUC 5-6 + paclitaxel 175 mg/m², q3weeks x 6 cycles + bevacizumab 7.5 m/kg q3weeks x 5-6 cycles (omitted cycle 1 if <4 weeks from surgery) → maintenance bevacizumab 7.5 m/kg q3weeks x 12 cycles|

AEs, adverse events; AUC, area under the curve; carbo, carboplatin; bev, bevacizumab; dc'd, discontinued; f/u, follow-up; G, grade; HR, hazard ratio; mo, months; NR, not reported; OS, overall survival; pac, paclitaxel; PFS, progression-free survival; q3weeks, every 3 weeks; R0, no visible residual disease.

ª All patients had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube cancer.

b All patients were treated with surgery followed by chemotherapy.

c Median follow-up duration, in months.

d HR and P-values are for comparison with control arm (Arm 1).

e Patients who discontinued therapy due to AEs.

f Multivariate analysis of GOG-0218 results after a median of 73.2 months follow-up confirmed that there was a significant difference in PFS between Arm 1 and Arm 3 (HR [95% CI], 0.74 [0.65–0.84]; P<.001) and no significant impact on OS (HR [95% CI], 0.87 [0.75–1.0]; P=.053).$^{820}$ Long-term follow-up results after a median of 102.9 months confirmed no significant difference in OS between control (median OS, 40.8 mo) and Arm 2 (median OS, 40.8 months; HR, 1.06; 95% CI, 0.94–1.20)

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or Arm 3 (median OS, 43.4 months; HR, 0.96; 95% CI, 0.85–1.09).$^{821}$ Exploratory analysis of disease-specific survival yielded similar results. Subgroup analysis showed no treatment-dependent differences in OS for patients with stage III disease, but did yield interesting results for patients with stage IV disease. Arm 1 and 2 had no significant difference in OS, but Arm 3 showed significantly longer OS compared with Arm 1 (42.8 mo vs. 32.6 mo; HR, 0.75; 95% CI, 0.59–0.95).$^{821}$ $^{9}$ Primary analysis of GCIG ICON7 after a median of 19.4 months follow-up showed improved PFS with bevacizumab (HR [95%CI], 0.81 [0.70–0.94]; P=.004). Both PFS and OS showed non-proportionality, with the maximum treatment-dependent differences for PFS and OS between 12–18 mo.$^{818}$ $^{10}$ Regimen recommended in the NCCN Guidelines as an option for patients with newly diagnosed stage II–IV, following cytoreductive surgery.

Bevacizumab in the First-Line Setting: Efficacy In GOG-0218, although PFS was similar for patients treated with carboplatin/paclitaxel (Arm 1, control) versus those who also had bevacizumab during initial treatment (Arm 2, carboplatin/paclitaxel/bevacizumab), patients treated with carboplatin/paclitaxel/bevacizumab followed by maintenance with single-agent bevacizumab (Arm 3) had a 3-month improvement in median PFS compared with the control arm (See Table 10A).817,820 OS was not significantly different across all three arms (Table 10A), even after long-term follow-up.817,820,821 The effects of treatment on PFS and OS were non-proportional over time, however, with the greatest difference between arms around 15 months, and the Kaplan-Meier curves converging again about 9 months later. Results from ICON7 were similar, with results from the primary analysis (median follow-up 19.4 months) showing longer PFS with carboplatin/paclitaxel/bevacizumab, followed by single-agent bevacizumab maintenance therapy (Arm 2) compared with carboplatin/paclitaxel along (Arm 1).818 Analyses after longer follow-up (median 48.9 months), however, showed no significant treatment-dependent differences in PFS or OS (Table 10A).819 Again the effects were non-proportional over time, with the treatment-dependent differences in PFS and OS increasing to a peak between 12–18 months, and the Kaplan-Meier curves subsequently converging.819

For both GOG-0218 and ICON7, outcomes with upfront paclitaxel/carboplatin/bevacizumab plus single-agent bevacizumab maintenance (Arm 3 in GOG-0218, Arm 2 in ICON7) were compared with

control (paclitaxel/carboplatin alone, Arm 1) for a variety of patient subgroups to determine whether there are particular groups of patients that benefit from bevacizumab. Results across both studies showed that patients with features associated with poor prognosis tend to derive a greater benefit from the addition of bevacizumab.$^{817}$ Interim analyses of data from GOG 0218 showed that bevacizumab improved OS in patients with stage IV disease and in patients with ascites, another high-risk group (more likely to have poor performance score, high-grade serous histology, higher median pre-treatment CA-125 level, and suboptimal surgical cytoreduction); however the final analyses did not show correlation between OS and ascites in the bevacizumab containing arms.$^{820-822}$ For ICON7, although after long-term follow-up (median 48.9 months) there were no significant effects of bevacizumab on PFS or OS for the total population, subgroup analyses identified a high-risk group for which bevacizumab improved both PFS (median PFS for Arm 1 vs. Arm 2: 10.5 vs. 16.0 months; HR, 0.73 [95% CI, 0.61-0.88]; P = .001) and OS (median OS for Arm 1 vs. Arm 2: 30.2 vs. 39.7 months; HR, 0.78 [95% CI, 0.63-0.97]; P = .03).$^{819}$ This high-risk group included those with either stage IV, inoperable stage III, or suboptimally debulked (residual disease >1 cm) stage III. Exploratory analyses suggest that stage may be more important than the extent of residual disease for identifying patients who may benefit from bevacizumab.$^{823}$ Although sample sizes were small, analyses found no significant impact of bevacizumab on OS for the following subgroups: clear cell carcinoma, low stage high-grade disease, and low grade serous.$^{819}$

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An exploratory analysis of GOG-0218, including 1195 patients with DNA samples that could be sequenced, showed that the presence of mutations in BRCA1, BRCA2, or non-BRCA homologous recombination repair (HRR) genes was associated with longer PFS and OS relative to patients with no mutations in these genes, even after adjusting for treatment, stage, size of residual disease, and performance status at baseline.$^{824}$ For patients without mutations in any of these genes, the addition of bevacizumab (to up-front chemotherapy and as maintenance) was associated with improved PFS (median PFS for Arm 1 vs. Arm 3: 10.6 vs. 15.4 months; HR, 0.71 [95% CI, 0.60–0.85]; P = .0001). This treatment effect on PFS was not observed in the group of patients with mutations in BRCA1/2 or a non-BRCA HRR gene. These findings are consistent with those from other exploratory analyses suggesting that patients with poorer prognosis may derive the most benefit from bevacizumab.$^{824}$ Nonetheless, mutation status did not significantly modify the effect of bevacizumab on PFS, so these data are insufficient to support using mutation status to identify patients who may benefit from first-line and maintenance bevacizumab.

Bevacizumab Safety and Quality of Life

Based on earlier studies, toxicities that may occur in patients treated with bevacizumab and are of particular concern, may require intervention, and often lead to treatment discontinuation include the following: pain (grade ≥2), neutropenia (grade ≥4), febrile neutropenia, thrombocytopenia, bleeding (grade ≥2; various types), hypertension (grade ≥2), thromboembolism (grade ≥3, various types), GI events (perforations, abscesses, and fistulas), reversible posterior leukoencephalopathy syndrome, renal injury and proteinuria (grade ≥3), and wound disruption. In both GOG-0218 and ICON7, the following types of toxicities were more common in the bevacizumab arm: bleeding, hypertension, proteinuria, thromboembolic events (grade ≥3), GI perforation (grade ≥3), and wound-healing complications.$^{817,818}$ For some of these the difference between arms was smaller than expected. Neutropenia occurred with similar rates

across arms, and reversible posterior leukoencephalopathy syndrome occurred in GOG-0218 in only the bevacizumab arms.

Data from both GOG-0218 and ICON7 showed that most toxicities developed during the chemotherapy phase of treatment, although there were a few AEs of concern that continued to develop during the bevacizumab maintenance phase, including hypertension, high-grade pain, proteinuria, and thromboembolism.$^{817}$ Exploratory analyses tried to identify factors that might be associated with increased risk of bevacizumab-associated AEs.$^{825,826}$ Analysis of GI-related AEs in GOG-0218 identified inflammatory bowel disease (IBD), and bowel resection at primary surgery as being associated with increased risk of grade ≥2 perforation, fistula, necrosis, or hemorrhage.$^{825}$ Another analysis of GOG-0218 reported that patients treated with bevacizumab had higher rates of readmission, and noted that most readmissions occur within the first 40 days after surgery but after the first cycle of chemotherapy was delivered.$^{826}$ Other factors associated with increased rates of readmission (across treatment arms) include baseline CA-125 level, disease stage, surgery involving bowel resection, residual disease, ascites, high body mass index, and poor performance score. Whereas shorter time to start of chemotherapy after surgery was associated with increased rates of readmission,$^{826}$ time to initiation longer than 25 days was associated with poorer OS (across treatment arms).$^{528}$

Both GOG-0218 and ICON7 reported some small but statistically significant differences between treatment arms in the global measures of QOL. Analyses of GOG-0218 showed that QOL improved somewhat during the course of the study across all arms (FACT-O TOI scores improved from ~67-68 to ~76-68).$^{817,827}$ Results showed slightly worse QOL for patients treated with bevacizumab during the chemotherapy phase (FACT-O TOI scores ≤3 points lower than for placebo; P < .001), but this difference did not persist in the maintenance phase.$^{817,827}$ There

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were no statistically significant differences in QOL scores for patients treated with bevacizumab during chemotherapy only (Arm 2) versus bevacizumab during chemotherapy plus maintenance (Arm 3),$^{827}$ which further supports the idea that bevacizumab maintenance did not impact QOL. For FACT-O TOI scores, the threshold for clinically meaningful differences has been suggested to be 5–7 points. Results from ICON7 showed that for both arms QOL improved somewhat over the course of the trial, during both the chemotherapy phase.$^{818,828}$ However, these increases were smaller in the bevacizumab arm (Arm 2), such that QOL scores were better in the control arm (Arm 1) versus the bevacizumab arm (Arm 2) at the end of chemotherapy (week 18; mean QL-C30 score difference of 6.1 points; P < .0001) and at the end of the maintenance phase (week 54; 6.4 points; P < .0001).$^{828}$ Although differences between the two arms (favoring placebo) were consistently present and statistically significant, it is unclear whether they are clinically meaningful, as the threshold for clinical significance is a matter of debate, and some have argued that it should be 10 points.

NCCN Recommendations

Based on results from GOG-0218 and ICON7, the NCCN Guidelines include bevacizumab-containing regimens as options for first-line

chemotherapy following cytoreductive surgery (Table 11). The regimens recommended are those used in these trials that consist of upfront carboplatin/paclitaxel/bevacizumab, followed by bevacizumab maintenance (shown in Table 10B, footnote h and Table 11). In both of these trials, treatment was discontinued upon disease progression, so the guidelines recommend single-agent bevacizumab maintenance only for those who have not progressed during the 6 cycles of upfront carboplatin/paclitaxel/bevacizumab (see Post-Primary Treatment: Maintenance Therapy in the Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section of the algorithm). Given that GOG-0218 found that patients treated with upfront carboplatin/paclitaxel/bevacizumab without single-agent bevacizumab maintenance did not have improved outcomes compared with control (carboplatin/paclitaxel), observation is not a recommended option for patients with response or stable disease following completion of a first-line regimen containing bevacizumab (see bottom two pathways in Post-Primary Treatment: Maintenance Therapy in the algorithm). Currently there are no data to support introducing bevacizumab as maintenance therapy if bevacizumab was not included in the initial primary regimens used (see top pathways in Post-Primary Treatment: Maintenance Therapy in the algorithm).

NCCN

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|Regimen Short Name|Detailed Dosing per Cycle|Cycle Length, Weeks|# $Cycles^{c}$|$Category^{d}$|Preference Category|Supporting References| |---|---|---|---|---|---|---| |Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(ICON-7)|Paclitaxel 175 mg/m² IV over 3 hours, followed by carboplatin AUC 5-6 IV over 1 hour, and bevacizumab 7.5 mg/kg IV over 30-90 minutes Day 1|3|5-6|2A|Preferred|ICON-7Perren 2011818Oza 2015819| |Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(ICON-7)|(Maintenance) bevacizumab 7.5 mg/kg IV over 30-90 minutes Day 1|3|≤12|BRCA1/2 wild-type/unknown: 2Ae BRCA1/2 mutation: bevacizumab alone not $recommended^{f}$||ICON-7Perren 2011818Oza 2015819| |Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(GOG-218)|Paclitaxel 175 mg/m² IV over 3 hours, followed by carboplatin AUC 6 IV over 1 hour, plus bevacizumab (cycles 2-6) 15 mg/kg IV over 30-90 minutes Day 1|3|6|2A|Preferred|GOG-0218Burger 2011817Tewari,2019821| |Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(GOG-218)|(Maintenance) bevacizumab 15 mg/kg IV over 30-90 minutes Day 1|3|≤16|BRCA1/2 wild-type/unknown: 2Ae BRCA1/2 mutation: bevacizumab alone not $recommended^{f}$||GOG-0218Burger 2011817Tewari,2019821|

AUC, area under the curve; CR, complete response; IV, intravenous; PR, partial response.

ª Includes high-grade serous, grade 2/3 endometrioid, clear cell carcinoma; stage IC only for mucinous, low-grade serous, and grade 1 endometrioid.

c NCCN-recommended number of cycles.

d NCCN Category of Evidence and Consensus.

e For patients with BRCA1/2 wild-type or unknown mutation status who are in CR/PR after chemotherapy plus bevacizumab, maintenance options include bevacizumab alone (category 2A) or bevacizumab + olaparib (category 2A). See Options After First-Line Chemotherapy section for more information.

f For patients with a BRCA1/2 mutation in CR/PR after chemotherapy plus bevacizumab + olaparib (category 1), olaparib monotherapy (category 2A), or niraparib monotherapy (category 2A). See Options After First-Line Chemotherapy section for more information.

GOG-0218 did not include patients with stage I-II disease, and ICON7 included patients with stage I-II disease only if they were considered "high risk" because of poor differentiation (high grade) or clear cell histology (Table 10A). Due to these entry criteria and the results of subgroup analysis suggesting that bevacizumab may only be beneficial in

patients with more advanced disease, the NCCN Guidelines do not include the bevacizumab-containing regimens (including bevacizumab maintenance) as options for stage I disease, but only recommend them for patients with stage II or higher.

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GOG-0218 and ICON7 included patients primarily with ovarian cancer, but also some with primary peritoneal or fallopian tube cancer.$^{817,818}$ These trials mostly included patients with serous histology, but did include patients with other cancer types (ie, mucinous, clear cell, endometrioid). Therefore, the NCCN recommendations regarding use of bevacizumab as part of first-line chemotherapy and maintenance apply to patients with any of these epithelial cancer types.

Bevacizumab Biosimilars

In September 2017 the FDA approved the first bevacizumab biosimilar, ABP-215, as bevacizumab-awwb, for use in certain indications in a number of cancers (ie, colorectal cancer, non-squamous non-small cell lung cancer [NSCLC], glioblastoma, renal cell carcinoma, cervical cancer), but not including any indications in ovarian, fallopian tube, or primary peritoneal cancers due to regulatory exclusivity.$^{829-831}$ This approval was based on data demonstrating that the ABP 215 is sufficiently structurally similar to bevacizumab, and functionally similar based on in vitro assays, in vivo assays (cell-based and preclinical models), pharmacokinetic data in healthy adult men, and efficacy and safety data in patients with advanced NSCLC.$^{829,832-838}$ Approval in other cancer types was based on extrapolation.$^{829,839}$ In 2019 the FDA approved another bevacizumab biosimilar, PF-06439535, as bevacizumab-bvzr, for the same indications as bevacizumab-awwb.$^{840}$ This approval was based on demonstration of structural similarity, and data showing functional similarity including in vivo studies, animal studies, pharmacokinetics in healthy subjects and patients with NSCLC, and efficacy and safety data in patients with NSCLC.$^{841-845}$ Several other bevacizumab biosimilars are in development.$^{846-860}$ Based on a Panel vote, the NCCN Guidelines for Ovarian state that an FDA-approved biosimilar is an appropriate substitute for bevacizumab, wherever bevacizumab is recommended.

Intraperitoneal/Intravenous Regimen

IP chemotherapy has been explored as an option for ovarian cancer based on the idea that localized delivery could improve efficacy, particularly against microscopic spread and peritoneal carcinomatosis, with an acceptable safety profile. Although results from smaller randomized trials (n < 120) suggested no clinical benefit (ie, response rate, PFS, OS) with IP/IV compared with IV regimens,$^{861,862}$ three larger randomized trials (n > 400) in newly diagnosed chemotherapy-naïve patients with stage III disease and residual disease 1 cm or less after primary surgery compared IV regimens with IP/IV regimens using similar agents, and found that IP/IV chemotherapy resulted in improved PFS and/or OS, with at least borderline statistical significance (See GOG-104, GOG-114, and GOG-172 in Table 12).$^{724,863,864}$ One phase II randomized trial (n = 218) in patients with stage IIIC–IV epithelial ovarian cancer with optimal debulking also showed that IP/IV administration improved PFS and OS compared with IV only.$^{865,866}$ Results from these trials suggest that IP/IV administration significantly increases risk of certain high-grade hematologic toxicities (eg, granulocytopenia, leukopenia, neutropenia, thrombocytopenia), and certain non-hematologic toxicities (eg, GI and metabolic toxicities, renal toxicity, abdominal pain, neurologic toxicities, infection, fatigue).$^{724,863-865,867}$ The increased risk of toxicity was considered acceptable given the improvement in OS, which was greater than a year (16 months) in one of the trials (Table 12).$^{724,863,864}$ Pooled analyses of GOG-114 and GOG-172 data showed that the IP/IV regimen was associated with lower risk of relapse in the peritoneal space,$^{868}$ and long-term follow-up (>10 years) showed significant PFS benefit (P = .01) and OS benefit (P = .042), especially after adjusting for other prognostic factors (P = .003 for PFS, P = .002 for OS).$^{869}$ This analysis also showed that survival improves with each cycle of IP chemotherapy.$^{869}$ Although the extent of residual disease was prognostic for outcome, IP/IV chemotherapy still provided PFS benefit even among those with some gross residual disease (>0–≤1 cm).$^{869}$ Based on these results, an IP/IV

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option similar to the regimen used in GOG-172 was added to the NCCN Guidelines (Table 13) for patients with optimally debulked (<1 cm residual) stage III disease.$^{724}$ Those with optimally debulked stage II disease may also receive IP chemotherapy, as the NCCN Panel has decided that many of the regimens tested in stage III-IV should also be offered to patients

with stage II disease. Patients with stage II were allowed in GOG-0252 and another (small) randomized trial, although in both of these studies the IP/IV regimens did not significantly improve PFS or OS compared with IV regimens.$^{862,870}$ IP chemotherapy is not recommended for stage I or IV disease.

Discussion update in progress

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|Trial|$Patients^{a}$|First-Line Systemic $Therapy^{b}$|n|Median (months), HR [95% CI], P-$value^{d}$|AEs G5|Dc'd $AEs^{e}$|| |---|---|---|---|---|---|---|---| |Trial|$Patients^{a}$|First-Line Systemic $Therapy^{b}$|n|PFS|AEs G5|Dc'd $AEs^{e}$|OS| |GOG-0104863|Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/10%/23% Tumor grade, 1/2/3: 12%/30%/58% Residual disease, R0/>0-≤1 cm/>1 cm: 26%/73%/0|IP/IV: Cyclophosphamide 600 mg/$m^{2}$ IV + cisplatin 100 mg/$m^{2}$ IP, Q3W x 6 cycles|279|NR|49, 0.76 [0.61- 0.96], P=.02|1%|9%| |GOG-0104863|Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/10%/23% Tumor grade, 1/2/3: 12%/30%/58% Residual disease, R0/>0-≤1 cm/>1 cm: 26%/73%/0|IV: Cyclophosphamide 600 mg/$m^{2}$ IV + cisplatin 100 mg/$m^{2}$ IV, Q3W x 6 cycles|267|NR|41|0|5%| |GOG-0114864|Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/12%/21% Tumor grade, 1/2/3: 12%/40%/48% Residual disease, R0/>0-≤1 cm/>1 cm: 35%/65%/0|IP/IV: Carboplatin AUC 9 IV Q4W x 2 cycles; then paclitaxel 135 mg/$m^{2}$ IV, then cisplatin 100 mg/$m^{2}$ IP, Q3W x 6 cycles|227|18, 0.78, P=.01|63; 0.81, P=.05|1%|NR| |GOG-0114864|Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/12%/21% Tumor grade, 1/2/3: 12%/40%/48% Residual disease, R0/>0-≤1 cm/>1 cm: 35%/65%/0|IV: Paclitaxel 135 mg/$m^{2}$ IV + cisplatin 75 mg/$m^{2}$ IV, Q3W x 6 cycles|235|22|52|1%|NR| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|IP/IV: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 100 mg/$m^{2}$ IP D2 + paclitaxel 60 mg/$m^{2}$ IP D8, Q3W x 6 cycles|214|23.8, 0.80 [0.64-1.00], P=.05|65.6, 0.75 [0.58-0.97], P=.03|2.4%|NR| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|IV: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 75 mg/$m^{2}$ IV D2, Q3W x 6 cycles|215|18.3|49.7|1.9%|NR| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|IV/IP pac/carbo bev: paclitaxel 80 mg/$m^{2}$ IV D1, D8, D15|518|27.4, 0.925 [0.802-1.07]|78.9, 0.949 [0.799- 1.128]|1.4%|28%| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|• carboplatin AUC 6 IP D1, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22|• 0.925 [0.802-1.07]|• 0.949 [0.799- 1.128]|• 0.949 [0.799- 1.128]|• 2%|NR| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|IV/IP pac/cis/bev: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 75 mg/$m^{2}$ IP D2 + paclitaxel 60 mg/$m^{2}$ IP D8, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22|521|26.2, 0.977 [0.847-1.13]|72.9, 1.05 [0.884-1.24]|2.0%|29%| |GOG-172 (NCT0003322)$^{724,867}$|Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0|IV pac/carbo/bev: Paclitaxel 80 mg/$m^{2}$ IV D1, D8, D15 + carboplatin AUC 6 IV D1, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22|521|24.9|75.5|1.6%|24%|

AE, adverse event; CI, confidence interval; D, day (of cycle); D'd, discontinued study treatment; FTC, fallopian tube cancer; G, grade; HR, hazard ratio; IP, intraperitoneal; IV, intravenous; NR, not reported; OC, ovarian cancer; OS, overall survival; PFS, progression-free survival; PPC, primary peritoneal cancer; Q3W, every 3 weeks; R0, removal of all macroscopic disease.

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ª All trials enrolled newly diagnosed, previously untreated/chemotherapy-naïve patients, with an epithelial cancer type.

b All patients were treated with surgery followed by chemotherapy.

c Percentages for each cancer type were not reported, but trial inclusion criteria allowed OC, FTC, and PPC.

d HR and P-values are for comparison with control arm (IV regimen).

e Patients who discontinued therapy due to AEs.

|Regimen Short Name|Detailed Dosing per Cycle||Cycle Length, Weeks|# Cycles|Category|Preference Category|Trials with Supporting Data| |---|---|---|---|---|---|---|---| |IV/IP Paclitaxel/cisplatin|Paclitaxel 135 mg/m² IV continuous infusion over 3 or 24 hours Day 1; + Cisplatin 75-100 mg/m² IP Day 2 after IV paclitaxel; + Paclitaxel 60 mg/m² IP Day 8|3|6|2A|Useful in Certain Circumstances|GOG-0172724||

IP, intraperitoneal; IV, intravenous.

a Optimally debulked is defined as <1 cm residual disease.

b Includes high-grade serous, grade 2/3 endometrioid, clear cell carcinoma.

$^{c}$ NCCN Category of Evidence and Consensus.

In the large randomized trials that showed that IP/IV benefit, most of the patients had serious or endometrioid disease, and high-grade tumor histology (Table 12), so it is unclear whether patients with LCOCs will benefit from IP/IV chemotherapy. In the NCCN Guidelines, the clear cell carcinoma and carcinosarcoma are the only LCOCs for which IP/IV chemotherapy is a recommended option, as these cancer types are associated with higher risk of poor outcomes.$^{6,871-873}$ Patients with carcinosarcoma were not included in the randomized trials testing IP/IV chemotherapy, but 2% to 6% of patients had clear cell carcinoma.$^{724,863,864,870}$ These trials included mostly patients with ovarian cancer, but in GOG-172, 12% of patients had primary peritoneal cancer. In the NCCN Guidelines the recommended IP/IV regimen is an option regardless of primary site (ovarian, fallopian, or primary peritoneal). All individuals should be counseled about the clinical benefit associated with

combined IV and IP chemotherapy administration before undergoing surgery.

Enthusiasm for IP/IV chemotherapy has waned considerably due to the results of GOG-0252, a large randomized trial in patients with stage II/III optimally resected (≤1 cm), or stage III/IV suboptimally resected (>1 cm) disease (Table 12).$^{870}$ Results showed that for combination therapy with paclitaxel/carboplatin/bevacizumab, IP administration of the carboplatin did not improve PFS or OS compared with IV administration (Table 12).$^{870}$ An IV/IP paclitaxel/cisplatin/bevacizumab regimen also did not improve PFS for OS relative to the control IV paclitaxel/carboplatin/bevacizumab regimen (Table 12).$^{870}$ These results suggest that given the PFS benefit of adding bevacizumab (during chemotherapy and maintenance), IP administration does not further improve outcomes.

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For the recommended IP chemotherapy regimen (Table 13), the IP paclitaxel was infused over 24 hours in the clinical trial (GOG-172).$^{724}$ A 3-hour infusion of paclitaxel has not been proven to be equivalent to a 24-hour infusion, although a 3-hour infusion has been reported to be more convenient, easier to tolerate, and less toxic.$^{874}$ Note that in all the supporting trials and in the NCCN Guidelines, IP regimens include IV regimens so that systemic disease can also be treated.

The IP paclitaxel/cisplatin regimen is associated with leukopenia, infection, fatigue, renal toxicity, abdominal discomfort, and neurotoxicity.$^{724,863-865,867}$ In GOG-172, only 42% were able to complete all 6 treatment cycles of the IP regimen;$^{724}$ with more experience, this percentage has improved in the major cancer centers.$^{875}$ It has been suggested that a lower IP cisplatin dose of 75 mg/m$^{2}$ may help to decrease toxicity.$^{874,875}$ However, the chemotherapy portion of the IV/IP paclitaxel/cisplatin/bevacizumab regimen used in GOG-0252 was very similar to the IV/IP paclitaxel/cisplatin regimen used in GOG-172, but with a lower dose of cisplatin (75 mg/m$^{2}$ vs. 100 mg/m$^{2}$), and did not improve PFS/OS relative to control (Table 12).$^{724,870}$ Therefore, it is unclear whether the IV/IP chemotherapy regimen with the lower cisplatin dose provides any benefit compared with IV administration.

Prior to the administration of the combined IP and IV regimen, patients must be apprised of the increased toxicities with the combined regimen when compared to using IV chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, GI toxicities, metabolic toxicities, and hepatic toxicities). Patients who are candidates for the IP cisplatin and IP/IV paclitaxel regimen should have normal renal function before starting, a medically appropriate PS based on the future toxicities of the IP/IV regimen, and no previous evidence of medical problems that could significantly worsen during chemotherapy, such as preexisting neuropathy. Reasons for discontinuing the IP regimen

included catheter complications, nausea/vomiting/dehydration, and abdominal pain.$^{876}$ Those unable to complete IP therapy should receive IV therapy. Expert nursing care may help to decrease complications.$^{877}$ Giving IV hydration before and after IP chemotherapy is a useful strategy to prevent certain toxicities (nausea, vomiting, electrolyte imbalances, and metabolic toxicities).$^{875}$ Prior to receiving and after receiving each cycle of IP cisplatin, adequate amounts of IV fluids need to be administered in order to prevent renal toxicity. After each cycle has been completed, patients need to be monitored carefully for myelosuppression, dehydration, electrolyte loss, end-organ toxicities (such as renal and hepatic damage), and all other toxicities. After chemotherapy, patients often require IV fluids (5–7 days) in the outpatient setting to prevent or help treat dehydration.

Neoadjuvant Chemotherapy

In the NCCN Guidelines for Ovarian Cancer, neoadjuvant therapy refers to treatment (eg, drugs and other treatments) that is given to reduce the tumor burden before cancer surgery. The therapeutic benefit of NACT followed by IDS remains controversial (see below).$^{480,694,878-885}$

For advanced-stage epithelial ovarian cancer, including fallopian tube and primary peritoneal cancers, the best outcomes have been observed in patients whose primary treatment included complete resection of all visible disease and combination chemotherapy.$^{868}$ Therefore, the NCCN Guidelines recommend that primary treatment for presumed advanced-stage disease consist of appropriate surgical debulking plus systemic chemotherapy in most patients. For most patients presenting with suspected advanced-stage malignant ovarian, fallopian tube, or primary peritoneal cancer, initial surgery should include a hysterectomy and BSO with comprehensive staging and debulking as indicated.$^{13,541,588}$ PDS is the recommended approach for advanced-stage disease if the patient is a surgical candidate, optimal cytoreduction (residual disease <1 cm [R1] and

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preferably removal of macroscopic disease [R0]) appears feasible, and fertility is not a concern. NACT with IDS should be considered for patients with advanced-stage disease who are not good candidates for PDS due to advanced age, frailty, poor performance status, comorbidities, or disease that is unlikely to be optimally cytoreduced. The anticipated benefit from NACT would be to allow for medical improvement and/or clinical response that would increase the likelihood of optimal cytoreduction at IDS. Patients treated with NACT and IDS should also receive postoperative adjuvant chemotherapy.

Randomized Trials Comparing NACT Versus Conventional Treatment

Several prospective randomized trials have compared an NACT approach (with IDS and postoperative chemotherapy) versus conventional treatment

(PDS plus postoperative chemotherapy; Table 14).481-483,639,640 These trials focused on patients with FIGO stage IIIC-IV ovarian, fallopian tube, or primary peritoneal cancer that was deemed unlikely to be completely resected. As shown in Table 14, the NACT regimens tested in these trials typically consisted of 3-4 cycles of upfront chemotherapy, followed by IDS with the goal of maximum cytoreduction, followed by 3-4 cycles of postoperative chemotherapy. Several of these trials (ie, EORTC 55971,483 SCORPION,639 JCOG0602482) allowed IDS in the neoadjuvant arm only for patients experiencing response or stable disease after NACT. The control arms in these trials consisted of PDS (with the goal of maximum cytoreduction) followed by postoperative chemotherapy to a total of 6 to 8 cycles. Specific chemotherapy regimens used in these trials are shown in Table 15.481-483,639,640

|Trial|$Patients^{a}$|Treatment Arms|Arm A Versus B|Arm A Versus B|Arm A Versus B| |---|---|---|---|---|---| |Trial|$Patients^{a}$|Treatment Arms|n|Surgical Outcomes|Median PFS/OS, months| |EORTC 55971 NCIC-CTG OV13 NCT00003636 Phase III Vergote $2010^{483}$ N = 670|FIGO Stage IIIC, IV: 76%, 24% Poor differentiation: 41%$^{b}$ Entry criteria: Diagnosis by $biopsy^{b}$|Arm 1: NACT x 3 cycles →IDS if response/SD →Chemo x ≥ 3 cycles →Second look allowed Arm 2: PDS →Chemo x 3 cycles →IDS option if response/SD and >1 cm after PDS →Chemo x ≥ 3 cycles →Second look allowed|334 vs. 336|Operative time, minutes: median 180 vs. 165 Residual disease: •R0: 51% vs. 19% •≤1 cm: 81% vs. 42% Death <28 days postop: 0.7% vs. 2.5%|PFS: 12 vs. 12; NS OS: 30 vs. 29; P = .01° •Hemorrhage: 4.1% vs. 7.4% •Infections: 1.7% vs. 8.1% •Venous complications: 0 vs. 2.6%| |CHORUS ISRCTN74802813 Phase III Kehoe $2015^{481}$ N = 550|FIGO stage IIIC, IV: 72%, $16^{d}$ Poor differentiation: 77% Entry criteria: diagnosis by imaging, CA- 125:CEA > $25^{d}$|Arm 1: NACT x 3 cycles →IDS →Chemo x 3 cycles Arm 2: PDS →Chemo x 3 cycles →IDS option for >1 cm residual after PDS →Chemo x 3 cycles|274 vs. 276|Operative time, minutes: median 120 vs. 120 Residual disease: •R0: 39% vs. 17%; P = .0001 •<1 cm: 73% vs. 41%; P = .0001 Hospital stay ≤14 days: 93% vs. 80%; P < .0001 Death <28 days postop: <1% vs. 6%; P = .001|PFS: 12.0 vs. 10.7; HR, 0.91 (95% CI, 0.76–1.09) OS: 24.1 vs. 22.6; HR, 0.87 (95% CI, 0.72–1.05)$^{e}$|

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|Trial|Patientsa|Treatment Arms|Arm A Versus B|Arm A Versus B|Arm A Versus B| |---|---|---|---|---|---| |Trial|Patientsa|Treatment Arms|n|Surgical Outcomes|Median PFS/OS, months| |SCORPION NCT01461850 Phase III Fagotti $2016^{639,886}$ N = 110|FIGO stage IIIC, IV: 89%, $11\%^{f}$ Poor differentiation: $NR^{f}$ Entry criteria: diagnosis by $S-LPS^{f}$|Arm 1: NACT x 3-4 cycles →IDS if response/SD →Chemo to a total of 6 cycles Arm 2: PDS →Chemo x 6 cycles|55 vs. 55|Operative time, minutes: median 275 vs. 451; P = .0001 Residual disease: • R0: 58% vs. 46%; NS • ≤1 cm: 85% vs. 91% Hospital stay, days: median 6 vs. 12; P = .0001 Death ≤30 days postop: 0 vs. 4%; NS PDS associated with more extensive and complex procedures and $blood loss^{g}$|NR| |JCOG0602 Phase III Onda $2016^{482}$ N = 301|FIGO stage III, IV: 68%, 32% (IIIC NR) Poor differentiation: NR Entry criteria: diagnosis by imaging plus cytology, h CA-125 >200 U/mL, CEA <20 ng/mL|Arm 1: NACT x 4 cycles →IDS if response/SD →Chemo x 4 cycles Arm 2: PDS →Chemo x 4 cycles →IDS option if residual >1 cm after $PDS^{i}$ →Chemo x 4 cycles|152 vs. 149|Operative time, minutes: median 273 vs. $341; P < .001^{i}$ Residual disease: • R0: 55% vs. 31% • <1 cm: 71% vs. $63^{i}$ Surgery-related death: 0 vs. 0.7%; NS PDS associated with more extensive surgery and blood/ascites $loss^{i}$|NR| |Liu $2017^{640}$ N = 108|FIGO stage III, IV: 68%, 32% Grade 2-3: 55% Entry criteria: diagnosis by imaging, serum CA-125; confirmed by LPS biopsy or laparotomy|Arm 1: NACT IP/IV x 2 cycles →IDS →Chemo IV x 6 cycles Arm 2: PDS →Chemo IV x 6–8 cycles|58 vs. 50|Operative time, hours: 2.36 vs. 3.63; P < .001 Successful cytoreduction: 74% vs. 46%; P = .0054 PDS associated with greater blood loss (P < .001)|PFS: 26 vs. 22; NS OS: 62 vs. 51; NS^{i}$|

Abbreviations: AE, adverse event; CA-125, cancer antigen 125; CEA, carcinoembryonic antigen; chemo, chemotherapy; HR, hazard ratio; IP, intraperitoneal; IV, intravenous; IDS, interval debulking surgery; LPS, laparoscopic surgery; MSKCC, Memorial Sloan Kettering Cancer Center; NACT, neoadjuvant chemotherapy; NS, not significantly different (between arms); NR, not reported; OS, overall survival; PDS, primary debulking surgery; PFS, progression-free survival; postop, postoperative; R0, removal of all macroscopic disease; SD, stable disease; S-LPS; staging laparoscopic surgery

a All trials included patients with ovarian, fallopian tube, or primary peritoneal cancer, including the following cancer types: serous, mucinous, clear cell, endometrioid, undifferentiated, or mixed. SCORPION excluded patients with borderline histology.

b In EORTC 55971, histologic grade was unknown for 41% of patients. Stage and cancer type were required to be proven by biopsy (image-guided or during laparoscopy or laparotomy). If no biopsy specimen, FNA showing adenocarcinoma allowed under certain circumstances: pelvic ovarian mass, metastases outside

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of pelvis >2 cm, regional lymph node metastases, proof of stage IV, or CA-125:CEA >25. If serum CA-125:CEA ≤25, barium enema or colonoscopy, gastroscopy, and mammograph had to be negative.

c In EORTC 55971, OS P-value was for non-inferiority. Post hoc subgroup analyses showed that there was no treatment-dependent difference in OS for any of the subgroups evaluated based on FIGO stage, WHO performance score, histologic type, or presence/absence of pleural fluid.$^{483}$ Subgroup analyses showed that NACT was associated with better OS in patients with more extensive disease (stage IV with largest metastasis >45 mm diameter; or stage IVB), and PDS was associated with better OS in patients with less extensive disease (stage III, ≤45 mm), and no treatment-dependent difference in OS in patients with an intermediate extent of disease (stage IIIC, >45 mm; or stage IVA).$^{583,887}$

d In CHORUS, patients were included if suspected FIGO stage III–IV based on imaging/clinical evidence, but after surgery only 96% had confirmed III–IV; the remaining had stage II or unknown stage. For those with CA-125:CEA ratio <25 (2%), gastrointestinal carcinoma had to be ruled out by imaging. Only patients in the NACT arm had histologic/cytologic confirmation of diagnosis prior to treatment. Methods used for histologic/cytologic confirmation in NACT arm included: laparoscopy (16%), image-guided biopsy (42%), and FNA cytology of tumor/effusion (41%).

* In CHORUS, analyses of subgroups showed that residual disease after surgery was prognostic for OS in both treatment groups. Post-hoc subgroup analyses showed that there was no treatment-dependent difference in OS for any of the subgroups evaluated based on age, cancer stage, tumor size (prior to surgery), performance score, or type of chemotherapy (single-agent carboplatin vs. carboplatin/paclitaxel).

$^{f}$ In SCORPION, patients with stage IV required to have pleural infusion or any insectable disease. All patients were required to have a predictive index of 8–12 and no mesenteric retraction. All patients had S-LPS for histologic confirmation and to assess tumor load (predictive index). The proportion of patients with poorly differentiated histology was not reported. However, 97% had type II histology per Kurman and Shih,$^{888}$ which includes conventional high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed modermal tumors (carcinosarcoma).

$^{9}$ In SCORPION, PDS was associated with a higher rate of upper abdominal procedures (P = .0001), surgical complexity (P = .0001), blood loss (P = .003), and time between surgery and starting postoperative chemotherapy (P = .0001).

$^{1}$ In JCOG0602 did not require histologic confirmation of diagnoses at trial entry. Diagnosis was based on both imaging and cytology of ascites, pleural effusions, or fluids obtained by centesis.

$^{1}$ In JCOG0602, patients in the control arm were allowed to have IDS for residual >1 cm after PDS; and IDS was mandatory if uter us, adnexa, or omentum were not removed at PDS, unless PD was noted. Of 128 patients in the control arm who completed the first 4 cycles of postoperative chemotherapy, 49 had IDS. Outcomes of surgery in this table include results from all surgeries performed. Patients in the PDS arm had higher rates of para-aortic and pelvic lymphadenectomy ($P < .001, P < .001$), resection of abdominal organ and distant metastases ($P = .012, P = .017$), and transfusions of albumin or fresh frozen plasma (FFP)/plasma protein fraction (PPF)/albumin ($P < .001$). They also had higher volumes of blood/ascites loss ($P < .001$),

$^{1}$ In the study reported by Liu et al, 2017$^{640}$, subgroup analysis showed that the following factors were prognostic for OS among patients in the NACT arm: tumor stage (III vs. IV), histologic grade (grade 1 vs. 2 vs. 3), residual tumor size (≤1 cm vs. >1 cm), and number of chemotherapy cycles.

Although there was some variability across these trials, results in general demonstrated that patients treated with NACT had improved surgical outcomes (eg, shorter operative time, less blood loss, fewer high-grade surgical complications or surgery-related AEs, shorter hospital stay), less extensive and complicated surgeries needed to achieve optimal cytoreduction, and a lower risk of postoperative death (Table 14).$^{481}$-$^{483,639,640}$ Most of these trials found that NACT increased the likelihood of achieving optimal cytoreduction and/or removal of all macroscopic disease (R0).

Although an NACT approach was associated with improved surgical outcomes and less residual disease after surgery, trials that reported PFS and OS found no significant differences when compared with the conventional PDS approach (Table 14). For some of these trials, post hoc analyses were conducted to determine whether there are any subgroups of patients for whom NACT may improve PFS or OS. Although analyses of CHORUS did not identify any subgroups with treatment-dependent differences in PFS or OS, analyses of EORTC 55971 and a pooled analysis of the per protocol populations from EORTC 55971 and CHORUS

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showed that NACT (with IDS and adjuvant chemotherapy) may improve

PFS and/or OS in patients with more extensive disease, but conventional treatment (PDS and postoperative chemotherapy) was associated with

better PFS and/or OS in patients with less extensive disease.583,887,889

Importantly, for some of these trials (ie, EORTC 55971, CHORUS) the

median PFS and OS for both treatment arms (Table 14) were inferior to

those reported in randomized studies of patients undergoing PDS followed by postoperative IV chemotherapy for advanced disease (OS mean, ~50 months in the United States).724,890 Although the median OS in the

international trial is 20 months lower than that reported in US trials using the customary sequence of therapeutic interventions (ie, PDS followed by chemotherapy), this difference may have been a result of selection of

higher risk patients in the NACT trials (which did not include patients with stage IIIB or earlier stages).

Selection of Patients for NACT

Based on the results from randomized trials shown in Table 14, the NCCN Guidelines recommend considering neoadjuvant therapy for patients with bulky disease that is unlikely to be optimally cytoreduced by up-front

surgery. The panel considers the current evidence to be insufficient for

justifying NACT as an option for patients who by assessment of a

gynecologic oncologist are likely to be optimally cytoreduced by upfront

surgery. When selecting patients for NACT with IDS, the cancer type of

the primary tumor and potential response to primary chemotherapy should be considered. NACT is not appropriate for patients with non-epithelial

cancer types (eg, sex cord-stromal or germ-cell tumors). NACT is not

appropriate for patients with disease apparently confined to the ovary.

NACT can also be considered for patients who are poor surgical

candidates, such as those with poor performance score, in the hopes that tumor load reduction may improve their condition and thereby reduce

perioperative risks. At least one of the randomized trials in Table 14 (Liu

2017640) showed that among patients (aged 60 to 75 years) with stage

III/IV disease, NACT improved the rate of successful cytoreduction and

other surgical outcomes (reduced operative time and blood loss), although similar to other randomized trials no improvement in PFS or OS was

observed.

NCCN recommendations for workup and selection of patients for NACT

are aligned with the eligibility criteria and protocols used in the randomized controlled trials shown in Table 14. For these trials, preoperative

evaluations and debulking surgeries were performed by gynecologic

oncologists; some trials included additional requirements to ensure that

the surgeons had sufficient experience performing the procedures.481-

483,639,640 The NCCN Ovarian Cancer Panel emphasizes that evaluation by a gynecologic oncologist is important for determining the most appropriate method of obtaining tissue for histologic confirmation and of determining the extent of disease. This recommendation is consistent with those from SGO and ASCO.480

Most of the trials in Table 14 required confirmation of staging and

diagnosis based on imaging plus histology of a biopsy specimen or

cytology of ascites or pleural effusion. Some trials had additional entry

criteria based on serum CA-125 and CEA levels, and some required

additional diagnostic tests to rule out other types of malignancies.

Laparoscopy to evaluate extent of disease and feasibility of resection was required in one of these trials (SCORPION) and also frequently used in

the other randomized trials shown in Table 14. Reports from several of

these trials noted that for some patients, the assignment of histologic type and disease stage was revised after biopsy or laparoscopic evaluation,

and sometimes revised after debulking surgery.481-483,639 The NCCN

Guidelines recommend histologic confirmation of diagnosis and cancer

subtype based on analysis of tumor tissue. If biopsy is not feasible,

cytopathology from ascites or pleural effusion combined with a CA-

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125:CEA ratio of >25 can be used.478,479,481,891 Although biopsy can be

obtained through a variety of methods, and minimally invasive techniques can be used, laparoscopic evaluation should be considered for

determining the feasibility of resection, because it may allow for a more

accurate evaluation of whether optimal cytoreduction can be achieved.

Because germline and/or somatic BRCA1 and BRCA2 status may inform future options for maintenance therapy, all patients with histologically

confirmed ovarian, fallopian tube, or primary peritoneal cancer should

undergo genetic risk evaluation and germline and somatic testing, if not

previously performed. In the absence of a BRCA1/2 mutation, homologous recombination deficiency testing may also be considered, as it may

provide information about the magnitude of benefit of PARP inhibitor

maintenance therapy following first-line chemotherapy (category 2B).

However, treatment should not be delayed for genetic counselling referral, because delay in treatment is associated with poorer outcomes.528,529 See Molecular Testing section above.

Regimen Options for Patients Treated with NACT

A wide variety of platinum-based regimens have been used in clinical trials testing NACT plus IDS and postoperative chemotherapy. All of the

randomized trials in Table 14 used platinum-based combination

chemotherapy or monotherapy (Table 15). Other chemotherapy regimens that have been tested in prospective trials in patients with ovarian,

fallopian tube, or primary peritoneal cancer are shown in Table 16.892-897

For most of the trials in Table 15 and Table 16, patients received the same chemotherapy regimen for both NACT and postoperative therapy. For the prospective trials comparing different chemotherapy regimens in patients treated with an NACT approach (ie, PRIMOVAR-1, GEICO 1205/NOVA,

ANTHALYA, OV21/PETROC), none has yet demonstrated the superiority of any regimen based on surgical outcomes, PFS, or OS (Table 16).893,895-897 Given that a wide variety of regimens have been successfully used in

prospective trials, and in the absence of data indicating that specific

regimens should be excluded or favored, the NCCN Guidelines provide a list of options that can be used before and/or after surgery in patients

treated with an NACT approach (Table 17), including all of the IV regimens recommended for conventional treatment of stage II–IV high-grade serous carcinoma (ie, PDS followed by chemotherapy).

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Table 15. Neoadjuvant Chemotherapy Regimens Tested in Randomized Prospective Trials Comparing NACT + IDS Versus PDSa,b

Trial

Chemotherapy Regimen Options

Route Cycle Length, Weeks Patients Treated, n (% of total population) NACT Arm PDS Arm

EORTC 55971483 Platinum-taxane, recommended options:

• Paclitaxel 135 mg/m2 + cisplatin 75 mg/m2

• Paclitaxel 175 mg/m2 + cisplatin 75 mg/m2

• Paclitaxel 175 mg/m2 + carboplatin AUC 5

283 (88%)

243 (78%)

Platinum only:

• Cisplatin ≥75 mg/m2

• Carboplatin AUC ≥5

20 (6%)

25 (8%)

Other

19 (6%)

21 (7%)

CHORUS481

Carboplatin AUC 5–6 + paclitaxel 175 mg/m2

178 (70%)

138 (61%)

Alternative carboplatin combination

1 (<1%)

Carboplatin AUC 5–6

75 (30%)

89 (39%)

SCORPION639 Carboplatin AUC 5 + paclitaxel 175 mg/m2

29 (56%)

31 (61%)

Carboplatin AUC 5 + paclitaxel 175 mg/m2 + bevacizumab

20 (39%)

14 (27%)

Carboplatin + paclitaxel

3 (6%)

5 (10%)

Carboplatin

1 (2%)

JCOG0602482

Paclitaxel 175 mg/m2 + carboplatin AUC 6

150

138

Liu 2017640

Before IDS: Cisplatin 75 mg/m2 IP + docetaxel 75 mg/m2 IV

IP/IV

After IDS: Cisplatin 75 mg/m2 IV + docetaxel 75 mg/m2 IV

Abbreviations: AUC, area under the curve; IDS, interval debulking surgery; IP, intraperitoneal; IV, intravenous; NACT, neoadjuvant chemotherapy; NR, not reported; PDS, primary debulking surgery.

a Trials shown in Table 14.

b All of these trials tested regimens consisting of NACT, followed by IDS (with the goal of maximum cytoreduction), followed by postoperative systemic therapy (for

the indicated number of cycles). Unless otherwise specified, the same regimen was used both as neoadjuvant and postoperatively. In some trials, only patients

meeting certain requirements were allowed to have IDS and/or postoperative chemotherapy.

References

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AUC, area under the curve; IDS, interval debulking surgery; IP, intraperitoneal; IV, intravenous; mo, months; NACT, neoadjuvant chemotherapy; NR, not reported; NS, no significant difference between arms; OL, open-label; OS, overall survival; PFS, progression-free survival; R, randomized; R0, no macroscopic residual

disease; RCT, randomized controlled trial; wks, weeks.

a All of these trials tested regimens consisting of neoadjuvant systemic therapy (for indicated number of cycles [number of cyc les before IDS]), followed by IDS (with the goal of maximum cytoreduction), followed by postoperative systemic therapy (for the indicated number of cycles [number or cycles after IDS]). Unless

otherwise specified, the same regimen was used both as neoadjuvant and postoperative, and agents were administered on day 1 o f each cycle. In some trials,

only patients meeting certain requirements were allowed to have IDS and/or postoperative chemotherapy.

b In SWOG S0009, patients with stage III were required to have large pelvic mass and/or bulky abdominal disease and/or malignant pleural effus ion; patients with

stage IV were required to have malignant pleural effusion.

c In SWOG S0009, 58 patients were eligible for NACT and 45 completed NACT. Patients were required to have ≥50% decrease in CA -125 to be eligible for IDS, so 36 received IDS. Patients were required to have optimal debulking (<1 cm and malignant pleural effus ion resolved) to be eligible for postoperative chemotherapy, so only 26 received postoperative chemotherapy, and 18 completed planned treatment. Rate of residual disease and PFS and OS s hown in the table is based on total number of patients eligible for NACT. For patients who were optimally debulked by IDS and received postoperative IP/IV chemotherapy, median PFS and OS were 29 and 34 months, respectively.

d PRIMOVAR-1 and ANTHALYA: all patients with stage III disease had stage IIIC.

e MITO-16A-MaNGO OV2A: all patients with stage III disease had stage IIIB/C.

f In the bevacizumab arm of GEICO 1205/NOVA, chemotherapy before IDS included at least 3 cycles with bevacizumab. In the bevacizumab arm of ANTHALYA,

chemotherapy included bevacizumab for cycles 1–3 and cycles 6–8.

g For GEICO 1205/NOVA, ASCO abstract reported “optimal surgery rate” without defining optimal surgery.

h In OV21/PETROC: <1% and 1% of patients had stage IIB and stage IIC disease. All patients with stage III disease had stage III B/C. All patients with stage IV

disease had stage IVA.

i In OV21/PETROC, patients were required to have had 3–4 cycles of platinum-based IV NACT (regimen details not reported) followed by optimal IDS (<1 cm); they were randomized after IDS. PFS and OS were measured from randomization. The study was not complete so comparisons of OS were not possible.

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Table 17. NCCN Guidelines for Ovarian Cancer: Recommended Regimens for NACT and for Adjuvant Chemotherapy After IDS

Optionsa

Cycle Length (weeks)

Cyclesb

Before

IDS After IDS

IP/IV Regimensc (Adjuvant Only)

For optimally debulked stage II–III disease: Paclitaxel 135 mg/m2 IV Day 1; cisplatin 75–100 mg/m2 IP Day 2 after IV paclitaxel; paclitaxel 60 mg/m2 IP Day 8.

≥3

Paclitaxel 135 mg/m2 IV Day 1, carboplatin AUC 6 IP Day 1, paclitaxel 60 mg/m2 IP Day 8.

≥3

IV Regimens (Neoadjuvant and Adjuvant)

Paclitaxel 175 mg/m2 + carboplatin AUC 5–6 Day 1.

3–6

≥3

Dose-dense paclitaxel 80 mg/m2 Days 1, 8, and 15 + carboplatin AUC 5–6 Day 1.

3–6

≥3

Paclitaxel 60 mg/m2 + carboplatin AUC 2.

3–6

≥3

Docetaxel 60–75 mg/m2 + carboplatin AUC 5–6 Day 1.

3–6

≥3

Carboplatin AUC 5 + pegylated liposomal doxorubicin 30 mg/m2.

3–6

≥3

ICON-7: Paclitaxel 175 mg/m2 + carboplatin AUC 5–6 + bevacizumab 7.5 mg/kg Day 1.

3–6d CT: ≥3 Bev: ≤15

GOG-218: Paclitaxel 175 mg/m2 + carboplatin AUC 6 Day 1. Starting Day 1 of cycle 2, bevacizumab 15 mg/kg.

3–6d CT: ≥3 Bev: ≤22

IV Regimens for Patients >70 years and Those with Comorbidities (Adjuvant Only) Carboplatin AUC 5.

≥3

Paclitaxel 135 mg/m2 + carboplatin AUC 5.

≥3

Paclitaxel 60 mg/m2 + carboplatin AUC 2.

≥3

AUC, area under the curve; bev, bevacizumab; CT, chemotherapy; IDS, interval debulking surgery; IP, intraperitoneal; IV, intravenous; NACT,

neoadjuvant chemotherapy; NR, regimen not recommended as an option in that setting; post-op, postoperative

a All options listed are category 2A.

b For all regimens recommended for use before IDS, surgery after 3 cycles of NACT is preferred; however, surgery may be performed after 4–6 cycles based on the clinical judgment of the gynecologic oncologist. A total of ≥6 cycles of treatment is recommended , including at least 3 cycles of

adjuvant therapy after IDS.

c There are limited data for the use of IP chemotherapy regimens after neoadjuvant therapy and IDS.

d Bevacizumab-containing regimens should be used with caution before IDS due to potential interference with postoperative healing. Withhold

bevacizumab for 6 weeks before IDS.

Bevacizumab-Containing Regimens for Patients Treated with NACT

Several prospective trials have explored whether adding bevacizumab to

platinum-based regimens improves outcomes for patients treated with

NACT. Preliminary results from GEICO 1205/NOVA found that adding

bevacizumab to a standard carboplatin/paclitaxel regimen did not

significantly change the rate of CR on NACT (prior to IDS), rate of “optimal surgery,” or PFS, but did show a lower rate of grade 3–4 AEs in the arm that included bevacizumab (70% vs. 42%, P = .026).895 The ALTHALYA

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trial used a similar carboplatin/paclitaxel regimen, but did not find a

significant difference in the rate of grade 3–5 AEs for patients treated

without versus with bevacizumab (63% vs. 62%).896 Results from

ALTHALYA also showed no difference between treatment arms for CR

rate prior to IDS, percent of patients with no macroscopic residual disease after IDS, or surgical outcomes (operative time, length of hospital stay,

length of stay in intensive care unit, frequency of blood transfusions, and rate of postoperative complications).896 Taken together, results from these trials indicate that although platinum-based regimens that include

bevacizumab have acceptable safety for patients treated with an NACT

approach, more data are needed to determine whether the addition of

bevacizumab impacts PFS. The NCCN Guidelines include two

bevacizumab-containing regimens as options for NACT and post-IDS

chemotherapy (Table 17). It is important to note that all of the prospective trials in Table 15 and Table 16 that allowed use of bevacizumab in the

NACT setting used a washout period before (and sometimes after) IDS,

usually of at least 28 days.639,894-896 Bevacizumab-containing regimens

should be used with caution before IDS due to potential interference with postoperative healing. If bevacizumab is being used as part of a

neoadjuvant regimen, bevacizumab should be withheld from therapy for at least 6 weeks prior to IDS.

Intraperitoneal/Intravenous Regimens for Patients Treated with NACT

Several trials have explored the use of IP/IV regimens in patients treated with an NACT approach. Both SWOG S0009 and OV21/PETROC tested postoperative IP/IV regimens for patients who had platinum-based NACT followed by optimal cytoreduction by IDS.892,897 In SWOG S0009, among patients with a 50% or greater decrease in CA-125 level during NACT,

optimal debulking by IDS (<1 cm and malignant pleural resolved), and

postoperative IP/IV chemotherapy, median PFS (29 months) and OS (34 months) compared favorably with results from other trials using IV

regimens (Table 16).892 To determine whether postoperative IP/IV

chemotherapy improves outcomes compared with IV regimens among

patients treated with NACT, the OV21/PETROC trial compared three

different postoperative regimens (Table 16) in patients previously treated with platinum-based IV NACT (3–4 cycles) and optimal cytoreduction by

IDS.897 Although trends in the rate of progression or death in the first 9

months (from randomization) favored the carboplatin/paclitaxel IP/IV

regimen (Arm 3, 24.5%) over the cisplatin/paclitaxel IP/IV regimen (Arm 2,

34.7%) or the carboplatin/paclitaxel IV regimen (Arm 1, 38.6%), later

results (median follow-up 33 months) showed no difference in median PFS for the IP/IV regimens versus the IV regimen (Table 16). OS rate at 2

years was also not significantly different (74% vs. 81% for Arm 1 vs. Arm 3).897

Based on these results, the NCCN Guidelines include both the

cisplatin/paclitaxel IP/IV regimen and the carboplatin/paclitaxel IP/IV

regimen as options for postoperative therapy in patients who have

received NACT and IDS (Table 17). Given the lack of survival

improvement in OV21/PETROC, more data are needed to establish

whether postoperative IP chemotherapy provides clinical benefit in

patients who have received IV NACT and IDS. Recent results from the

phase III randomized controlled GOG-0252 trial have also called into

question the value of postoperative IP chemotherapy for patients with

advanced-stage disease treated with PDS.870 Although earlier trials

showed improved PFS and/or OS with IP versus IV

chemotherapy,724,863,864,868 results from GOG-0252 showed no

improvement.870 However, unlike previous trials, all regimens used in

GOG-0252 contained bevacizumab, which may have compensated for the effect of IP chemotherapy administration.

Number of Chemotherapy Cycles Before and After IDS

As shown in Table 16, results from the PRIMOVAR-1 phase II randomized trial showed that treatment with 3 versus 2 cycles of NACT did not impact

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response rate, extent of cytoreduction achieved in IDS, operative time,

extent of surgery needed, or PFS or OS.893 Nonetheless, because most of the randomized trials testing NACT protocols used 3 to 4 cycles before

IDS (Table 15 and Table 16), the NCCN Guidelines indicate that 3 to 4

cycles of NACT before IDS is preferred, although surgery after 4 to 6

cycles may be used based on the clinical judgment of the treating

gynecologic oncologist.

After 3 to 4 cycles of NACT, patients should be evaluated by a

gynecologic oncologist to determine the likelihood of optimal

cytoreduction. For patients whose disease responded to NACT and are

likely to have optimal cytoreduction, IDS with completion

hysterectomy/BSO and cytoreduction should be performed. Those with

stable disease after 3 to 4 cycles of NACT can consider IDS (with

completion hysterectomy/BSO, and cytoreduction), but also should

consider either 1) switching to treatment for persistent/recurrent disease; or 2) treatment with additional cycles of NACT (to a total of ≥6 cycles),

then re-evaluating to determine whether to perform IDS (with completion hysterectomy/BSO, and cytoreduction) or switch to therapy for

persistent/recurrent disease. The option to continue on beyond 6 cycles is usually reserved for those who are tolerating therapy and have signs that a response may be achieved, such as those whose CA-125 is continuing to fall. Patients who experience disease progression during NACT should switch to therapy for persistent/recurrent disease.

Most of the trials testing NACT regimens used at least 3 cycles of adjuvant chemotherapy after IDS, or indicated that the total number of cycles

should be 6 to 8 (Table 14, 15, and 16). The NCCN Guidelines

recommend that regardless of the number of cycles of NACT received,

IDS should always be followed by adjuvant chemotherapy. For all patients who undergo NACT plus IDS, a minimum of 6 cycles of treatment is

recommended, including at least 3 cycles of adjuvant therapy after IDS.

Patients with stable disease who are tolerating therapy may continue past 6 cycles.

Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer

Analyses of data from multiple prospective trials found that the extent of

residual disease after NACT plus IDS was prognostic for PFS and

OS.481,483,640,893 As shown in Table 14, 15, and 16, these trials reported

optimal cytoreduction in 45% to 91% of patients, with complete removal of all macroscopic disease in 30% to 59%. Therefore, as with a primary

debulking procedure, every effort should be made to achieve complete

removal of macroscopic disease (R0) during IDS. Maximal effort should be made to remove all gross disease in the abdomen, pelvis, and

retroperitoneum. NCCN-recommended procedures for IDS are similar to those used in the trials listed in Table 14, 15, and 16,481-483,639,892-894,896 and similar to those recommended for PDS. As mentioned earlier, these trials required experienced gynecologic oncologists for preoperative evaluation and IDS.481,483,639,896 Some NCCN Panel members use online surgical risk calculators to determine whether IDS is safe in a patient who chose NACT (over PDS) due to a medical condition. Examples include the Modified

Charlson Comorbidity Index (score <2),899-903 ASA Physical Classification Status (score <3),904-906 the Edmonton Frail Scale (score <3),907 and the

ACS NSQIP Surgical Risk Calculator.908-910 It is recommended that a

gynecologic oncologist be consulted and perform the surgery. An open

laparotomy including a vertical midline abdominal incision should be used in most patients in whom an interval debulking procedure is planned.

Minimally invasive techniques can be used for IDS in select patients.

Patients whose disease is unable to be optimally debulked using minimally invasive techniques should be converted to an open procedure. Prior to

IDS, patients should be counseled about port placement if subsequent IP chemotherapy is being considered.

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All interval debulking procedures should include completion hysterectomy and BSO with comprehensive staging. All peritoneal surfaces should be

visualized, and any peritoneal surface or adhesion suspicious for

harboring metastasis should be selectively excised or biopsied. Suspicious and/or enlarged nodes should be resected, if possible. Removal of lymph nodes noted to have potential metastasis at the time of initial diagnosis

should be considered, even if the nodes are not currently suspicious or

enlarged. An omentectomy should be performed, and additional

procedures that may be considered include bowel resection and/or

appendectomy, stripping of the diaphragm or other peritoneal surfaces,

splenectomy, partial cystectomy and/or ureteroneocystostomy, partial

hepatectomy, partial gastrectomy, cholecystectomy, and/or distal

pancreatectomy.

Hyperthermic Intraperitoneal Chemotherapy at the Time of IDS

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a technique in

which chemotherapy is delivered in a heated solution perfused throughout the peritoneal space. The rationale for hyperthermic delivery is that heat can increase penetration of the chemotherapy at the peritoneal surface

and enhance the sensitivity of cancer cells to chemotherapy by inhibiting DNA repair.911-913 Concerns about the inconvenience of delivery and

toxicities associated with postoperative IP/IV chemotherapy motivated

researchers to determine whether HIPEC could improve safety and QOL. Although raising body temperature carries substantial risks, methods have been developed for raising the temperature of the IP space with minimal increase in the temperature of the rest of the body.

Over the past several decades a few randomized trials (Table 18)914-917

and numerous prospective nonrandomized trials918-931 have reported on

the use of HIPEC in patients with ovarian cancer. HIPEC methods have

evolved over the years to reduce intraoperative and postoperative

complications. Both “open” and “closed” abdominal techniques have been

developed and tested in these prospective studies.914,915,917-931 HIPEC

protocols used in these prospective studies usually perfused

chemotherapy for 60 or 90 minutes (depending on agent and dose used) with solution heated to achieve an IP temperature of 41°C to 43°C.914-931

The duration and safety of cytoreductive surgery plus HIPEC procedures varied across trials, with median procedure time ranging from 300 to 600 minutes and median hospital stay ranging from 8 to 24 days.917-924,926-931

Excessive blood loss was common, and in some studies, more than half of the patients required transfusions. Intraoperative and postoperative

mortality (<30 days from surgery) ranged from 0% to 7%,918-925,927 although the most recent trials all report no deaths related to the procedure.929-931

The rate of complications from surgery vary across trials, with

major/severe complications (<30 days from surgery) occurring in 9% to

40% of patients.918-927,929,930 Studies from one center reported that

complication rates decreased in more recent years compared with when

their center first started performing debulking and HIPEC procedures.920,932 Common major/severe complications observed across trials include

various types of fistulas, abscesses, and infections (eg, wound infection, sepsis, pneumonia, central line-associated infection, intra-abdominal

infection), surgical wound dehiscence, bowel perforation, ileus,

hemorrhages, venous thromboembolism, myocardial infarction, pleural

effusions, pneumothorax, and renal failure/insufficiency.914,919-

923,925,927,928,930,933 Many studies reported that additional procedures were

needed to manage complications.914,920,921,924,926,927,929,930,933,934

Given the risks associated with HIPEC, prospective studies have focused on using HIPEC immediately after debulking (as part of the same

procedure) in patients with high-volume IP disease (FIGO stage III–IV at diagnosis or recurrence), particularly those with peritoneal carcinomatosis, who are at risk for widespread residual microscopic disease even after

resection to no visible disease. Compared with postoperative IP therapy, intraoperative IP administration may enable better perfusion of the

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peritoneal space because adhesions will not yet have formed. Patients

with less extensive disease were excluded because they are less likely to have widespread microscopic disease after debulking, and therefore the

potential benefit is unlikely to outweigh risks of the procedure. Patients

with distant extra-abdominal metastases were often excluded from HIPEC studies because of concerns that IP therapy would not be effective

treatment for extra-peritoneal disease.

Only a few phase III prospective comparative studies have tested whether HIPEC improves outcomes for patients with advanced ovarian cancer

(summarized in Table 18). The most recent and largest (n = 245) of these, M06OVH-OVHIPEC, showed that HIPEC improved recurrence-free

survival and OS in patients with FIGO stage III primary epithelial ovarian, fallopian tube, or peritoneal cancer who underwent NACT due to extensive abdominal disease or suboptimal PDS.917 Although the total procedure

time for debulking + HIPEC was longer than for debulking alone, HIPEC

did not appear to have any major effects on hospital stay (median, 10 vs. 8 days) or administration of postoperative IV chemotherapy (ie, time to

initiation, rate of completion of all 3 cycles). Most important, no differences in rates of toxicity were observed between arms (grade 3–4 toxicities: 27% vs. 25%) or in any of the health-related quality-of-life metrics evaluated.

Because of these positive results, the NCCN Guidelines now include an

option to consider HIPEC at the time of IDS in patients with stage III

disease treated with NACT. Similar to the trial, which required patients to have response or stable disease after 3 cycles of NACT and which treated patients with postoperative chemotherapy (3 cycles), the NCCN

Guidelines recommend HIPEC as an option for patients who have

response or stable disease after NACT (3 cycles preferred, but 4–6

allowed) and recommend that all patients treated with NACT and IDS (±

HIPEC) receive postoperative chemotherapy. Analyses of M06OVHOVHIPEC showed that the effect of HIPEC was consistent across a wide

variety of subgroups (eg, age, cancer type, prior surgery, extent of

disease, laparoscopy before surgery). Therefore, the NCCN Guidelines

indicate that HIPEC can be considered for all patients with stage III

disease for which NACT and IDS is performed, without any further

requirements for selection of patients. Importantly, HIPEC is not

recommended for patients treated with PDS (no NACT) based on initial

results from a randomized controlled trial showing that HIPEC did not

improve PFS or OS in a population of patients with optimal cytoreduction (<1 cm residual) after PDS or after NACT + IDS (Table 18).916 In the

subset of patients who underwent NACT and IDS, however, long-term

follow-up showed a trend toward improved PFS and OS with HIPEC.916

In most prospective studies testing HIPEC, the surgery prior to HIPEC was conducted with the goal of maximal cytoreduction (R0 resection) and

involved TAH/BSO, omentectomy, and a variety of other procedures,

depending on the extent of disease. Optimal cytoreduction (residual

disease <1 cm) was achieved in most patients in these trials, and, in some studies, was a requirement for receiving subsequent HIPEC.914,915,917-931

Rates of complete cytoreduction (R0 resection) varied from 50% to 100% in these trials,918-920,922-928,930,931 and univariable and multivariable analyses showed that residual disease after debulking was the strongest predictor of OS. 918,919,923-925,933,935 Therefore, NCCN recommends maximum effort to achieve complete cytoreduction during IDS, regardless of whether or not HIPEC is planned.

The NCCN-recommended HIPEC agent is cisplatin, 100 mg/m2, as was

used in M06OVH-OVHIPEC.917 Although this trial tested only one regimen for NACT and postoperative chemotherapy (carboplatin, area under the

curve [AUC] 5–6 + paclitaxel, 175 mg/m2 body surface area [BSA]), other studies have used a variety of agents, and the optimal pairing of

pre/postoperative regimens with HIPEC agent has not been determined. The NCCN Guidelines currently do not restrict the HIPEC

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Abstract

NCCN Guidelines Version 3.2025 Ovarian Cancer recommendation based on the regimen selected for NACT or postoperative chemotherapy.

References

Keywords

MS-62 NCCN Guidelines Version 3.2025 Ovarian Cancer Trial Patients Treatment Arms HIPEC Method & Regimen Surgical/Safety Outcomes, Arm A vs. B Efficacy Outcomes, Arm A vs. B

b Major or minor postoperative complications included both those related to surgery and those related to chemotherapy. Grade 1 was defined as no complications; grade 2, minor complications; grade 3, major complications requiring reoperations or ICR admission; grade 4, in -hospital mortality. c Greater extent of resection and lower PCI were correlated with improved OS. d Excluded patients with pleural disease or lung metastasis, > 3 sites of bowel obstruction, bulky disease in retroperitoneal ar ea or mesentry, disease beyond the abdomen, or splanchnic metastasis. e No differences in morbidity or mortality except for anemia (67% vs. 50%, P = .025) and creatinine elevation (15% vs. 4%, P = .026). f NACT and post-op chemo regimen: carboplatin (AUC 5-6) + paclitaxel (175 mg/m 2 ). Randomization was performed after NACT, before interval CRS. g In M06OVH-OVHIPEC, grade 3-4 AEs were reported for the period starting at randomization to 6 weeks after the last cycle of chemotherapy.

Monitoring Response to Adjuvant Systemic Therapy

After completion of chemotherapy, patients should be assessed for response during and following treatment and monitored for any long-term complications. Consider symptom management and best supportive care, and refer for palliative care assessment, if appropriate. See NCCN Guidelines for Palliative Care and NCCN Guidelines for Survivorship (available at www.NCCN.org).

Patients who have completed primary treatment for stage I disease (surgery alone or with adjuvant systemic therapy) should be monitored for recurrence. See Follow-up Recommendations below.

For patients who have completed postoperative chemotherapy as part of primary therapy for stage II-IV disease, imaging is recommended as clinically indicated to determine the extent of disease, if any. Recommended imaging modalities include chest/abdominal/pelvic CT, MRI, PET/CT, or PET (skull base to mid-thigh). All imaging should be performed with contrast unless contraindicated. Patients who have CR, with no evidence of disease, or PR may be eligible for maintenance

References

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therapy as described in the next section (Options After First-Line

Chemotherapy). Those with stable, persistent, or progressive disease should be managed as described in the section entitled Therapy for Persistent Disease or Recurrence.

Options After First-Line Chemotherapy

After initial treatment (eg, surgery followed by chemotherapy), patients

should undergo regular clinical re-evaluation. Observation with follow-up is recommended for patients who had stage I disease at presentation and

have no signs of new disease. Recommendations for surveillance during observation are in the Monitoring/Follow-up section (within the Epithelial

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section in the algorithm).

For patients who had stage II–IV disease at presentation, options following surgery and chemotherapy depend on the success of these interventions. These patients should be evaluated with imaging as clinically indicated to determine the extent of residual disease or progression and screen for

new metastases. Imaging should include chest/abdominal/pelvic CT, MRI, PET/CT, or PET (skull base to mid-thigh).

Patients with persistent disease or progression during initial treatment

should be treated with second-line approaches (see Epithelial Ovarian

Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for

Persistent Disease or Recurrence in the algorithm and Recurrent Disease section below).936,937

For patients with advanced-stage (stages II–IV) disease who, after primary therapy (surgery plus chemotherapy), are in complete clinical remission

(ie, complete response [CR], defined as no definitive evidence of

disease936,937), partial remission (ie, partial response [PR]), or stable

disease, recommended options depend on the extent of their response

and the type of primary chemotherapy they received (see Post-Primary

Treatment: Maintenance Therapy within the Epithelial Ovarian

Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section of the algorithm). These recommendations have been revised several times

recently due to emerging data from clinical trials, summarized in Tables 19, 20, and 21. These recent data and their impact on the

recommendations are discussed in the sections below.

Bevacizumab Maintenance Therapy

As described in detail in the previous section entitled Bevacizumab in the First-Line Setting, results from the phase III GOG-0218 and ICON7 trials support the use of single-agent bevacizumab maintenance therapy for

patients with stage II–IV disease who experience response or stable

disease after postoperative chemotherapy with one of the

carboplatin/paclitaxel/bevacizumab regimens used in these trials (and

recommended by NCCN).817-819 Based on these results bevacizumab

monotherapy was a recommended option for maintenance for patients

with stage II–IV disease who were in CR/PR after a primary treatment with surgery and one of the bevacizumab-containing regimens recommended in the first-line setting. However, due to results from subsequent trials

showing benefit from PARP inhibitors, as described below, bevacizumab monotherapy is no longer recommended for patients with BRCA1/2

mutations, but is still recommended as an option for patients who have

wild-type or unknown BRCA1/2 mutation status (in CR/PR after a

recommended bevacizumab-containing first-line chemotherapy regimen), as these patients have fewer PARP inhibitor options (See Table 23).

PARP Inhibitor Maintenance Therapy After Primary Chemotherapy

Several PARP inhibitors have been shown to be active in recurrent

ovarian cancer,938-945 and have been FDA approved for multiple indications in ovarian cancer (summarized in Table 22); the corresponding

recommendations can be found in the NCCN Guidelines algorithm for

Post-Primary Treatment: Maintenance Therapy (OV-5), Therapy for

NCCN Guidelines Version 3.2025 Ovarian Cancer

3] [754] [755] Characteristics of the patient populations in these trials are summarized in Table 20 , and efficacy and safety results are summarized in Table 19 and Table 21 .

References

MS-65

Abstract

NCCN Guidelines Version 3.2025 Ovarian Cancer e First-line therapy was for 6 cycles, maintenance for 30. Veliparib dose during chemotherapy was 150 mg BID. Only those who complete d the 6 cycles of first-line therapy without progression were treated with single-agent maintenance veliparib 300 mg (or placebo) BID x 2 weeks, then veliparib 400 mg (or placebo) BID.

• Response after systemic therapy: CR, PR h 82%, 18% 73%, 27% 69%, 31% NR • CA-125 ≤ULN after systemic therapy 95% 86% 92% NR Abbreviations: CA-125, cancer antigen 125; CR, complete response; HRD, homologous recombination deficient; HRP, homologous recombination profic ient; IDS, interval debulking surgery (after neoadjuvant therapy); NED, no evidence of disease; NR, not reported; PDS, upfront primary debulking surgery; PR, partial response; RCT, randomized controlled trial; ULN, upper limit of normal. a All patients had newly diagnosed, histologically confirmed disease. Data show percent of total randomized population (n = 310 for SOLO-1, 806 for PAOLA-1, 733 for PRIMA, 1140 for VELIA). b In SOLO-1, other cancer types were mixed endometrioid and serous. In PAOLA-1, other cancer types included clear cell, undifferentiated, or other; entry criteria allowed high-grade serous, high-grade endometrioid, and other non-mucinous with deleterious germline BRCA1/2 mutation. In PRIMA, study entry criteria required high-grade serous or high-grade endometrioid histology, yet 17 patients were listed as "other" without further explanation. VELIA entry criteria required histologic confirmation of high-grade serous, and no data on this were reported. c For PAOLA-1 and PRIMA, homologous recombination deficiency was defined as BRCA1/2 mutation or an GIS ≥42 on myChoice CDx assay (Myriad Genetic Laboratories). For VELIA, homologous recombination deficiency was defined as BRCA1/2 mutation or a GIS ≥33 on myChoice CDx assay (Myriad Genetic Laboratories). d Entry criteria for PRIMA required patients to have either 1) stage III disease with visible residual tumor after primary surg ery; 2) inoperable stage III disease; or 3) any stage IV disease (residual disease after surgery not required). 23.1% of patients had stage III disease with residual dis ease after primary surgery. e Chemotherapy agents used in both arms were paclitaxel (98% of patients), carboplatin (91%), cisplatin (20%), docetaxel (6%), and gemcitabine ( < 1%). Other agents were used in < 1% of patients in the olaparib arm only: nab-paclitaxel, doxorubicin, cyclophosphamide, and bevacizumab.

References

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f Information is based on entry criteria because data were not reported.

g In SOLO-1, 1% of patients had 4 cycles of chemotherapy.

h In SOLO-1 and PAOLA-1, CR was defined as NED on imaging (no measurable/assessable disease) and CA-125 ≤ULN. In SOLO-1, PR was defined as 30%

reduction in tumor volume or NED on imaging with CA-125 >ULN. In PAOLA-1, PR was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. In PRIMA, CR and PR were judged by “investigator assessment”; more specific criteria were not disclosed. In VELIA, the response rate for the whole

population was not reported, and response was not required prior to maintenance therapy.

Olaparib Monotherapy

The SOLO-1 trial demonstrated a remarkable improvement in PFS with

single-agent olaparib versus placebo as maintenance therapy for patients with a germline or somatic BRCA1/2 mutation who had a CR/PR after firstline platinum-based chemotherapy (Table 19).752 The risk of progression or death was 70% lower, with the median PFS (from randomization) of

13.8 months for placebo, and the median PFS for olaparib had not been reached after a median follow-up of 41 months; OS data are also

immature. A subsequent subgroup analysis showed that the PFS benefit was significant regardless of BRCA mutation type (BRCA1 vs. BRCA2).946 Based on results from SOLO-1, the NCCN Guidelines include olaparib

monotherapy as a maintenance therapy option for patients who have a

BRCA1/2 mutation and have a CR or PR after completion of primary

therapy including surgery and platinum-based chemotherapy (Table 23).

SOLO-1 excluded patients who received bevacizumab as part of primary systemic therapy, so the efficacy of single-agent olaparib after

chemotherapy/bevacizumab primary therapy is unknown. Nonetheless,

the benefit from olaparib was sizeable and significant across many

subgroups analyzed.752,946 It is important to note that the effects of

maintenance olaparib on PFS (70% improvement; Table 19)752 are far

greater than the effects on PFS reported for the addition of bevacizumab to both upfront and maintenance therapy (<30% improvement).817,819,820

PFS curves from SOLO-1 show large separation between olaparib versus placebo throughout the time course of the study (median follow-up, 41

months),752 in contrast to results from GOG-0218 and ICON7 showing

PFS curves converging well before 40 months, even for the high-risk

groups shown to benefit most from bevacizumab.819,820 In addition, the

exploratory analysis of GOG-0218 based on BRCA mutation status

suggests that bevacizumab may not improve PFS in patients with

BRCA1/2 mutations.824 The PAOLA-1 trial (described in the next section) suggested that maintenance olaparib could provide PFS benefit in patients who had bevacizumab during first-line chemotherapy.753 For these

reasons single-agent olaparib is a category 1 option only for patients who did not have bevacizumab as part or primary therapy, but is a category 2A option for patients who received prior bevacizumab, provided that they

were in a CR or PR after completion of chemotherapy (Table 23). The

NCCN Panel included a footnote to make it clear that data are limited on the use of single-agent olaparib after first-line platinum-based

chemotherapy plus bevacizumab, but that evidence from other subgroups suggests that it should be considered as an option for these patients.

Olaparib + Bevacizumab

The phase III double-blind, randomized PAOLA-1 trial demonstrated a

remarkable improvement in PFS (HR, 0.59) when olaparib (vs. placebo)

was added to maintenance bevacizumab in patients who have a CR or PR after first-line platinum-taxane chemotherapy plus bevacizumab for

advanced disease (Table 19).753 Unlike SOLO-1, PAOLA-1 included both patients with and without BRCA1/2 mutations. Subgroup analyses showed that similar to the SOLO-1 trial, for patients with BRCA1/2 mutations,

maintenance olaparib reduced the risk of progression or death by

approximately 70% (Table 19).753 A subsequent sub-analysis found that

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the PFS benefit of adding olaparib to bevacizumab maintenance was

similar and significant regardless of BRCA mutation type (BRCA1 vs.

BRCA2).947 Based on these results, maintenance with bevacizumab +

olaparib is a category 1 option for patients who have a CR/PR after

completing bevacizumab-containing first-line therapy, and single-agent

bevacizumab was removed as a maintenance therapy option in this

setting.

PAOLA-1 also showed that adding olaparib to maintenance bevacizumab resulted in a smaller but still significant improvement in PFS for those with BRCA1/2 wild-type or unknown (Table 19).753 Due to the smaller

magnitude of this effect, the NCCN Guidelines include olaparib +

bevacizumab combination and bevacizumab monotherapy as category 2A maintenance therapy options for patients with BRCA1/2 wild-type or

unknown mutation status who are in a CR or PR after completion of firstline platinum-based chemotherapy/bevacizumab combination (Table 23).

In PAOLA-1 the population without BRCA1/2 mutations was further

subdivided based on results of MyChoice CDx (Myriad Genetic

Laboratories), a proprietary tumor tissue assay that uses multiple

molecular tests and combines several metrics (loss of heterozygosity

[LOH],948 telomeric allelic imbalance [TAI],949 and large-scale state

transitions [LST]950 to determine the genomic instability score (GIS), a

proxy measure for the presence of homologous recombination

deficiency.951,952 A GIS cutoff of 42 was used to define homologous

recombination deficiency status based on a prior analyses of a population of breast and ovarian cancer cases showing that this cutoff identified 95% of patients who had BRCA1/2 deficiency, defined as either 1) one

deleterious mutation in BRCA1 or BRCA2, with LOH in the wild-type copy; 2) two deleterious mutations in the same gene; or 3) promoter methylation of BRCA1 with LOH in the wild-type copy.953 Among those without

BRCA1/2 mutations, the PFS benefit of maintenance olaparib was

significant for those with homologous recombination deficiency (as defined by the proprietary assay) but was not significant for those who did not

have homologous recombination deficiency (Table 19). For this reason,

the NCCN Panel included the following footnote relating to the use of

maintenance bevacizumab + olaparib: In the absence of a BRCA1/2

mutation, homologous recombination deficiency status may provide

information on the magnitude of benefit of PARP inhibitor therapy

(category 2B).

OS results from PAOLA-1 were not mature.

Niraparib Monotherapy

Similar to the SOLO-1 results for olaparib monotherapy, the PRIMA trial

demonstrated a remarkable improvement in PFS with single-agent

niraparib (versus placebo) as maintenance therapy for patients with a

BRCA1/2 mutation who were in a CR/PR after first-line platinum-based

chemotherapy (Table 19).754 Based on these results the NCCN Guidelines include single-agent niraparib as a maintenance therapy option for

patients with BRCA1/2 mutations who have completed primary treatment including surgery and platinum-based first-line therapy (Table 23). PRIMA likely did not include many patients who had prior bevacizumab as part of primary systemic therapy, so for patients with a BRCA1/2 mutation

maintenance niraparib is a category 1 option for those who had first-line

platinum-based chemotherapy without bevacizumab, and a category 2A

option for those who had bevacizumab in conjunction with first-line

platinum-based chemotherapy (Table 23).

Unlike SOLO-1, the presence of a BRCA1/2 mutation was not part of the entry criteria for the PRIMA trial. PRIMA included patients who did not

have deleterious mutations in BRCA1/2, and results showed significant

PFS improvement with niraparib (vs. placebo) for the overall population.

Subgroup analyses showed that the effect of maintenance niraparib on

PFS was still significant among patients without a BRCA1/2 mutation (HR,

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0.71 [95% CI, 0.58–0.88]), although the size of the effect appears smaller than that seen in patients with BRCA1/2 mutations (Table 19). Based on these results, the NCCN Guidelines include single-agent niraparib as an option for maintenance therapy for patients with BRCA1/2 wild-type or

unknown, provided they are in a CR or PR after completion of primary

platinum-based chemotherapy (without bevacizumab) (Table 23). Given

the smaller magnitude of the PFS effect in patients without BRCA1/2

mutation, and that PRIMA likely included very few patients who had

bevacizumab as part of primary therapy, single-agent niraparib is not a

recommended maintenance therapy option for those who have BRCA1/2 wild-type or unknown and received bevacizumab as part of primary

therapy (Table 23).

As in PAOLA-1, in PRIMA the patient group without BRCA1/2 mutation

was further subdivided into homologous recombination deficient and

proficient based on a GIS cutoff of 42 using the MyChoice CDx (Myriad

Genetic Laboratories).754 Results showed that the PFS effect of niraparib (vs. placebo) remained significant for the smaller subgroup of patients with homologous recombination deficiency but no BRCA1/2 mutation, and was significant, with a trend toward smaller magnitude, for the homologous

recombination-proficient subgroup (Table 19).754 Because of these results, the NCCN Panel chose to include the following footnote relating to the use of maintenance niraparib: in the absence of a BRCA1/2 mutation,

homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor therapy (category 2B).

OS data from the interim analysis was reported (Table 19), but it is

premature to draw conclusions from those results.

Veliparib

The phase III VELIA study design was similar to GOG-0218 and ICON7

bevacizumab trials in that it tested the effect of adding veliparib during

first-line chemotherapy and as subsequent single-agent maintenance after

completion of chemotherapy.755 VELIA did not require that patients have

CR/PR before receiving maintenance therapy; they only needed to have

absence of progression during first-line systemic therapy (6 cycles) and no limiting toxicities. Results showed that whereas adding veliparib during

first-line chemotherapy did not significantly improve PFS compared with

chemotherapy alone, those who received veliparib during first-line

chemotherapy and maintenance therapy had significantly improved PFS compared with those who received chemotherapy alone (with placebo

during first-line systemic therapy and maintenance; Table 19). Subgroup analyses showed that whereas the PFS benefit from veliparib appeared to be the greatest for those with a BRCA1/2 mutation, and was significant for those with homologous recombination deficiency (BRCA1/2 mutation or a GIS ≥33 on myChoice CDx assay), the effect was smaller and not

significant for the subgroup without BRCA1/2 mutation and the subgroup that was homologous recombination-proficient (no BRCA1/2 mutation and GIS <33; Table 19). OS results were not mature.755 Veliparib is not

recommended in the NCCN Guidelines because it is not FDA approved for any indications. Nonetheless the consistency of the results observed in

VELIA support the use of PARP inhibitors as maintenance therapy after

first-line platinum-based chemotherapy, and suggest that adding PARP

inhibitors during primary chemotherapy may not provide substantial clinical benefit.

PARP Inhibitor Safety

Table 21 summarizes key safety data for the four phase III trials testing

PARP inhibitor therapy as maintenance following first-line systemic

therapy. Across trials, PARP inhibitor maintenance was associated with

higher rates of a number of common non-hematologic AEs, such as

fatigue/asthenia, nausea, and vomiting (Table 21). These non-hematologic AEs tended to be low-grade and rarely led to study-drug

discontinuation.752-755 PARP inhibitor therapy was also associated with

increased risk for a number of hematologic AEs, such as anemia,

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neutropenia, and thrombocytopenia (Table 21). Hematologic AEs were the most common high-grade AEs (grade ≥3), and the most common cause of study drug discontinuation due to toxicity.752-755 Although rare (≤2%),

PARP inhibitor therapy was also associated with risk of myelodysplastic

syndrome or acute myeloid leukemia,752-755 and is mentioned in the FDA

labels.954,955 Bevacizumab is associated with risk of hypertension; in the

PAOLA-1 trial, hypertension was a common AE and a common high-grade AE in both arms, although it did not lead to discontinuation.753 Across

trials, rates of high-grade AEs (grade ≥3) were higher for single-agent

PARP inhibitor maintenance therapy compared with placebo. In PAOLA-1,

however, there was only a small difference between arms in the rate grade ≥3 AEs (Table 21), and serious AEs occurred in 31% in each arm, 753

showing that risk of high-grade/serous AEs was similar for maintenance

bevacizumab with versus without olaparib. Rates of study-drug

discontinuation due to toxicity were higher with PARP inhibitor

maintenance therapy across all trials, including PAOLA-1, largely due to

hematologic AEs.

In the SOLO-1, PAOLA-1, PRIMA, and VELIA trials, there were no

statistically significant differences between treatment arms in the heathrelated QOL metrics evaluated.752-755

NCCN Guidelines Version 3.2025 Ovarian Cancer Table 21. Adverse Events Associated with PARP Inhibitor Maintenance after First-Line Systemic Therapy a

Keywords

Nausea: 77% vs. 38% Fatigue/asthenia: 63% vs. 42% Vomiting: 40% vs. 15% Diarrhea: 34% vs. 25% Constipation: 28% vs. 19% Dysgeusia: 26% vs. 4% Decreased appetite: 20% vs. 10% Nausea: 53% vs. 22% Fatigue/asthenia: 53% vs. 32% Vomiting: 22% vs. 11% Hypertension: 46% vs. 60% Nausea: 57 vs. 28% Vomiting: 22% vs. 12% Constipation: 39% vs. 19% Headache: 26% vs. 15% Insomnia: 25% vs. 15% Nausea: 56% vs. 24% Vomiting: 34% vs. 12% Arthralgia: 16% vs. 20% Common nonhematologic AEs ( > 5%), grade ≥3 None Fatigue/asthenia: 5% vs. 1% Hypertension: 19% vs. 30% Hypertension: 6% vs. 1% Nausea: 5% vs. 1% Fatigue: 6% vs. 1% Common hematologic AEs ( > 20%), any grade, differing between arms by ≥9% Anemia: 39% vs. 10% Neutropenia: 23% vs. 12% Anemia: 41% vs. 10% Lymphopenia: 24% vs. 9% Anemia: 63% vs. 18% Neutropenia: 26% vs. 7% Neutrophil count decreased: 17% vs. 2% Thrombocytopenia: 46% vs. 4% Platelet count decreased: 28% vs. 1% Thrombocytopenia: 20% vs. 5% Common hematologic AEs ( > 5%), grade ≥3 Anemia: 22% vs. 2% Neutropenia: 9% vs. 5% Anemia: 17 vs. < 1% Lymphopenia: 7% vs. 1% Neutropenia: 6% vs. 3% Anemia: 31% vs. 2% Neutropenia: 13% vs. 1% Neutrophil count decreased: 8% vs. 0 Thrombocytopenia: 29% vs. < 1% Platelet count decreased: 13% vs. 0

Abstract

SOLO-1 PAOLA-1 PRIMA 754 VELIA 755 Maintenance therapy tested Olaparib vs. placebo Bevacizumab + olaparib vs. bevacizumab + placebo Niraparib vs. placebo Veliparib vs. placebo b PARP inhibitor maintenance dose 300 mg BID 300 mg BID 300 mg QD c 300 mg BID x 2 weeks, then 400 mg BID AEs Grade 5 none < 1% vs. 1% 0.4% vs. 0.4% None AEs Grade ≥3 39% vs. 18% 57% vs. 51% 71% vs. 19% 45% vs. 32% AEs leading to discontinuation 12% vs. 2% 20% vs. 6% 12.0% vs. 2.5% 17% vs. 1% Common nonhematologic AEs ( > 20%), any grade, differing between arms by ≥9%

References

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treatment after response to first-line chemotherapy in patients with newly diagnosed advanced disease (Table 22). The FDA-approved indications are for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR/PR to first-line platinum-based

chemotherapy (Table 22). The FDA indication for single-agent olaparib in this setting is limited to those with a deleterious or suspected deleterious BRCA mutation, and the FDA indication for bevacizumab plus olaparib in this setting is limited to those with homologous recombination deficiency,

as defined by a deleterious or suspected deleterious BRCA mutation and/or genetic instability, as measured using an FDA-approved

companion diagnostic. Veliparib is not currently FDA approved.

Maintenance with single-agent bevacizumab is FDA approved in this setting for patients with stage III–IV epithelial ovarian, fallopian tube, or primary peritoneal cancer that has been treated with surgical resection and combination carboplatin/paclitaxel/bevacizumab (Table 22).

Table 22. FDA-Approved Indications for Bevacizumab and PARP Inhibitors in Ovarian Cancer

Agent

USPI Date

First-Line

Chemotherapy

Maintenance After First-Line Chemotherapy

Recurrence Therapy

Maintenance After Recurrence Therapy

Bevacizumab

September 2020956

For epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with carboplatin and paclitaxel,

followed by bevacizumab as a single agent, for stage III or IV disease following initial surgical resection.

For epithelial ovarian, fallopian tube, or

primary peritoneal cancer in combination

with paclitaxel, pegylated liposomal

doxorubicin, or topotecan for platinumresistant recurrent disease who received

≤2 prior chemotherapy regimens.

For epithelial ovarian, fallopian tube, or primary peritoneal cancer, in

combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by bevacizumab as a single agent, for platinum-sensitive recurrent disease.

Niraparib

April 2020954

None

For the maintenance treatment of adult patients with advanced epithelial

ovarian, fallopian tube, or primary

peritoneal cancer who are in a CR or PR to first-line platinum-based

chemotherapy.

For the treatment of adult patients with

advanced ovarian, fallopian tube, or

primary peritoneal cancer who have been treated with ≥3 prior chemotherapy

regimens and whose cancer is

associated with HRD-positive status

defined by either:

• a deleterious or suspected deleterious BRCA mutation,a or

• genomic instabilitya and who have

progressed >6 months after response to the last platinum-based chemotherapy.

For the maintenance treatment of adult patients with recurrent

epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-based chemotherapy.

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Agent

USPI Date

First-Line

Chemotherapy

Maintenance After First-Line Chemotherapy

Recurrence Therapy

Maintenance After Recurrence Therapy

Olaparib

May 2020955

None

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCAmutatedb advanced epithelial ovarian,

fallopian tube, or primary peritoneal

cancer who are in CR or PR to first-line platinum-based chemotherapy.

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian,

fallopian tube, or primary peritoneal

cancer who are in CR or PR to first-line platinum-based chemotherapy and

whose cancer is associated with HRDpositive status defined by either:

• a deleterious or suspected deleterious BRCA mutationb, and/or

• genomic instabilityb

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutatedb advanced

ovarian cancer who have been treated with ≥3 prior lines of chemotherapy.

For the maintenance treatment of adult patients with recurrent

epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in CR or PR to platinum-based

chemotherapy.

Rucaparib Oct 2020957

None

For the treatment of adult patients with deleterious BRCA mutationc (germline

and/or somatic)–associated epithelial

ovarian, fallopian tube, or primary

peritoneal cancer who have been treated with ≥2 prior lines of chemotherapies.

For the maintenance treatment of adult patients with recurrent

epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-based chemotherapy.

Abbreviation: CR, complete response; HRD, homologous recombination deficiency; PR, partial response; USPI, US prescribing information.

a Select patients for therapy based on an FDA-approved companion diagnostic for niraparib.

b Select patients for therapy based on an FDA-approved companion diagnostic for olaparib.

c Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib.

NCCN Recommendations for Maintenance After Primary Chemotherapy

For patients who have completed primary surgery and systemic therapy, the NCCN-recommended options for the treatment of patients who have completed primary therapy are summarized in Table 23, including

maintenance therapy options. The recommended options depend on

disease stage, agents used for primary systemic therapy, response to

primary treatment, and BRCA1/2 mutation status. For the maintenance

therapy options, Table 23 also shows which NCCN-recommended options are consistent with an FDA-approved indication, as well as options

consistent with an FDA-approved indication that are not recommended in the NCCN Guidelines. Discrepancies between the NCCN

recommendations and FDA-approved indications are highlighted in yellow. Table 23 shows the trials that provided data that support the maintenance

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therapy options. As illustrated in Table 23, there are several key

discrepancies between the FDA labels and NCCN Guidelines

recommendations.

1) The FDA-approved indication for maintenance bevacizumab is

limited to patients with stage III–IV disease, whereas the NCCN

Guidelines include this as an option for stage II disease. The

rationale for this is discussed below in the section on Selecting

Patients for Maintenance Therapy, Disease Stage.

2) The FDA-approved indication for maintenance bevacizumab is not qualified based on BRCA1/2 mutation status. In contrast, the

NCCN Guidelines single-agent bevacizumab maintenance is

limited to those without a BRCA1/2 mutation. The rationale for this is discussed above in the section entitled Olaparib + Bevacizumab.

3) The FDA-approved indication for olaparib/bevacizumab

combination maintenance therapy does not specify that patients

must have had prior bevacizumab, whereas the NCCN Guidelines restrict this option to those with prior bevacizumab, as there are no prospective randomized trial data to suggest that maintenance

bevacizumab provides any clinical benefit to those who did not

receive prior bevacizumab in combination with platinum-based

chemotherapy.

4) The FDA-approved indication for olaparib/bevacizumab

combination maintenance therapy is restricted to patients with

BRCA1/2 mutations or genomic instability, presumably based on

the results of the subgroup analysis in PAOLA-1 showing no PFS benefit for those without homologous recombination deficiency.

The NCCN Guidelines include olaparib/bevacizumab combination maintenance therapy as an option regardless of homologous

recombination deficiency status, choosing instead to focus on the PFS benefit observed for the larger subgroup of patients without

BRCA1/2 mutation (not further subdivided by homologous

recombination deficiency status).

5) The FDA-approved indication for niraparib maintenance is not

restricted by BRCA1/2 mutation status or whether bevacizumab

was given in combination with platinum-based chemotherapy. In

the NCCN Guidelines, however, for patients who received

bevacizumab as part of primary therapy, niraparib is a

maintenance option only for those with a BRCA1/2 mutation. The rationale for this is described in the section above entitled Niraparib Monotherapy.

When determining whether a patient is a candidate for maintenance after first-line therapy, and selecting among recommended maintenance

therapy options, it is important to consider the eligibility criteria and

characteristics of the patient population enrolled in the trials supporting the maintenance therapy options. The following sections describe

considerations for selecting maintenance therapy.

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Table 23. NCCN Recommended Options for Maintenance After First-Line Chemotherapya Pathologic

Stage

BRCA1/2 Status

Primary Systemic Therapyb

Response to Primary Therapy

Recommended Options

Category FDA Indicatione

Supporting Trial (and citations)

Any

SD/PD Therapy for persistent disease or recurrence

N/A

Stage I

Any

CR/PR Observe

N/A

Stage II–IV Mutated Platinum-based chemotherapy

CR Observe

N/A

CR/PR Olaparib

Yes

SOLO-1752

Bevacizumab + olaparib NR

Yes

Extrapolation from PAOLA-1753

Niraparib

Yes

PRIMA754

Stage II–IV Mutated Platinum-based chemotherapy + bevacizumab

CR/PR Bevacizumab

Only for stage III–IV GOG-0218,817 ICON7818,819

Olaparibd

Yes

Extrapolation from SOLO-1752 and PAOLA-1753

Bevacizumab + olaparib

Yes

PAOLA-1753

Niraparibd

Yes

Extrapolation from PRIMA754

Stage II–IV Wild-type or

unknown

Platinum-based chemotherapy

CR Observe

N/A

CR/PR Bevacizumab + olaparib NR Yes for patients with genomic instability

Extrapolation from PAOLA-1753

Niraparibc

Yes

PRIMA754

SD/PD Therapy for persistent disease or recurrence

N/A

Stage II–IV Wild-type or

unknown

Platinum-based chemotherapy + bevacizumab

CR/PR Bevacizumab

Only for stage III–IV GOG-0218,817 ICON7818,819 Bevacizumab + olaparibc 2A Only for patients with

genomic instability

PAOLA-1753

Niraparib

Yes

Extrapolation from PRIMA754

CR, complete clinical remission/response, with no evidence of disease; N/A, not applicable; PD, progressive disease; PR, partial remission/response; NR, not

recommended by NCCN; SD, stable disease

a Options shown in this table are for patients with ovarian, fallopian tube, or primary peritoneal cancer who have undergone primary treatment per NCCN Guidelines

recommendations with either 1) upfront surgery plus adjuvant systemic therapy; or 2) NACT, IDS, and postoperative adjuvant systemic therapy.

b Recommended maintenance therapy options are for those who have undergone primary systemic therapy with an NCCN-recommended regimen. See Principles of

Systemic Therapy: Primary Systemic Therapy Regimens in the algorithm for options.

c In the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor therapy (category 2B).

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d After first-line therapy with bevacizumab, data are limited on maintenance therapy with a single-agent PARP inhibitor (olaparib or niraparib) for patients with a

BRCA1/2 mutation. However, based on the magnitude of benefit of PARP inhibitor maintenance therapy for other subgroups, single -agent PARP inhibitors can be considered.

e FDA indication column indicates options consistent with an FDA-approved indication.

Selecting Patients for Maintenance Therapy

Diagnosis and Cancer Type

As shown in Table 20, the trials testing PARP inhibitors as maintenance

therapy after first-line systemic therapy enrolled patients with newly

diagnosed, histologically confirmed ovarian, primary peritoneal, or

fallopian tube cancer. The FDA indications in this setting for olaparib,

olaparib + bevacizumab, and niraparib all apply to cancers originating in

any of these primary sites (Table 22).

Although most patients in the trials testing PARP inhibitor maintenance

after primary therapy had high-grade serous histology (95%–100%),

several of these trials (ie, SOLO-1, PAOLA-1, PRIMA), included a small

percentage of patients with high-grade endometrioid (2.3%–2.7%), and a

small percentage with other cancer types (1.5%–2.3%; Table 20). The

NCCN Guidelines recommendations for maintenance options apply to

patients with high-grade serous or grade 2/3 endometrioid cancer types. It

is not clear whether these maintenance therapies are appropriate for

patients with less common epithelial ovarian cancer types (ie,

carcinosarcoma, clear cell carcinoma, mucinous carcinoma, grade 1

endometrioid, low grade serous). The FDA indications for PARP inhibitors

in this setting are all for “epithelial” cancer (Table 22).

Disease Stage

The trials testing PARP inhibitor maintenance therapy after first-line

treatment all required patients to have FIGO stage III–IV, and most

patients had stage III disease (65%–83%; see Table 20). Cases of stage II

disease at initial diagnosis are rare, especially among patients who have

undergone complete surgical staging, so there are little data and low

probability of future trials that will address the question of whether it is

appropriate to use PARP inhibitors as maintenance after completing

primary therapy for stage II disease. For this reason, the NCCN Panel

decided that the PARP inhibitor maintenance therapy options (ie, olaparib, niraparib, olaparib + bevacizumab) for patients who have completed firstline chemotherapy are recommended for stage III–IV disease, and should also be considered for patients who have stage II disease, noting that

supporting data are limited for stage II. These maintenance therapy

options are not recommended for patients with stage I disease (Table 23). The FDA indications for olaparib, olaparib + bevacizumab, and niraparib as maintenance therapy options after first-line chemotherapy are for

patients with “advanced” disease, which is not clearly defined (Table 22).

The GOG-0218 and ICON7 regimens for first-line platinum-based

chemotherapy with concurrent bevacizumab followed by single-agent

maintenance bevacizumab are recommended in the NCCN Guidelines as options for stage III–IV disease, and the NCCN Panel recommends that

these can be considered for patients with stage II disease. They are not

recommended for stage I disease. Use in stage II should take into

consideration that GOG-0218 included only stage III–IV,817 and although ICON7 included patients with high-risk stage I/II, sub-analyses showed the greatest benefit from bevacizumab among patients with more advanced

disease, with no significant impact of bevacizumab on OS for patients with earlier stage disease.819 The corresponding FDA-approved indication for carboplatin/paclitaxel/bevacizumab followed by single-agent bevacizumab is limited to stage III–IV disease (Table 22).

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BRCA1/2 Mutation Status

Because BRCA1/2 mutation status is important for selection of

maintenance therapy in patients with stage II–IV disease that responds to primary treatment, the NCCN Guidelines recommend screening for

BRCA1 and BRCA2 mutations earlier in the course of workup and primary treatment. Genetic risk evaluation and BRCA1/2 testing should be initiated as soon as the diagnosis has been confirmed histologically by evaluation of tumor tissue. Primary chemotherapy should not be delayed for a genetic counseling referral, because delay between surgery and start of

chemotherapy is associated with poorer outcomes,528,958 and maintenance would not be initiated until completion of platinum-based first-line

chemotherapy, which takes (at least) 18 weeks. The NCCN Guidelines

recommend that BRCA testing be performed using an FDA-approved test or other validated test performed in a CLIA-approved facility.

Homologous Recombination Deficiency

There is consensus that the presence of a deleterious germline or somatic mutation in BRCA1 or BRCA2 confers a level of homologous

recombination deficiency that is clinically relevant to the selection of

therapy for patients with ovarian cancer. However, for patients with

ovarian cancer who do not have a deleterious or suspected deleterious

mutation in BRCA1 or BRCA2, various molecular markers and metrics

have been proposed to determine whether the cancer is associated with a clinically relevant level of homologous recombination deficiency. Different methods and cutoffs were used in the PAOLA-1, PRIMA, and VELIA

trials.753-755 Because in PRIMA the study regimen being tested improved

PFS (compared with control) even among the homologous recombination “proficient” subgroups, but the same was not true in PAOLA-1 or VELIA

(Table 19), it is not clear whether the assays and cutoffs used to assign

homologous recombination deficiency in those studies should be used to inform selection of maintenance therapy after first-line treatment. This is

an area of ongoing investigation and as such, the NCCN Panel is not

ready to recommend any particular approach for determining homologous recombination deficiency in patients with ovarian cancer who do not have a BRCA1/2 mutation.

Primary Treatment

All four trials testing PARP inhibitor maintenance after primary treatment included both patients who had received upfront PDS followed by adjuvant chemotherapy, as well as patients who had received NACT with IDS and adjuvant chemotherapy (Table 20). For trials with reported data regarding the types of primary surgery received (ie, SOLO-1, PAOLA-1, VELIA),

more than half of the patients had upfront PDS, most of the remainder had NACT and IDS, and very few did not have any primary surgery (≤7%;

Table 20). In these three trials, more than half of the population had

surgery resulting in no macroscopic residual disease after surgery (Table 20). In SOLO-1 and PAOLA-1, subgroup analyses showed significant PFS benefit from PARP inhibitor maintenance regardless of the type of primary surgery (PDS vs. IDS) and presence versus absence of macroscopic

residual disease after primary surgery.753,946 Subgroup analyses of VELIA showed PFS benefit from veliparib regardless of the type of primary

surgery (PDS vs. IDS).755

In contrast to the other three trials, the PRIMA trial required that patients with stage III have either unresectable disease or visible residual disease after primary surgery, and likely included more patients treated with IDS

(vs. PDS), such that a much smaller proportion of the population had a

surgery that resulted in no macroscopic disease. For PRIMA the data on primary surgeries received and extent of residual disease after surgery

were not reported clearly. The PRIMA report did not include subgroup

analyses based on type of surgery or residual disease after surgery, but

did show that the PFS benefit associated with maintenance niraparib was significant for both those with and those without prior NACT.754

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In SOLO-1, PAOLA-1, and PRIMA, most patients had at least 6 cycles of platinum-based chemotherapy as part of primary treatment (Table 20).

Both IV regimens and IP/IV regimens were allowed in SOLO-1 and

PAOLA-1.752,753 In the NCCN Guidelines, all the IV and IP/IV regimens

recommended for neoadjuvant/adjuvant primary chemotherapy in patients with stage II–IV high-grade serous or endometrioid disease include 6

cycles of platinum-based combination chemotherapy (See Principles of

Systemic Therapy: Primary Systemic Therapy Regimens in the algorithm).

SOLO-1, PAOLA-1, and PRIMA required patients to have CR or PR

before initiation of maintenance therapy, and most had CR after primary

systemic therapy, although the definitions of CR and PR varied (Table 20). Subgroup analyses in SOLO-1 and PRIMA showed that PFS benefit from single-agent PARP inhibitor maintenance was significant regardless of

depth of response (CR vs. PR) after first-line systemic therapy.752,754

VELIA did not require that patients have CR or PR after primary

chemotherapy as a criterion for receiving veliparib maintenance therapy, and did not report response rate for the overall population.755

The NCCN recommendations for maintenance bevacizumab and PARP

inhibitors apply to patients with a CR (no evidence of disease) or PR after debulking surgery and chemotherapy, including those treated with PDS

followed by adjuvant chemotherapy, and those treated with NACT, IDS,

and adjuvant chemotherapy. Maintenance therapy is not recommended for patients who have progressive or stable disease on primary treatment;

these patients should be treated with recurrence therapy options as shown in Therapy for Persistent Disease or Recurrence in the Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section of the

algorithm.

Maintenance Therapies No Longer Recommended

Paclitaxel Maintenance Therapy

Based on results from the randomized GOG-178 trial, paclitaxel used to

be a post-remission therapy option for patients with stages II–IV and CR

after first-line therapy. In patients with CR after initial 5–6 cycles of

platinum/paclitaxel combination, those receiving 12 versus 3 additional

cycles of paclitaxel sustained a PFS advantage (22 vs. 14 months; P =

.006), although no significant improvement in OS.959,960 Longer

maintenance with paclitaxel was associated with higher rates of grade 2–3 neuropathy and grade 3 pain.960 More recent results from phase III

randomized trials have shown that for patients with CR after first-line

platinum/taxane-based chemotherapy, maintenance treatment with

paclitaxel (vs. observation) did not improve PFS or OS, and was

associated with higher rates of GI toxicity and neurotoxicity.961,962 For

these reasons, the NCCN Guidelines no longer include paclitaxel as an

option for maintenance therapy after primary chemotherapy.

Pazopanib Maintenance Therapy

Pazopanib used to be a recommended post-remission therapy option for patients with stages II–IV disease in clinical CR after first-line

chemotherapy. This recommendation was based on the AGO-OVAR 16

phase III randomized trial showing improved PFS with pazopanib versus placebo (17.9 vs. 12.3 months; HR, 0.77; 95% CI, 0.64–0.91; P = .0021) in patients with FIGO stage II–IV and no evidence of progression or

persistent disease (>2 cm) after surgery plus platinum-taxane

chemotherapy (≥5 cycles).963,964 Pazopanib was a category 2B

recommendation for post-remission therapy because the FDA has not

approved this indication,965 there was no increase in OS, and the safety

profile was concerning.964 Safety results from AGO-OVAR 16 showed that pazopanib was associated with significantly increased rates of certain

grade 3–4 toxicities, including hypertension, neutropenia, liver-related

toxicity, diarrhea, fatigue, thrombocytopenia, and palmar-plantar

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erythrodysesthesia, and that many of these toxicities were contributing to an increased rate of treatment discontinuation (discontinuation rate due to AEs for pazopanib vs. control: 33.3% vs. 5.6%).963 A recent analysis of

AGO-OVAR 16 showed that maintenance pazopanib was associated with poorer QOL, often due to persistent diarrhea.958 At NCCN Member

Institutions, pazopanib is rarely or never used for maintenance after

primary chemotherapy for ovarian cancer. The NCCN Panel consensus supported the removal of post-remission pazopanib as an option for

maintenance therapy after first-line chemotherapy.

Drug Reactions

Virtually all drugs have the potential to cause adverse reactions while

being infused, which can be classified as infusion reactions or allergic

reactions, and can occur either during the infusion or following completion of the infusion (even days later).966-970 Drugs used in gynecologic oncology treatment that more commonly cause adverse reactions include

carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, and

paclitaxel.970 Drug reactions can occur with either IV or IP administration of these drugs.971 Most of these drug reactions are mild infusion reactions,

but more severe hypersensitivity (allergic) reactions and life-threatening

anaphylaxis can occur.971-974

Symptoms of (mild) infusion reactions include hot flushing, rash, fever,

chest tightness, mild blood pressure changes, back pain, and chills (Table 24). Adverse reactions associated with taxane drugs (ie, docetaxel,

paclitaxel) and biotherapeutic agents tend to be mild infusion-related

reactions, are often attributed to cremophor in paclitaxel, and tend to occur during the first few cycles of treatment (although they can be seen during any infusion regardless of how many previous cycles were administered).

Mild infusion reactions are common with paclitaxel (27% of patients),975

but mild reactions can also occur with liposomal doxorubicin,976 docetaxel, or even platinum agents (ie, carboplatin, cisplatin).

Allergic reactions (ie, true drug allergies) are more common with platinum agents such as carboplatin (16% of patients), cisplatin, and

oxaliplatin,975,977 and tend to occur following re-exposure to the inciting

drug or less commonly at the completion of initial chemotherapy (ie, cycle 6 of a planned 6 treatments).974 Symptoms of allergic reactions include

rash, edema, shortness of breath (bronchospasm), syncope or presyncope, chest pain, tachycardia, generalized hives/itching, changes in

blood pressure, nausea, vomiting, chills, changes in bowel function, and

occasionally feeling of impending doom (Table 24). Symptoms of allergic reactions may continue to persist after stopping infusion and/or after

treatment interventions. Patients who are at higher risk of developing a

hypersensitivity (allergic) reaction include those undergoing re-introduction of the drug after a period of no exposure and following multiple cycles of the drug during the first and subsequent exposures;978,979 those

undergoing IV administration of the drug rather than oral or IP

administration; those with allergies to other drugs; and those who have

previously had a reaction. Severe allergic reactions include those that

cause shortness of breath, changes in blood pressure requiring treatment, and GI symptoms (eg, nausea, vomiting). Anaphylaxis is a rare type of

very severe allergic reaction that can occur with the platinum and taxane agents (and others less commonly), can cause cardiovascular collapse,

and can be life-threatening.972,973,980 Life-threatening allergic reactions

such as anaphylaxis are distinguished from other severe reactions by

acute onset, generalized hives, respiratory compromise, and severe

hypotension (Table 24).

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Table 24. Drug Reactions: Symptoms

Severity of Reaction

Mild (infusion)

Severe (allergic)

Life-Threatening (allergic)

Drug causing reaction Platinum Non-platinuma Platinum Non-platinuma Platinum Non-platinuma

Symptoms Hot flushing

Dermatologic Rash

Pruritus

Generalized hives

Pain in chest, abdomen, pelvis, or back

Respiratory

Shortness of breath, dyspnea

Respiratory compromise

Cardiovascular

Changes in BP requiring Tx

Severe hypotension

GI symptoms [eg, nausea, vomiting]

Acute onset

Feeling of impending doom, anxiety, or something wrong

Symptoms often resolve quickly after stopping infusion

BP, blood pressure; GI, gastrointestinal; Tx, treatment.

a Taxane, liposomal doxorubicin, or biotherapeutic agents.

Preparation for a Possible Drug Reaction

Patients and their families should be counseled about the possibility of a drug reaction and the signs and symptoms of one. Patients should be told to report any signs and symptoms of a drug reaction, especially after they have left the clinic (ie, delayed rash). Clinicians and nursing staff should be prepared for the possibility of a drug reaction every time a patient is

infused with a drug. Standing orders should be written for immediate

intervention in case a severe drug reaction occurs and the treatment area should have appropriate medical equipment in case of a life-threatening reaction.980 Epinephrine (intramuscular 0.3 mL of 1 mg/mL

solution/EpiPen) should be used for any patient experiencing hypotension

(systolic BP of <90 mm Hg) with or without other symptoms of an

allergic/hypersensitivity reaction during or shortly after any chemotherapy drug treatment. In the setting of acute cardiopulmonary arrest, standard resuscitation (advanced cardiovascular life support [ACLS]) procedures should be followed.

Management of Drug Reactions

Algorithms are provided for management of mild, severe, and

life-threatening reactions (summarized in Table 25).981 These drug

reaction algorithms are also useful for patients with other gynecologic cancers (eg, cervical, vulvar, and uterine cancers) who are receiving carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, or

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paclitaxel. The management recommendations depend on the severity of the reaction and the type of drug that caused the reaction (platinum vs.

non-platinum [taxane, liposomal doxorubicin, or biotherapeutic agents];

see Table 25). Typically, the infusion should be stopped for patients

having a reaction. The one exception to this rule is that mild infusion

reactions occurring during first exposure to a platinum agent may be

managed by decreasing the infusion rate and administering an H1 blocker antihistamine (eg, diphenhydramine or hydroxyzine), and usually resolve after stopping the infusion. Whereas H1 blocker antihistamine such as

diphenhydramine or hydroxyzine is recommended for managing drug

reactions, regardless of severity, H2 blockers such as cimetidine and

famotidine are reserved for severe or life-threatening reactions.

Corticosteroids are also generally reserved for severe or life-threatening reactions, but may be needed for mild reactions to platinum agents in

patients with prior exposure, if symptoms do not quickly resolve after

administering an H1 blocker. IM epinephrine is recommended for lifethreatening reactions, but may sometimes be needed for severe (but not life threatening) reactions, or for mild reactions to platinum agents if

symptoms are not responding to other interventions. Life-threatening

reactions require oxygen and nebulized bronchodilators, and saline bolus may also be needed for life-threatening reactions to platinum agents.

Standard resuscitation procedures (ie, ACLS) should be followed for

patients with acute cardiopulmonary arrest.982-985

Table 25: Drug Reactions: Management Severity of Reaction

Mild (infusion)

Severe (allergic)

Life-Threatening (allergic)

Drug causing reaction

Platinum

Non-platinuma Platinum Non-platinuma Platinum Non-platinuma

Prior exposure

≥1

≥0

Infusion recommendation Decrease infusion rate

Stop infusion

Recommended therapy

H1 blocker antihistamine (eg,

diphenhydramine or hydroxyzine)

H2 blockers (eg, cimetidine, famotidine)

Corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone)

If needed

IM epinephrine

If needed

If needed If needed

Oxygen

Nebulized bronchodilators

Saline bolus

If needed

IM, intramuscular.

a Taxane, liposomal doxorubicin, or biotherapeutic agents.

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Rechallenge and Desensitization

Recommendations for rechallenge and desensitization depend on the

number and severity of the previous reactions. Patients who have had mild reactions to a drug may develop more serious reactions upon re-exposure even when the drug is slowly infused.975 Therefore, for patients who have experienced a reaction to a platinum agent, consider consultation with an allergist (or qualified medical or gynecologic oncologist) for skin testing

and to evaluate sensitization and the risk for further, more severe

reactions.975,981,986,987 Skin testing is associated with false-negative

results.988,989 In cases of prior mild infusion reaction to the first exposure of a platinum or non-platinum agent, rechallenge may be attempted if the

patient, physician, and nursing staff are all comfortable with this plan, the patient has been counseled appropriately, vital signs remain stable,

emergency equipment is available in the clinic area, and the patients has received premedication with H1 blocker antihistamine, corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone), and H2 blockers

(eg, cimetidine, famotidine).990-993 For rechallenge with non-platinum

agents after mild reaction to first exposure, slower infusion rate should be used. Typically, a taxane infusion can be re-started at a much slower rate, and the rate can be slowly increased as tolerated as per the treating

clinician’s judgment.975,994 Many institutions have policies that stipulate

how to reinfuse the drug if the patient has had a prior infusion reaction.

Note that this rechallenge with slow infusion is different from

desensitization. Desensitization refers to a process of rendering the

patient less likely to react in response to an allergen, and can be

considered an option for patients who have had drug reactions.970,994-996

For patients with allergic reactions, various desensitization protocols have been published.967,970,987,994,995,997-1001 To maximize safety, patients may be desensitized in an intensive care unit.970,998 Almost all patients complete

the desensitization protocol with only mild breakthrough reactions (about 90%).970,999,1001-1003 For patients with more than one prior mild reaction or

any severe or life-threatening reactions—such as those involving blood

pressure changes, dyspnea, tachycardia, widespread urticaria,

anaphylaxis, or hypoxia— the implicated agent should not be used again unless under the supervision and guidance of an allergist or specialist with desensitization experience. For those with more than one mild reaction to a non-platinum agent, consider switching to paclitaxel (albumin-bound)

due to medical necessity (ie, hypersensitivity reaction),1004,1005 or consider switching to docetaxel; however, there are no data to support switching

taxanes. Cross reactions have occurred and have been life-threatening.

Some reactions to paclitaxel may occur because of the diluent, in which

case switching to albumin-bound paclitaxel could diminish future risks. For patients with hypersensitivity to platinum-reagents, data suggest that readministration of platinum-based treatment resulted in hypersensitivity

reactions in approximately one third of patients, although none were

severe (grade ≥3), and survival was improved compared with patients who were switched to non-platinum agents.1006

If a mild allergic reaction is suspected, and it is appropriate to administer the drug again, patients should be desensitized prior to resuming

chemotherapy even if the symptoms have resolved.968 Patients must be

desensitized with each infusion if they previously had a drug reaction.994-996 Data suggest that an extended infusion schedule and use of

premedication may decrease the number of hypersensitivity reactions to

carboplatin.978,1007

Radiation Therapy

Whole abdominal radiation therapy is rarely used for epithelial ovarian,

primary peritoneal, and fallopian tube cancers at NCCN Member

Institutions. It is not included as a treatment recommendation in the NCCN Guidelines for Ovarian Cancer. Palliative localized RT is an option for

symptom control in patients with recurrent disease (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for

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Persistent Disease or Recurrence in the algorithm).1008-1012 Patients who receive pelvic radiation are prone to developing vaginal stenosis, which can impair sexual function.1013 Vaginal dilators can be used to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after RT is

completed and can be done indefinitely.1014

Follow-up Recommendations

Recurrent disease may be identified clinically (eg, pelvic pain, weight

loss), biochemically (ie, elevated CA-125 levels), and/or with imaging.

After the completion of primary surgery and chemotherapy in patients with all stages of ovarian cancer (or Fallopian tube cancer or primary peritoneal cancer) who have had a CR, the standard recommendation is observation with follow-up to monitor for recurrent disease. Recommendations for

monitoring are described in the algorithm and also apply to some of the

LCOC (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer: Monitoring/Follow-up in the algorithm).

Chest/abdominal/pelvic CT, MRI, FDG-PET/CT, FDG-PET scans (skull

base to mid-thigh), and chest x-ray may be ordered if clinically indicated; imaging is done with contrast unless contraindicated.1015-1018 Patients

should be educated about the signs and symptoms suggestive of

recurrence (eg, pelvic pain, bloating, early satiety, obstruction, weight loss, fatigue). Patients who have had fertility-sparing surgery should be

monitored by US examinations of the abdomen and pelvis if indicated;

completion surgery should be considered (category 2B) after they finish

childbearing. For the 2017 update (Version 1), the NCCN Panel added a recommendation for long-term wellness care (see the NCCN Guidelines

for Survivorship, available at www.NCCN.org).

If the CA-125 level was initially elevated, then measurement of a CA-125 level or other tumor markers is recommended. A multi-institutional

European trial assessed the use of CA-125 for monitoring for ovarian

cancer recurrence after primary therapy.1019,1020 The data suggest that

treating recurrences early (based on detectable CA-125 levels in patients who are asymptomatic) is not associated with an increase in survival and is associated with a decrease in QOL.1021 Recommendations from the

SGO state that use of CA-125 levels for surveillance is optional.1017 The NCCN Panel feels that the European trial has limitations and patients

should discuss the pros and cons of CA-125 monitoring with their

physicians. In addition, patients seem reluctant to give up monitoring.1022 Others have discussed this study in greater detail.385,1023,1024

Management of an Increasing CA-125 Level

The care of patients in a clinical complete remission is somewhat

controversial; this includes patients who are found to have an increasing CA-125 level (during routine monitoring and follow-up) but no signs or

symptoms of recurrent disease (eg, pelvic pain, bloating, obstruction),

following an evaluation including a negative pelvic examination and

negative chest/abdominal/pelvic CT scans.1025 Patients who have never

received chemotherapy (ie, naïve to chemotherapy) should be treated

using recommendations for newly diagnosed patients, should undergo

clinically appropriate imaging studies and surgical debulking, and should be treated as previously described (see Epithelial Ovarian

Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Primary

Treatment in the algorithm).

Recurrence therapy refers to drugs, radiation, or other treatment that is

given to decrease tumor burden, control symptoms, or increase length

and/or QOL for patients with recurrent disease. After the documentation of an increased CA-125 level (ie, biochemical relapse), the median time for a clinical relapse is 2 to 6 months. Data suggest that immediate treatment

for biochemical relapse is not beneficial; therefore, immediate treatment is a category 2B recommendation in the NCCN Guidelines.1019 After

biochemical relapse, recommended options include enrollment in a clinical trial, delaying treatment (ie, observation) until clinical symptoms arise, or

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immediate treatment (category 2B) (see Epithelial Ovarian

Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for

Persistent Disease or Recurrence in the algorithm). Because tamoxifen

and other hormonally active agents have a defined response rate for

patients with recurrent disease who have progressed after platinum-based chemotherapy,1026 these agents are frequently administered to patients

who have only a rising CA-125 level1027 as evidence of tumor

progression.1028 Tamoxifen, other hormonal agents, or other recurrence

therapy are acceptable recommendations for this clinical situation

(category 2B for all).

Recurrent Disease

The prognosis is poor either 1) for patients who progress after 2

consecutive chemotherapy regimens without ever sustaining a clinical

benefit (refractory);1029 or 2) for those whose disease recurs in less than 6 months (platinum resistant). Note that progression is typically defined

using RECIST (Response Evaluation Criteria in Solid Tumor) criteria.936,937 Panel members emphasized the importance of clinical trials to identify

agents active in this group of patients.1030,1031 Because their disease was resistant to the primary induction regimen, retreatment with a platinum

compound or paclitaxel is not generally recommended. Although panel

members do not recommend retreatment with platinum agents, they

recognize that altering the schedule of paclitaxel may produce secondary responses.1032,1033 Before any drug is given in the recurrent setting, the

clinician should be familiar with the drug’s metabolism and should make

certain that the patient is an appropriate candidate for the drug (eg, that

the patient has adequate renal or hepatic function). Clinical judgment must be used when selecting postoperative chemotherapy.

Options for patients with platinum-resistant disease or for those with

stages II to IV disease who have a PR include clinical trial, recurrence

therapy (see Principles of Systemic Therapy: Acceptable Recurrence

Therapies for Epithelial Ovarian Cancer [including LCOC]/Fallopian

Tube/Primary Peritoneal Cancer in the algorithm),1034 and/or best

supportive care (see NCCN Guidelines for Palliative Care, available at

www.NCCN.org). Although palliative care is appropriate at many stages

during the disease course, an assessment for palliative care is especially appropriate for those with platinum-resistant disease who may be

receiving continuous systemic therapy. Patients who relapse 6 months or more after initial chemotherapy are termed platinum sensitive.1035,1036

Combination platinum-based chemotherapy for a total of 6 cycles is

preferred for first recurrence (category 1) in patients with

platinum-sensitive disease (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for Persistent Disease or

Recurrence in the algorithm); other recurrence therapies are also an

option.1036,1037 Possible regimens are discussed in the following section

(see Acceptable Recurrence Modalities in this Discussion).

Patients with ovarian cancer will often be retreated with multiple courses of recurrence therapy. Caution should be used in patients who receive

multiple sequential courses of chemotherapy, because they may

experience excessive toxicity and may not be able to tolerate doses used for first-line recurrence therapy; thus, clinical judgment should be used

when selecting doses (see Principles of Systemic Therapy in the

algorithm). Potential ancillary palliative, surgical, and/or supportive care

procedures for selected patients are summarized in the algorithm (see

Principles of Surgery in the algorithm).1038-1043 Secondary cytoreductive

surgery can be considered for patients who recur (ie, radiographic and/or clinical relapse) after a long disease-free interval (6 months or

more).694,1044-1049 A meta-analysis suggests that survival increases for

patients with recurrent disease who have complete debulking.696 The

duration of the disease-free interval has not been established, although

panel members agreed that it should be at least 6 months before surgery is considered.588,1050

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Although chemotherapy/resistance assays and/or other biomarker assays are being used in some NCCN Member Institutions to aid in selecting

chemotherapy in situations where multiple equivalent chemotherapy

options are available; the current level of evidence (category 3) is not

sufficient to supplant standard-of-care chemotherapy.1051,1052 The NCCN

Panel feels that in vitro chemosensitivity testing to choose a chemotherapy regimen for recurrent disease situations should not be recommended

(category 3), owing to the lack of demonstrable efficacy for such an

approach. ASCO also does not recommend use of chemotherapy

sensitivity and resistance assays, unless in a clinical trial setting.1053 Note that a category 3 recommendation reflects strong disagreement about the intervention. At least 3 different NCCN Member Institutions must agree to include the category 3 intervention in the guideline, otherwise it is deleted.

Regardless of which regimen is selected initially, reevaluation should

follow after 2 to 4 cycles of chemotherapy (depending on the agent) to

determine if patients benefited from chemotherapy. Patients who primarily progress on 2 consecutive chemotherapy regimens without evidence of

clinical benefit may not benefit from additional therapy.1029 Decisions to

offer supportive care, additional therapy, or clinical trials should be made on a highly individual basis. Localized RT can also provide effective

palliation when radiation ports are tailored to specific symptomatic disease sites.1008,1009

Acceptable Recurrence Modalities

The NCCN Panel feels that no single therapeutic agent should be

currently recommended as the treatment of choice for recurrent ovarian carcinoma. Some regimens and agents are preferred based on expert

opinion primarily for reasons of decreased toxicity and/or marginally

increased effectiveness (see Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the algorithm).877 A meta-analysis of

chemotherapy for recurrent ovarian cancer was published in 2007.1035

Recurrence therapy refers to therapy (eg, drugs, radiation, or other

treatment) that is given for recurrent cancer to control symptoms and

increase length or QOL for clinical, biochemical, or radiographic evidence of recurrent cancer following initial treatment.

Preferred Therapies

The consensus of the NCCN Panel for the treatment of recurrent disease is summarized in the algorithm (see Principles of Systemic Therapy:

Acceptable Recurrence Therapies for Epithelial Ovarian (including

LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the algorithm).

Platinum-based combination chemotherapy is recommended (category 1) for a total of 6 cycles for platinum-sensitive recurrence (see Epithelial

Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer:

Therapy for Persistent Disease or Recurrence in the algorithm).1035,1036 For patients with platinum-sensitive disease who cannot tolerate combination therapy, the preferred single agent is carboplatin or cisplatin.1036,1054,1055

Preferred combinations for platinum-sensitive recurrent disease include

carboplatin/paclitaxel (category 1),1036 carboplatin/liposomal doxorubicin

(category 1),1056-1058 carboplatin/weekly paclitaxel,760

carboplatin/albumin-bound paclitaxel (for taxane hypersensitivity),

carboplatin/docetaxel,1059,1060 carboplatin/gemcitabine (which has been

shown to improve PFS),1036,1054,1055 cisplatin/gemcitabine, or

carboplatin/gemcitabine/bevacizumab.1054

The category 1 recommendation for carboplatin/liposomal doxorubicin is based on recent data and uniform consensus from the panel.1056,1057,1061-

1064 Carboplatin/liposomal doxorubicin is equivalent to

carboplatin/paclitaxel but has a different toxicity profile.

Carboplatin/liposomal doxorubicin is easier to tolerate; patients tend to

discontinue therapy with carboplatin/paclitaxel more often than they do

with carboplatin/liposomal doxorubicin. Other combination regimens,

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including those with bevacizumab, are discussed in the following

paragraphs. For the 2017 update (Version 1), the NCCN Panel added a

recommendation (category 2A) for carboplatin/albumin-bound paclitaxel as recurrence therapy for those with platinum-sensitive disease and

confirmed taxane hypersensitivity. Preliminary data from a phase 2 study

of carboplatin/nab-paclitaxel in platinum-sensitive patients indicated that

the overall response rate was 79%; 39% (15/38) of patients had a CR

rate.1065 A recent study of carboplatin/albumin-bound paclitaxel in patients with gynecologic tumors included 22 patients with ovarian cancer; the

regimen was well tolerated and no patients had hypersensitivity

reactions.1005

For platinum-resistant disease, non-platinum–based agents or regimens

are preferred (ie, docetaxel, oral etoposide, gemcitabine, weekly paclitaxel with or without pazopanib, liposomal doxorubicin with or without

bevacizumab, weekly paclitaxel/bevacizumab, topotecan with or without

bevacizumab); sequential therapy using single agents is typically

used.943,1066 A phase 2 trial (MITO-11) assessed weekly paclitaxel with (or without) pazopanib in patients with platinum-resistant or refractory

advanced ovarian cancer.1066 The data show that PFS was increased in

the paclitaxel/pazopanib arm when compared with paclitaxel alone

(median 6.35 months [95% CI, 5.36–11.02] vs. 3.49 months [2.01–5.66];

HR, 0.42 [95% CI, 0.25–0.69]; P = .0002). Combination regimens with

bevacizumab (AURELIA trial) are described later in this section (see

Bevacizumab in this Discussion). Combination therapy is not preferred

over single-agent therapy for platinum-resistant disease. For the 2017

update (Version 2), the NCCN Panel clarified this point by adding a

footnote stating that the panel recommends combination, platinum-based regimens for platinum-sensitive recurrent disease, especially first relapses.

The response rate of the following agents appears to be similar:

topotecan, 20%;1067 gemcitabine, 19%;1068,1069 liposomal doxorubicin,

26%;1068-1070 and oral etoposide, 27%.1071 In patients with

platinum-resistant disease, the response rate for docetaxel is 22% and for weekly paclitaxel is 21%.1032,1072,1073 Reports suggest that weekly

topotecan is less toxic than the daily regimen.1074,1075 Palliative

chemotherapy has been shown to reduce symptoms in patients with

platinum-resistant disease.1076

Other Potentially Active Agents

Other potentially active agents include altretamine, capecitabine,

cyclophosphamide, doxorubicin, ifosfamide, irinotecan, melphalan,

oxaliplatin, paclitaxel, nanoparticle albumin-bound paclitaxel

(nab-paclitaxel), pemetrexed, and vinorelbine (see Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian

(including LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the

algorithm).1073,1077-1081 Nab-paclitaxel has an overall response rate of

64%.1082 Vinorelbine has a response rate of 20%.1083,1084 Altretamine has a 14% response rate1085 and ifosfamide has a 12% response rate,1086

although less information is available regarding their use in patients with paclitaxel-refractory disease. In those with platinum-resistant disease, the response rate for pemetrexed is 21%.1032,1072,1073 Single-agent paclitaxel, nab-paclitaxel, and oxaliplatin can be used in appropriate

patients.959,1036,1072,1087 Capecitabine has activity if disease was resistant to platinum and taxanes.1088 Other alkylating agents, including

cyclophosphamide and melphalan, can also be used.783,791 In addition,

hormonal therapy with tamoxifen or other agents including aromatase

inhibitors (such as anastrozole and letrozole), leuprolide acetate, or

megestrol acetate continues to be a viable therapeutic option for patients who cannot tolerate or those whose disease have not responded to

cytotoxic regimens.1089-1095 Studies are ongoing for new agents to treat

platinum-resistant disease.1096 The NCCN Panel also recommends

(category 2B) single-agent pazopanib as a potentially active targeted

recurrence therapy in patients who had a CR to initial therapy.1097 In a

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phase 2 trial in 36 patients, the overall response rate was 18% with grade 3 elevations in ALT and AST in a few patients (8%).

Bevacizumab

Based on phase 2 trials, panel members feel that single-agent

bevacizumab is a preferred option in patients who have recurrent disease (especially those with ascites), which is reflected in the category 2A

recommendation for bevacizumab alone for those with either

platinum-sensitive or platinum-resistant disease.542,943,1098,1099 The

response rate for single-agent bevacizumab is about 20%;542,1098,1100-1103 it may cause hypertension, arterial thrombosis, or intestinal perforation.

Bevacizumab combination regimens, or single-agent bevacizumab, are

contraindicated in patients at increased risk of GI perforation.825,1104 For

the 2017 update (Version 2), the NCCN Panel added a footnote that there are limited data about the efficacy of bevacizumab as recurrence therapy (either single-agent or combination therapy) for patients previously treated with bevacizumab. The NCCN Panel added another footnote to clarify that bevacizumab can be continued as single-agent maintenance therapy until disease progression or unacceptable toxicity if the disease responds to the initial recurrence chemotherapy/bevacizumab regimens described in the

following paragraphs (see Principles of Systemic Therapy: Acceptable

Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian

Tube/Primary Peritoneal Cancer in the algorithm).

Several phase 3 randomized trials have assessed combination therapy

with bevacizumab for recurrent ovarian cancer (ie, AURELIA,

OCEANS).1104,1105 The AURELIA trial assessed bevacizumab combined

with chemotherapy—either liposomal doxorubicin, weekly paclitaxel, or

topotecan—versus chemotherapy alone in patients with advanced

platinum-resistant ovarian cancer. For patients receiving

bevacizumab/chemotherapy, the primary endpoint of PFS was 6.7 months versus 3.4 months with chemotherapy alone. The median OS was 16.6

months for the bevacizumab/chemotherapy arm versus 13.3 months for

chemotherapy alone; the OS HR was 0.85 (95% CI, 0.66–1.08; P < .174). Hypertension and proteinuria (≥ grade 2) were more common with

bevacizumab. GI perforation occurred in 2.2% of patients on the

bevacizumab arm. Based on the results of the AURELIA trial, the NCCN Panel recommends the following combination regimens for patients with

platinum-resistant recurrent ovarian cancer: weekly

paclitaxel/bevacizumab, liposomal doxorubicin/bevacizumab, and

topotecan/bevacizumab.1104,1106

A phase 3 randomized trial (OCEANS) assessed carboplatin/gemcitabine with and without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer who had not previously received bevacizumab. In the

OCEANS trial, PFS was increased in patients receiving the

chemotherapy/bevacizumab arm when compared with chemotherapy

alone (12.4 vs. 8.4 months, P < .0001).1105 The final survival analysis did not show an increase in OS with the chemotherapy/bevacizumab arm

when compared with chemotherapy alone (bevacizumab/chemotherapy:

33.6 months; chemotherapy alone: 32.9 months; HR, 0.95; P = .65).1107 GI perforation occurred in 2 patients in the chemotherapy/bevacizumab arm. One patient died from intracranial hemorrhage in the

chemotherapy/bevacizumab arm. For the 2017 update, the NCCN Panel revised the recommendation for carboplatin/gemcitabine/bevacizumab to category 2A (from category 2B) based on clinical experience. However,

category 1 combination regimens are recommended over this

bevacizumab regimen. The carboplatin/gemcitabine/bevacizumab regimen is not recommended in patients who are at risk for GI perforation.

A recent phase 3 randomized trial (GOG-0213) assessed recurrence

combination therapy with carboplatin/paclitaxel/bevacizumab in patients

with platinum-sensitive recurrent ovarian cancer.1108 Those receiving

chemotherapy/bevacizumab had slightly increased median OS when

compared with chemotherapy alone (42.2 months [95% CI, 37.7-46.2) versus 37.3 months (32.6-39.7) (HR, 0.829; 95% CI, 0.683-1.005; P=.056). Most patients in both arms had at least one grade 3 or worse AE; 96% (317/325) of patients in the chemotherapy/bevacizumab group versus 86% (282/332) with chemotherapy alone; the most common of these AEs were hypertension, fatigue, and proteinuria. Nine (3%) treatment-related deaths occurred in the bevacizumab arm versus 2 (1%) deaths in the chemotherapy alone arm. For the 2017 update, the NCCN panel added carboplatin/paclitaxel/bevacizumab as a potentially active regimen based on this trial.

PARP Inhibitors

9] [940] [941] [942] [943] If disease is resistant or refractory to platinum, then a lower response rate to olaparib is observed. 939,941 A trial assessed olaparib in individuals with recurrent advanced ovarian cancer; the overall response rate was 34% (CR, 2%; and PR, 32%). 1109, 1110 The FDA approved olaparib for patients with advanced ovarian cancer who have received treatment with 3 or more lines of chemotherapy and who have a germline BRCA mutation. 1110, 1111 The NCCN Panel recommends single-agent olaparib as recurrence therapy for patients with advanced ovarian cancer (platinum sensitive or resistant) who have received 3 or more lines of chemotherapy and who have a germline BRCA mutation (detected using an FDA-approved test or other validated test performed in a CLIA-approved facility) based on this trial and the FDA approval. 1112

A recent phase 3 randomized trial (SOLO2/ENGOT-Ov21) assessed olaparib (tablets) as maintenance therapy for those (n=295) with platinum-sensitive high-grade serous ovarian cancer and BRCA mutations who had received 2 or more lines of chemotherapy; the trial also included patients with high-grade endometrioid cancer, primary peritoneal, or fallopian tube cancer. 944 4% [4/99]). In the olaparib group, one (1%) patient died from a treatment-related AE (acute myeloid leukemia). The FDA recently approved olaparib (tablets) as maintenance therapy for those with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had complete or PRs to platinum-based chemotherapy.

For the 2017 update (Version 3), the NCCN Panel recommends that olaparib (tablets) be considered as maintenance therapy for those with ovarian cancer who have received 2 or more lines of chemotherapy based on this trial (SOLO2/ENGOT-Ov21) and the FDA approval. 944 Note that olaparib is transitioning from capsules (original FDA approval) to tablets for the maintenance and recurrence therapy indications. Olaparib tablets (100 mg and 150 mg) should not be substituted with olaparib capsules (50 mg) because of differences in the dosing and bioavailability of each formulation.

Rucaparib

Rucaparib is also an oral PARP inhibitor.

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0.27; 95% CI, 0.16–0.44, P<.0001). For those taking rucaparib, serious

AEs were small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anemia (9 [4%]). During the trial, 3

patients died (2 with disease progression; one with sepsis and disease

progression); deaths were not reported as related to treatment. Based on this trial and the FDA approval, the NCCN Panel recommends

single-agent rucaparib as recurrence therapy for patients with

platinum-sensitive or platinum-resistant ovarian cancer who have been

treated with 2 or more lines of chemotherapy and have BRCA mutations

(detected as previously described).1114,1115 The NCCN Panel feels that

rucaparib is preferred for patients with platinum-resistant disease, because there are fewer good options for this setting. In a pooled analysis, the

overall response rate with rucaparib was reported as 66% (52/79; 95% CI, 54–76) for platinum-sensitive disease and 25% (5/20; 95% CI [9–49]) for platinum-resistant disease.1113 A recent phase 1 to 2 study reported a

response rate of 59.5% in patients with platinum-sensitive disease and

BRCA mutations who had received 2 to 4 courses of therapy.1113

Niraparib

Niraparib is another oral PARP 1/2 inhibitor.1116 A phase 3 trial (NOVA)

assessed niraparib as maintenance therapy for patients whose

platinum-sensitive ovarian cancer responded to recurrence therapy.1116

For the 2017 update (Version 1), the NCCN Panel added a

recommendation to repeat the prior imaging to assess response. Data

showed that niraparib increased PFS regardless of whether patients had a BRCA mutation when compared with placebo. Patients receiving niraparib without a germline BRCA mutation had increased PFS (12.9 months vs.

3.8 months). Individuals with a germline BRCA mutation had a much

greater increase in PFS (21.0 vs. 5.5 months) (HR, 0.27; 95% CI, 0.17–

0.41). For those taking niraparib, grade 3 or 4 AEs that were commonly

reported included thrombocytopenia (33.8%), anemia (25.3%), and

neutropenia (19.6%). For the 2017 update (Version 1), the NCCN Panel

recommends niraparib as maintenance therapy for patients with

platinum-sensitive disease who have had 2 or more lines of

platinum-based therapy and a CR or PR to the most recent line of recurrence therapy based on this trial and the FDA approval.1116,1117

Less Common Ovarian Cancers

The LCOC include carcinosarcomas (MMMTs), clear cell carcinoma,

mucinous carcinoma, low-grade (grade 1) serous/endometrioid epithelial carcinoma, borderline epithelial tumors, malignant sex cord-stromal

tumors, and malignant germ cell tumors.139 The complete histologic

classification for ovarian cancer from the WHO describes the different

types of LCOC (see WHO Histologic Classification in the algorithm).1 The AJCC/FIGO staging system for ovarian cancer is also used to stage the

LCOC (see Staging: Table 1 and other staging tables in the algorithm).

Panel members believe there is value in identifying pathways that may

serve as therapeutic targets for the LCOC because of the promise of new and novel approaches to treatment.139 However, there are limited data for these rare histologies because of their infrequency and it will be difficult to acquire prospective data. Clinical trials for eligible patients and

individualized treatment plans, for those who are ineligible for trials, may be the most suitable approaches to treatment in these patients at this time. The different IV and IV/IP chemotherapy regimens used for high-grade

serous ovarian cancer may also be recommended for patients with LCOC; however, the recommendations are only category 2A for LCOC because of the limited data.

Recommended Workup

Patients may obtain consultation at an NCCN Member Institution for

recommendations and treatment of an undiagnosed pelvic mass, or for

management of a previously biopsied malignant ovarian tumor. Many such patients come to NCCN Member Institutions after having had previous

surgery at other institutions. Patients having a histologically undiagnosed

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pelvic mass should undergo evaluation and staging as described in the

algorithm (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). The diagnosis of LCOC is

often not made until after surgery for a suspicious pelvic mass (see

Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal

Cancer: Primary Treatment in the algorithm). Therefore, the workup for

LCOC is the same as for other types of ovarian cancer except that tumor markers are measured and other testing is done to determine the specific histopathology (see Epithelial Ovarian Cancer/Fallopian Tube

Cancer/Primary Peritoneal Cancer: Workup in the algorithm). Tumor

markers may include CA-125, inhibin, beta-hCG, alfa-fetoprotein, and

carcinoembryonic antigen (CEA). Individuals younger than 35 years with a pelvic mass should have AFP levels measured to assess for germ cell

tumors and to rule out pregnancy.433-435 A GI tract evaluation is

recommended for mucinous histology to determine whether an occult GI primary has metastasized to the ovaries.527 An intraoperative frozen

section evaluation is recommended for those who would like to maintain their fertility (see next section).

Surgery

In contrast to high-grade serous epithelial ovarian cancer or MMMTs,

many patients with other LCOC present at an early stage. Some of the

tumors may be confined to one ovary. Thus, some of these patients are

candidates for fertility-sparing surgery, which may be done

laparoscopically (see Principles of Surgery in the algorithm).675,676,679,1118-

1122 Fertility-sparing surgery may be performed (if technically feasible) if

the intraoperative frozen section results are positive for apparent

early-stage tumors and/or low-risk tumors (ie, malignant germ cell tumors, borderline epithelial tumors, clinical stage I epithelial ovarian tumors,

clinical stage I mucinous tumors, or clinical stage I sex cord-stromal

tumors).675,676,679,1119-1122 Patients who do not desire fertility preservation; those who have a clinical stage II, III, or IV epithelial ovarian cancer; those

with a clinical stage II, III, or IV sex cord-stromal tumor; or those with

MMMT should undergo comprehensive surgical staging as per the ovarian cancer guidelines (see Principles of Surgery in the algorithm).

Patients may have been referred to an NCCN Member Institution after

receiving a diagnosis of an LCOC tumor. The recommended initial surgical recommendation depends on the specific histologic diagnosis. Often,

patients have been comprehensively staged (having met the standards for surgical staging of the GOG) and have undergone cytoreductive surgery. In some instances, they are referred after having had incomplete staging (ie, uterus and/or adnexa intact, omentum not removed, surgical stage not documented).

Clear Cell Carcinoma

Clear cell carcinomas are considered high-grade tumors; they are more

common than the other LCOC.562 Most clear cell carcinomas are negative for WT1 and estrogen receptors.562 The NCCN Guidelines provide an

algorithm for clear cell carcinomas (see Less Common Ovarian Cancers: Clear Cell Carcinoma of the Ovary and WHO Histologic Classification in

the algorithm).1 Because patients are typically diagnosed with clear cell

carcinoma after pathologic analysis of a surgical specimen, the workup for suspicious or palpable pelvic masses is done before surgery as described in the algorithm (see Epithelial Ovarian Cancer/Fallopian Tube

Cancer/Primary Peritoneal Cancer: Workup in the algorithm).

Primary treatment for these patients includes completion surgery with

comprehensive staging followed by postoperative therapy (see Less

Common Ovarian Cancers: Clear Cell Carcinoma of the Ovary in the

algorithm).1123 Fertility-sparing surgery is not recommended for stage IA to C clear cell carcinomas. Lymphadenectomy has been shown to improve survival.1124 The staging system for high-grade serous ovarian and primary peritoneal cancer is also used for clear cell carcinomas (see Staging:

Table 1 in the algorithm). 547 6] [1127] For patients with stage IA to IC disease, recommended postoperative treatment is the standard IV taxane-carboplatin regimens (with paclitaxel or docetaxel) used for high-grade serous ovarian cancer. 1124 Fertility-sparing surgery and/or observation/monitoring are an option for patients with unilateral clear cell borderline tumors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm). For patients with stage II to IV clear cell carcinoma, postoperative treatment is standard regimens used for epithelial ovarian cancer (eg, IV carboplatin with paclitaxel, docetaxel, or liposomal doxorubicin). Patients with advanced clear cell carcinoma have a poor prognosis. 1123, 1124 Data suggest that 6 or 3 cycles of postoperative chemotherapy are equivalent for patients with clear cell carcinoma. 802, 1128

Mucinous Carcinomas

Mucinous tumors are unusual because they may be very large cystic masses that may fill the abdomen and pelvis; this presentation often suggests mucinous histology. Patients with mucinous carcinoma of the ovary are often diagnosed with early-stage disease and have a good prognosis; the 5-year DFS is about 80% to 90%. 527, 1129 Individuals with mucinous tumors typically present at a younger age (20-40 years) than those with high-grade serous ovarian cancer. The NCCN Guidelines provide an algorithm for mucinous carcinoma (see Less Common Ovarian Cancers: Mucinous Carcinoma of the Ovary and the WHO Histologic Classification in the algorithm). 1 For the 2017 update (Version 1), the NCCN Panel added a recommendation for fertility-sparing surgery, if not previously done, for select patients with stage IA to C disease.

Patients are typically diagnosed with mucinous carcinoma after surgery for a suspicious pelvic mass (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Primary Treatment in the algorithm). Therefore, the initial workup is the same as for other types of ovarian cancer (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). Primary treatment for these patients includes completion surgery with comprehensive staging followed by postoperative therapy or observation (see Less Common Ovarian Cancers: Mucinous Carcinoma of the Ovary in the algorithm). 527 An appendectomy is also recommended at primary surgery in patients with suspected or confirmed mucinous ovarian tumors. Fertility-sparing surgery is an option for select patients with stage I mucinous tumors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).The staging system for high-grade serous epithelial ovarian cancer and primary peritoneal cancer is also used for mucinous carcinomas (see Staging: Table 1 in the algorithm). 547 e additional workup includes a GI tract evaluation and CEA level for patients with mucinous histology to determine whether patients have either occult GI primary that has metastasized to the ovaries or primary mucinous carcinoma of the ovaries (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). 527 Metastases to the ovaries are more common, and primary mucinous tumors of the ovaries are uncommon; it is difficult to distinguish between metastatic adenocarcinomas to the ovaries and primary mucinous carcinomas. 574-576 PAX8 immunostaining may be useful. 574 stoperative observation and monitoring are recommended for patients with stage IA or IB mucinous tumors because most of these tumors are benign or borderline. 527, 562 For patients with stage IC mucinous carcinomas, postoperative options include: 1) observation; 2) IV carboplatin with either paclitaxel or docetaxel; 3) 5-FU/leucovorin/oxaliplatin GI regimen); or 4) capecitabine/oxaliplatin (GI regimen). 527 Some clinicians feel the GI regimens are appropriate because NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12,19:17在医脉通平台下载，仅供个人使用，严禁分发。2026 美国国家综合癌症网络版权所有。

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mucinous carcinomas of the ovary are similar to GI tumors.1130 For

patients with stages II to IV mucinous carcinomas, postoperative options include: 1) chemotherapy using the regimens for epithelial ovarian cancer (eg, IV carboplatin with paclitaxel, docetaxel, or liposomal doxorubicin); 2) 5-FU/leucovorin/oxaliplatin (GI regimen); or 3) capecitabine/oxaliplatin (GI regimen). For the 2017 update (Version 1), the NCCN Panel added

recommendations for recurrence therapy for mucinous carcinomas: 1)

5-FU/leucovorin/oxaliplatin with or without bevacizumab (category 2B for bevacizumab); or 2) capecitabine/oxaliplatin.

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Low-Grade Serous Carcinoma

Low-grade serous carcinoma is a subtype of serous carcinoma that is

considered pathologically distinct from the more commonly diagnosed

high-grade serous carcinoma, and represents less than 5% of epithelial ovarian cancers.139,1131 Low-grade serous carcinoma is characterized by mild to moderate nuclear atypia, and up to 12 mitoses per 10 highpowered fields (HPF), while high-grade serous carcinoma is

characterized by marked nuclear atypia and over 12 mitoses per 10

HPF.560,1131,1132 Additionally, activating mutations in the mitogen-activated protein kinase (MAPK) pathway are frequently identified in low-grade, but not high-grade, serous carcinomas; in contrast, TP53 mutations are

generally associated with high-grade, but not low-grade, serous

carcinomas.1133-1138 Low-grade serous carcinomas are associated with

more indolent disease and present at a younger age than high-grade

serous carcinomas; however, they are also often advanced at

diagnosis.560,579,1132,1139 Approximately 60% of low-grade serous

carcinomas (vs. 2% of high-grade serous carcinomas) are also

associated with serous borderline tumors (low malignant potential).560

Due to these distinctions, patients with low-grade serous carcinomas are generally treated differently than those with high-grade serous

carcinomas, as described below.

Primary Treatment

Primary treatment for low-grade serous carcinomas is comprised of

completion surgery with comprehensive staging, followed by adjuvant

therapy or observation.579 Typically the diagnosis of low-grade serous

carcinoma is made via comprehensive pathology review after initial

surgery. The staging system for high-grade serous ovarian, fallopian

tube, and primary peritoneal cancer is also used for low-grade serous.547 Low-grade serous carcinomas often respond poorly to chemotherapy

compared with high-grade serous carcinomas1140; therefore, neoadjuvant

chemotherapy is less favored for patients with low-grade serous

carcinoma.579

Recommendations for adjuvant treatment are stratified by stage in the

guidelines (see LCOC-6). Postoperative observation is a category 2A

recommendation for patients with stage IA and IB disease and a category 2B recommendation for those with stage IC disease. Several adjuvant

systemic therapy options, including paclitaxel/platinum-containing

regimens, are recommended for patients with stage IC or stage II–IV

disease, although there are limited data on systemic therapy regimens in patients with low-grade serous carcinoma in general.

Patients with low-grade serous carcinomas may also benefit from

maintenance hormone therapy following adjuvant chemotherapy. One

database study observed that patients with stage II–IV low-grade serous carcinoma who received maintenance hormone therapy after completing primary cytoreductive surgery and first-line platinum-based chemotherapy experienced longer progression-free survival (PFS) than those who did not receive maintenance hormone therapy (median PFS, 64.9 vs. 26.4

months; P < .001).1141 The majority of patients in the study received

letrozole (54.3%), with a lower proportion receiving tamoxifen (28.6%).

Based on these data, maintenance hormone therapy (letrozole,

anastrozole, exemestane, leuprolide acetate, or tamoxifen) is a category 2B recommendation in the guidelines.

Adjuvant hormone therapy as a substitute for adjuvant chemotherapy is

another potential option for these patients.1142 However, as there are no

supporting prospective data, this is a category 2B recommended option in the guidelines. A randomized trial of paclitaxel/carboplatin chemotherapy followed by maintenance hormonal therapy versus hormonal therapy

alone in patients with low-grade serous carcinoma is currently

underway.1143

Monitoring/Follow-up for Recurrent Disease

Unfortunately, patients with low-grade serous carcinoma, particularly those with advanced stage disease, may experience disease relapse; therefore, continued monitoring of these patients is essential. The guidelines recommend monitoring for potential recurrence of low-grade serous carcinoma through follow-up visits every 2 to 4 months for 2 years, followed by 3 to 6 months for 3 years, and then annually after 5 years (see LCOC-7). These visits should consist of a physical examination, including a pelvic examination. Tumor molecular testing is recommended, if not previously done; more comprehensive somatic genetic testing may be particularly important in low-grade serous carcinoma, which has limited approved therapeutic options. Imaging and complete blood count (CBC)/chemistry profile are also recommended, as clinically indicated. CA-125 or other tumor markers should be assessed if initially elevated. Refer patients for a genetic risk evaluation, if not previously done. For guidance on long-term wellness care for patients who have been treated for low-grade serous carcinoma, please refer to the NCCN Guidelines for Survivorship (www.NCCN.org).

Recurrence Therapy

The NCCN Guidelines recommend several options for patients with recurrent low-serous carcinoma (see LCOC-7). Secondary cytoreduction can be considered for patients with a long disease-free interval, isolated masses rather than diffuse carcinomatosis on imaging, and/or bowel obstruction. Systemic therapy is another option for this patient population; however, the guidelines emphasize that there is no standard sequencing of drugs for recurrent disease. Therefore, each patient should be evaluated on an individual basis, taking into consideration prior therapies, disease burden, molecular profile, and the relative efficacy and toxicity profile before initiating systemic therapy. Recommended systemic therapies for this patient population in this setting include chemotherapy (if not previously used) and hormonal therapy. 579, 1144 wever, it has been reported that low-grade serous carcinoma may be more chemo-resistant than high-grade serous carcinoma in the recurrent setting. 1145 Thus, effective systemic options for recurrent low-grade serous carcinoma have remained an unmet need. Importantly, recent studies have suggested that MEK inhibitors have activity in recurrent low-grade serous carcinoma. A phase 2/3 open-label, randomized study evaluated the efficacy and safety of trametinib, a MEK1/2 inhibitor, compared with five standard-of-care options (SOC; paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, or tamoxifen) in 260 patients with recurrent low-grade serous carcinoma. 1146 The median progressionfree survival was 13.0 months in the trametinib arm, compared with 7.2 months in the standard-of-care group (HR, 0.48; 95% CI, 0.36-0.64; P < .0001). The overall response rate (ORR) of the trametinib group was 26%, which was significantly higher than the 6% ORR of the SOC group (P < .0001). The most common grade 3 or 4 adverse events reported in the trametinib group were skin rash, anemia, hypertension, diarrhea, nausea, and fatigue. Due to the superior outcomes reported in this trial, the NCCN panel recommends trametinib as a category 2A option for patients with recurrent low-grade serous carcinoma.

The efficacy and safety of another MEK1/2 inhibitor, binimetinib, was evaluated in a phase 3 open-label study in 303 patients with recurrent low-grade serous carcinoma. 1147 Patients were randomized to receive either binimetinib or physician's choice chemotherapy (PCC; pegylated liposomal doxorubicin, paclitaxel, or topotecan). The median PFS for the binimetinib group was 9.1 versus 10.6 months in the PCC group (HR, 1.21; 95% CI, 0.79-1.86; P = .807); therefore, the primary endpoint of PFS by blinded independent central review (BICR) was not met in this study. However, binimetinib was numerically superior to PCC across NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12,19:17在医脉通平台下载，仅供个人使用，严禁分发。2026 美国国家综合癌症网络版权所有。

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certain endpoints, such as PFS by local investigator assessment (12.5

months in the binimetinib group compared with 11.6 months in the PCC group) and ORR by BICR (16% in the binimetinib group compared with 13% in the PCC group). Additionally, PFS and ORR data from a post hoc analysis suggested that a response to binimetinib may be associated

with the presence of a KRAS mutation. Based on these data, the NCCN panel recommends binimetinib as a category 2B option for patients with recurrent low-grade serous carcinoma.

Recently a new option became available for patients with recurrent lowgrade serous carcinoma with a BRAF V600E mutation. In June 2022, the U.S. Food and Drug Administration granted accelerated approval to

selective BRAF inhibitor dabrafenib in combination with trametinib for the treatment of adult and pediatric patients (6 years and older) with

unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory

alternative treatment options.1148-1150 This approval was based on several studies; one of these was the phase 2 open-label single-arm NCIMATCH trial (subprotocol H), where dabrafenib in combination with

trametinib was evaluated in patients with solid tumors, lymphoma, or

multiple myeloma who progressed on at least one standard therapy.1151 Out of the 29 patients included in the primary analysis, five had lowgrade serous carcinoma and one had mucinous-papillary serous

adenocarcinoma of peritoneum. The ORR of the overall population was 38%, with a PFS of 11.4 months. Notably, a clinical benefit was observed in all 6 patients with primary gynecologic cancer; 5 patients achieved a

partial response (PR) (>12 months for 3 patients) and 1 patient had

stable disease (SD) for 8 months following treatment. Based on the

results, the combination of dabrafenib and trametinib has been added to the guidelines as a category 2A recurrence therapy option for patients

with BRAF V600E-positive tumors (including low-grade serous

carcinoma).

In addition to the options described above, other acceptable systemic

recurrence therapies listed in the Principles of Systemic Therapy section of the guidelines (OV-C 8 of 11 and OV-C 9 of 11, available on

http://www.NCCN.org) can be considered. Clinical trial enrollment and

observation are other recommended options for patients with recurrent low-grade serous carcinoma.

In response to the availability of novel treatment options for recurrent

low-grade serous carcinoma, the NCCN panel has developed a new

algorithm page with recommendations for the management of recurrent low-grade serous carcinoma; please refer to LCOC-7 for additional

details.

Endometrial Epithelial Carcinoma

Section development in progress

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Malignant Germ Cell Tumors

These malignant tumors include dysgerminomas, immature teratomas,

embryonal tumors, and endodermal sinus (yolk sac) tumors (see the Less Common Ovarian Cancers: Malignant Germ Cell Tumors and the WHO

Histologic Classification in the algorithm).1 They mainly occur in younger individuals who are often diagnosed with stage I disease; the median age at diagnosis is 16 to 20 years.428,1152 Germ cell tumors are the predominant ovarian tumor in this age group.470 The recommended workup may include pulmonary function studies if bleomycin is being considered (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer:

Workup in the algorithm).433,1153 In young individuals (<35 years) with a

pelvic mass, AFP levels can indicate the presence of germ cell tumors.433-435 However, pregnancy should also be ruled out. Gonadal dysgenesis is a risk factor for germ cell tumors.470 Malignant germ cell tumors have an

excellent prognosis.1154 After appropriate treatment, 5-year survival is

more than 85%.1152,1155,1156

Treatment

Fertility-sparing surgery is recommended for those desiring fertility

preservation, regardless of stage (see Less Common Ovarian Cancers:

Malignant Germ Cell Tumors in the algorithm).428,679,1156-1159 Surgery for

children or adolescents may differ from that for adults (see Principles of

Surgery in the algorithm). In children or adolescents with early-stage germ cell tumors, comprehensive staging may be omitted.685,1160 Completion

surgery with comprehensive staging is recommended as initial surgery for patients who do not desire fertility preservation (see Less Common

Ovarian Cancers: Malignant Germ Cell Tumors in the algorithm).470 The

staging system for high-grade serous ovarian and primary peritoneal

cancer is also used for malignant germ cell tumors (see Staging: Table 1 in the algorithm).547 After comprehensive surgical staging, observation with monitoring is recommended for patients with stage I dysgerminoma or

stage I, grade 1 immature teratoma.1161 If patients have had incomplete

surgical staging, recommended options depend on the type of tumor, the results of imaging and tumor marker testing (eg, AFP, beta-HCG), the age of the patient, and whether the patient desires fertility preservation (see

Less Common Ovarian Cancers: Malignant Germ Cell Tumors in the

algorithm). Patients who chose fertility-sparing surgery should be

monitored by US examinations if necessary; completion surgery (category 2B) should be considered after finishing childbearing.

After surgery, observation with surveillance is the recommended option for patients with stage I dysgerminoma or stage I, grade I immature teratoma based on European and pediatric reports.448,450,451,1162 Observation or

chemotherapy may be considered for children or adolescents with select stage IA or IB tumors (see Less Common Ovarian Cancers: Malignant

Germ Cell Tumors in the algorithm).428,448,1162-1165 For patients with stage II to IV malignant dysgerminomas or immature teratomas, postoperative

chemotherapy is recommended (see Principles of Systemic Therapy:

Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord-Stromal

Tumors in the algorithm).

Postoperative chemotherapy for 3 to 4 cycles with

bleomycin/etoposide/cisplatin (BEP) (category 2B for 3 vs. 4 cycles) is

recommended for: 1) any stage embryonal tumors or endodermal sinus

tumors; 2) stages II to V dysgerminoma; or 3) stage I, grade 2 to 3, or

stage II to IV immature teratoma (see the Principles of Systemic Therapy: Systemic therapy Regimens - Malignant Germ Cell/Sex Cord-Stromal

Tumors in the algorithm).1153,1166-1168 If considering the use of bleomycin,

pulmonary function tests are recommended.1153,1155 The 4-cycle BEP

regimen is recommended (category 2A) as the standard regimen.

Although most clinicians avoid a 3-week BEP regimen, some feel that a

3-week BEP regimen (3 cycles) may be useful in patients with low-risk or stage 1 disease, although this is a category 2B recommendation; the

Memorial Sloan Kettering Cancer Center criteria can be used to identify

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tumors that are low risk.444,448,1169-1175 In select patients with stage IB to III dysgerminoma for whom minimizing toxicity is critical, 3 courses of

etoposide/carboplatin can be used (carboplatin 400 mg/m2 [AUC =~5–6] on day 1 plus etoposide 120 mg/m2 on days 1–3 every 4 weeks for 3

courses).1176 Dose reductions or delays are not recommended even in the setting of neutropenia.

Surveillance recommendations for germ cell tumors are described in the algorithm (see Surveillance for Malignant Germ Cell and Sex

Cord-Stromal Tumors in the algorithm).1017 Patients achieving a complete clinical response after chemotherapy should be observed clinically every 2 to 4 months with AFP and beta-HCG levels (if initially elevated) for 2

years. For those with abnormal markers and definitive recurrent disease, options (category 2B) include: 1) high-dose chemotherapy;1177 or 2)

consider additional chemotherapy (see Principles of Systemic Therapy:

Systemic Therapy Regimens – Malignant Germ Cell/Sex Cord-Stromal

Tumors in the algorithm). Referral of these patients to a tertiary care

center for stem-cell transplant consultation and potentially curative therapy is strongly recommended. Several case reports suggest that patients who have received chemotherapy for germ cell tumors may later present with growing teratoma syndrome.1178-1181

Residual or Recurrent Disease

For patients having radiographic evidence of residual tumor (after surgery and chemotherapy) but with normal AFP and beta-HCG, consider surgical resection of the tumor; observation with monitoring is also an option.

Clinical judgment should be used regarding the frequency of imaging.1182 Further options depend on which findings are present: residual

malignancy, benign teratoma, or necrotic tissue (see Therapy for

Recurrent/Persistent Disease for Malignant Germ Cell Tumors in the

algorithm). For patients with definitive residual disease and with

persistently elevated AFP and/or beta-HCG after first-line chemotherapy,

recommendations include TIP (paclitaxel, ifosfamide, cisplatin)1183 or

high-dose chemotherapy. Referral to a tertiary care center for potentially curative treatment is strongly recommended.1184 There are small series but no major trials in adult patients.

Patients with recurrent or residual malignancy after multiple

chemotherapeutic regimens may be treated with a recurrence modality

(see Principles of Systemic Therapy: Acceptable Systemic Therapy

Regimens - Malignant Germ Cell/Sex Cord-Stromal Tumors in the

algorithm), including potentially curative high-dose chemotherapy or TIP. Other regimens include VAC (vincristine, dactinomycin,

cyclophosphamide), VeIP (vinblastine, ifosfamide, cisplatin), VIP

(etoposide, ifosfamide, cisplatin), cisplatin/etoposide,

docetaxel/carboplatin, paclitaxel/carboplatin, paclitaxel/gemcitabine,

paclitaxel/ifosfamide, docetaxel, paclitaxel, RT, or supportive care

only.1171,1184-1188 These recurrence regimens (see Principles of Systemic

Therapy: Systemic Therapy Regimens - Malignant Germ Cell/Sex

Cord-Stromal Tumors in the algorithm) are not generalizable for all of the uncommon histology tumors; therefore, patients should be referred to

tertiary care institutions for treatment.

Malignant Sex Cord-Stromal Tumors

Malignant sex cord-stromal tumors are rare and include granulosa cell

tumors (most common) and Sertoli-Leydig cell tumors; they are typically

associated with a good prognosis.660,1189 Most patients with granulosa

tumors present with early-stage disease; the disease is typically

indolent.659 The complete histologic classification for ovarian cancer from the WHO includes the different types of sex cord-stromal tumors; it is

important to determine whether the sex cord-stromal tumor is benign or

malignant (see WHO Histologic Classification: Sex Cord-Stromal Tumors in the algorithm).1 The staging system for high-grade serous ovarian and

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primary peritoneal cancer is also used for sex cord-stromal tumors (see

Staging: Table 1 in the algorithm).547

Patients with stage IA or IC sex cord-stromal tumors desiring to preserve their fertility should be treated with fertility-sparing surgery (see Less

Common Ovarian Cancers: Malignant Sex Cord-Stromal Tumors in the

algorithm).658,659,1190,1191 Although complete staging is recommended for all other patients, lymphadenectomy may be omitted for tumors grossly

confined to the ovary.1192 For patients who choose fertility-sparing surgery, completion surgery (category 2B) should be considered after childbearing is finished. Postoperative options in the NCCN Guidelines have category 2B recommendations (see Less Common Ovarian Cancers: Malignant

Sex Cord-Stromal Tumors in the algorithm).1190 For patients with high-risk stage I tumors (tumor rupture, stage 1C, poorly differentiated tumor, and tumor size >10–15 cm467), postoperative recommendations (all are

category 2B) include observation or consideration of platinum-based

chemotherapy.1193 Observation is recommended for those with surgical

findings of low-risk stage I tumor (ie, without high-risk features) (see

Surveillance for Malignant Germ Cell and Sex Cord-Stromal Tumors in the algorithm). For patients with granulosa cell tumors who are being

observed, inhibin levels can be followed if they were initially elevated

(category 2B). For patients with stage II to IV tumors, recommended

options (all are category 2B) include RT for limited disease or

platinum-based chemotherapy (BEP or paclitaxel/carboplatin regimens are preferred).1194-1197

Surveillance recommendations for malignant sex cord-stromal tumors are provided in the algorithm, which are based on the SGO recommendations (see Surveillance for Malignant Germ Cell and Sex Cord-Stromal Tumors in the algorithm).1017 Prolonged surveillance is recommended for

granulosa cell tumors, because they can recur years later (eg, 30

years).660,1158,1189,1198 For patients with stage II to IV tumors who

subsequently have a clinical relapse, options include a clinical trial or

recurrence therapy (see Principles of Systemic Therapy: Systemic

Therapy Regimens - Malignant Germ Cell/Sex Cord-Stromal Tumors in the algorithm).1189,1198-1201 Cytotoxic recurrence therapy includes:

docetaxel, paclitaxel, paclitaxel/ifosfamide, paclitaxel/carboplatin, and

VAC. Hormone recurrence therapy includes: aromatase inhibitors,

leuprolide, and tamoxifen. Note that single-agent bevacizumab or

leuprolide is an option for patients with recurrent granulosa cell

tumors.1201,1202 Secondary cytoreductive surgery may also be considered. Palliative localized RT may also be useful.

Carcinosarcomas (Malignant Mixed Müllerian Tumors)

MMMTs are rare tumors with a poor prognosis; they are the most

aggressive tumors in the algorithm.1203-1206 Most pathologists now consider MMMTs to be a variant of poorly differentiated epithelial ovarian cancer

(metaplastic carcinoma).566 Patients with MMMTs are not candidates for

fertility-sparing surgery regardless of age or stage. The staging system for ovarian and primary peritoneal cancer is also used for MMMTs (see

Staging: Table 1 in the algorithm).547,1205

Optimal surgical debulking is recommended for patients with MMMTs (see Principles of Surgery in the algorithm).1205,1207-1209 After complete surgical staging, several postoperative chemotherapy regimens are recommended for patients with stage I to IV MMMT. Patients with stage I to IV MMMT or recurrence may be treated using the same primary chemotherapy

regimens that are recommended for epithelial ovarian cancer; for the 2017 update (Version 1), the panel decided these chemotherapy regimens are preferred options (see Principles of Systemic Therapy: Primary Systemic Therapy Regimens in the algorithm).566,1210-1215 For example, IV carboplatin with either paclitaxel, docetaxel, or liposomal doxorubicin are

recommended for patients with stage I-IV MMMT. The IP chemotherapy

regimen described for ovarian cancer can be used for select patients with

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MMMT. Other recommended postoperative chemotherapy options include cisplatin/ifosfamide (category 2A), carboplatin/ifosfamide (category 2A), and ifosfamide/paclitaxel (category 2B).566,1203,1210,1216 After treatment, the surveillance and follow-up recommendations for epithelial ovarian cancer are also used for MMMTs.

Borderline Epithelial Tumors (Low Malignant Potential)

Diagnosis

Borderline epithelial tumors are rare tumors and are managed differently than high-grade carcinomas (see Less Common Ovarian Cancers:

Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the

algorithm).1118,1217 Five-year survival exceeds 80%.1218 In contrast to

patients with frankly invasive ovarian carcinoma, those with borderline

epithelial tumors tend to be younger, are often diagnosed with stage I

disease, and are candidates for fertility-sparing surgery.1219,1220 A

borderline tumor is a primary epithelial lesion with cytologic characteristics suggesting malignancy but without frank invasion and with a clinically

indolent course and good prognosis.1221,1222

The terms for borderline epithelial tumors (also known as LMP tumors or atypical proliferative tumors) have changed over the years.562 The 2016

and 2017 CAP cancer protocols for ovarian cancer use borderline and do not use LMP.1223,1224 Borderline epithelial tumors are typically serous or

mucinous; other histologic subtypes can also occur (see WHO Histologic Classification in the algorithm).1,1118

The characteristic pathologic hallmark of typical epithelial ovarian cancer is the identification of peritoneal implants, which microscopically and/or

macroscopically invade the peritoneum. A borderline epithelial tumor may grossly resemble an invasive cancer. However, microscopic evaluation

fails to reveal evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the

diagnosis of borderline epithelial lesions) can be identified microscopically by the pathologist.

Treatment

Surgery is the primary treatment for borderline epithelial tumors, including standard ovarian cancer debulking surgery or fertility-sparing surgery

depending on the surgical evaluation and other factors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant

Potential] in the algorithm).1225 Treatment guidelines for borderline

epithelial tumors depend on the histologic and clinical characteristics, the age of the patient,1220 and whether invasive implants are present. Patients should be evaluated by a gynecologic oncologist. At NCCN Member

Institutions, patients may be initially evaluated with an undiagnosed pelvic mass or with an established diagnosis of borderline epithelial tumor.

NCCN Panel Members are less likely to recommend aggressive treatment after surgery; observation is one of several possible approaches.1118,1226

Although the staging system for epithelial ovarian cancer is used for

borderline epithelial tumors, the NCCN Guidelines use the presence or

absence of invasive implants to determine the need for postoperative

therapy (see Less Common Ovarian Cancers: Ovarian Borderline

Epithelial Tumors [Low Malignant Potential] in the algorithm).

Patients with a borderline epithelial tumor who desire to maintain their

fertility may undergo surgery limited to a USO (preserving the uterus,

contralateral ovary, and contralateral Fallopian tube) with resection of

residual disease.675,676,1227 BSO and preserving the uterus is an option for select patients. If the patient does not desire fertility-sparing surgery,

standard ovarian cancer surgery (TAH, BSO, and debulking as needed)

and resection of residual disease are recommended. Data do not show

increased survival with lymphadenectomy and omentectomy for borderline epithelial tumor, although upstaging does occur.728,1228 Lymph node

evaluation may be considered on a case-by-case basis.

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For patients with known borderline epithelial tumors who had incomplete previous surgery and/or were incompletely staged at the time of their initial laparotomy, recommendations depend on whether invasive implants are present and whether fertility preservation is desired (see the prior

incomplete surgical resection pathway in Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the

algorithm). Patients who want to preserve their fertility should have

fertility-sparing surgery and resection of residual disease. Some clinicians feel that the appearance of invasive implants on the peritoneal surfaces in patients with borderline epithelial tumors portends a less favorable

prognosis; therefore, postoperative chemotherapy with the same regimens used for low-grade (grade 1) serous epithelial ovarian cancer can be

considered for these patients (see Less Common Ovarian Cancers:

Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the

algorithm).1219,1220,1229 Postoperative IV carboplatin with either docetaxel or paclitaxel is recommended. The benefit of chemotherapy, either IP or IV, is controversial in patients with borderline epithelial tumors. The

significance of invasive implants remains under investigation.1118,1230 The benefit of postoperative chemotherapy has not been demonstrated for

patients who have no microscopically demonstrable invasive implants.1231 Although observation is an option for all patients, it is a category 3

recommendation for patients with invasive implants and a category 2B

recommendation for patients without invasive implants (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant

Potential] in the algorithm).

Follow-up

Treatment recommendations after surgery depend on the presence or

absence of invasive implants. The initial therapeutic approach for patients having invasive implants may include treatment with the same

chemotherapeutic regimens used for low-grade (grade 1) serous epithelial ovarian cancer or observation (category 3) (see Less Common Ovarian

Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).1230 Patients with no invasive implants may be observed (category 2B) and monitored (see Monitoring/Follow-Up in Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).1219,1232 Patients who chose fertility-sparing

surgery should be monitored by US examinations if necessary. After

childbearing is completed, completion surgery should be considered

(category 2B).1118

Relapse

At the time of clinical relapse, surgical evaluation and debulking are

recommended if appropriate. Patients who have low-grade invasive

carcinoma or invasive implants from borderline epithelial tumors may be treated using the same recommendations as for low-grade (grade 1)

serous epithelial ovarian cancer; those with high-grade invasive implants may be treated using the same recommendations as for epithelial ovarian cancer (see Recurrence Therapy in Less Common Ovarian Cancers:

Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the

algorithm). Observation is recommended for those with noninvasive

disease.

Summary

Epithelial ovarian cancer is the leading cause of death from gynecologic

cancer in the United States and is the country’s fifth most common cause

of cancer mortality in females. More than 70% of patients present with

advanced disease. The literature does not support routine screening for ovarian cancer in the general population, and routine screening is not

currently recommended by any professional society. These NCCN

Guidelines discuss epithelial ovarian cancer and LCOC, including

carcinosarcomas (MMMTs of the ovary), clear cell carcinomas, mucinous carcinomas, low-grade serous carcinomas/endometrioid epithelial

carcinomas, borderline epithelial tumors (also known as LMP tumors),

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malignant sex cord-stromal tumors, and malignant germ cell tumors.

Primary peritoneal and Fallopian tube cancers are treated in the same

manner as epithelial ovarian cancer.

The complete histologic classification for ovarian cancer from the WHO

describes the different types of LCOC. Panel members believe there is

value in identifying pathways that may serve as therapeutic targets for the LCOC because of the promise of new and novel approaches to treatment. However, there are limited data for these rare histologies because of their infrequency and it will be difficult to acquire prospective data. Clinical trials for eligible patients, and individualized treatment plans for those who are not eligible for trials, may be the most suitable approaches to treatment in these patients at this time.

Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen. Based on published improved outcomes, it is recommended (category 1) that a gynecologic oncologist

perform the primary surgery. Primary treatment for presumed ovarian

cancer consists of appropriate surgical staging and debulking surgery,

followed in most (but not all) patients by systemic chemotherapy.

Debulking surgery is the initial treatment recommendation for patients with clinical stage II, III, or IV disease. For most patients, initial surgery should include hysterectomy, BSO, and debulking as needed. Procedures that

may be considered for optimal surgical debulking include: radical pelvic

dissection, bowel resection and/or appendectomy, lymphadenectomy,

diaphragm or other peritoneal surface stripping, splenectomy, partial

hepatectomy, partial gastrectomy, or partial cystectomy and/or

ureteroneocystostomy, cholecystectomy, and/or distal pancreatectomy.

Most patients have a hysterectomy with BSO, omentectomy, and

lymphadenectomy of suspicious/enlarged nodes. Patients with low-volume residual disease after surgical debulking for stage II or III invasive

epithelial ovarian or peritoneal cancer are candidates for IP therapy. In

these patients, consideration should be given to placement of an IP

catheter with initial surgery. In those with optimally debulked stage III

cancer, the IP regimen has yielded median survival of 65.6 months. In

those receiving a dose-dense weekly paclitaxel/carboplatin regimen,

median OS was 100.5 months.

For a young patient who wishes to maintain fertility, a USO (preserving the uterus and contralateral ovary) and comprehensive surgical staging may be adequate for select unilateral stage I tumors (stage 1A and 1C, but not stage 1B) and/or low-risk ovarian tumors (ie, early-stage, grade 1 tumors; borderline tumors). For those with stage IB tumors who wish to maintain

fertility, a BSO (preserving the uterus) and comprehensive surgical staging are recommended.

Most patients with epithelial ovarian cancer receive postoperative systemic chemotherapy. Consideration of palliative care interventions is appropriate at several stages during the disease course. Recommendations regarding initial primary systemic therapy include IV with [or without] IP options. All of the regimens (including the combined IV/IP chemotherapy) may be

used for epithelial ovarian, primary peritoneal, and Fallopian tube cancers; some of these regimens are recommended for some of the LCOC. NACT may be considered (category 1) for patients with bulky stage III to IV

disease or high-risk surgical candidates; a gynecologic oncologist should make this assessment before NACT is administered.

For all patients, the NCCN Guidelines recommend symptom management, best supportive care, and long-term wellness care; patients should be

referred for palliative care assessment if appropriate. Patients should be

educated about signs and symptoms suggestive of recurrence such as

pelvic pain, bloating, early satiety, obstruction, weight loss, and fatigue.

Recurrent disease may be identified clinically (eg, pelvic pain, weight

loss), biochemically (ie, elevated CA-125 levels), and/or with imaging. The NCCN Guidelines recommend a number of different regimens and agents

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for recurrence therapy; some of them are designated as preferred

regimens. Patients with ovarian cancer will often be retreated with multiple courses of recurrence therapy. Patients who relapse 6 months or more

after initial chemotherapy are termed platinum sensitive. Those who

relapse after less than 6 months are termed platinum resistant.

Platinum-based combination chemotherapy is preferred in patients with

platinum-sensitive disease, especially for first recurrence. For

platinum-resistant disease, non-platinum–based agents or regimens are preferred. Some of the new additions for 2017 include: 1)

carboplatin/liposomal doxorubicin for first-line therapy; 2) niraparib and

olaparib for maintenance therapy; and 3) rucaparib,

carboplatin/albumin-bound paclitaxel, and

carboplatin/paclitaxel/bevacizumab for recurrence therapy.

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References

表 1
Malignant Germ Cell Tumors
	Year 1	Year 2	Year 3	Years 4-5	After 5 Years
Clinical evaluation	Every 3 mo	Every 3 mo	Every 6 mo	Every 12 mo	Every 12 mo
Pelvic $USA^{a}$	Every 3 mo	Every 3 mo	Every 6 mo	--	--
Tumor $markers^{b}$	Every 2 mo	Every 3 mo	Every 6 mo	Every 12 mo	Every 12 mo up to 10 y
Chest x-ray	--	--	--	Every 6 mo	As clinically indicated
C/A/P CT	Every 3 mo	Every 3 mo	Every 6-12 mo	As clinically indicated	As clinically indicated

表 2
Malignant Sex $Cord-Stromal$ Tumors^{c}$
	0–2 Years	After 2 Years	After 2 Years
Physical exam	As clinically indicated based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)	As clinically indicated based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)	(ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)
Serum tumor $markers^{b}$	Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)	Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)	Testing as clinically indicated, if applicable • If done, frequency based on stage (ie, 6–12 mo if early-stage, low-risk disease; 4–6 mo if high-risk disease)
$Imaging^{d}$	Reserved for patients with symptoms, elevated biomarkers, or suspicious findings on physical exam	Reserved for patients with symptoms, elevated biomarkers, or suspicious findings on physical exam

表 3
Regimen	Setting	Dose/Administration	Duration
Olaparib + bevacizumab1	Maintenance post primary chemotherapy + bevacizumab	• Olaparib 300 mg PO twice daily • Bevacizumab 15 mg/kg IV every 21 days	• Olaparib: Until disease progression or unacceptable toxicity or up to 2 years • Bevacizumab: Until disease progression or unacceptable toxicity or up to 15 months
Niraparib + bevacizumab2	Maintenance post primary chemotherapy + bevacizumab	• Niraparib: 300 mg PO once daily (or 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3) • Bevacizumab: 15 mg/kg IV every 21 days	• Niraparib: Until disease progression or unacceptable toxicity or up to 3 years • Bevacizumab: Until disease progression or unacceptable toxicity or up to 15 months
Niraparib monotherapy3,4	Maintenance post primary chemotherapy	300 mg PO once daily (or 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3)	Until disease progression or unacceptable toxicity or up to 36 months
Niraparib monotherapy3,4	Maintenance post recurrence chemotherapy	300 mg PO once daily (or an initial dose of 200 mg once daily for patients with a baseline body weight of <77 kg, and/or a platelet count of <150,000/mm3); after 2 to 3 months, in the absence of hematologic toxicity, may consider escalation to 300 mg once daily)	Until disease progression or unacceptable toxicity
Olaparib monotherapy5-7	Maintenance post primary chemotherapy	300 mg PO twice dailyb	Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity
Olaparib monotherapy5-7	Maintenance post recurrence chemotherapy	300 mg PO twice dailyb	Until disease progression or unacceptable toxicity
Rucaparib monotherapy8,9	Maintenance post primary chemotherapy	600 mg PO twice dailyb	Until disease progression or unacceptable toxicity or up to 24 months
Rucaparib monotherapy8,9	Maintenance post recurrence chemotherapy	600 mg PO twice dailyb	Until disease progression or unacceptable toxicity
Fluzoparib monotherapy*	Maintenance post primary chemotherapy	150 mg PO twice daily	Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity
Fluzoparib monotherapy*	Maintenance post recurrence chemotherapy	150 mg PO twice daily	Until disease progression or unacceptable toxicity
Senaparib monotherapy	Maintenance post primary chemotherapy	100 mg PO once daily	Until disease progression or CR (no evidence of disease) at 2 yearsb or unacceptable toxicity

表 4
Primary Therapy for Stage I Disease
High-grade serousEndometrioid (grade 2/3)Clear cell carcinomadCarcinosarcomad	Preferred RegimensPaclitaxel/carboplatin every 3 weeks9,h	Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin	Useful in Certain CircumstancesPaclitaxel/cisplatinFor carcinosarcoma:Carboplatin/ifosfamideCisplatin/ifosfamidePaclitaxel/ifosfamide (category 2B)9
Mucinous carcinoma(stage IA, IB, and IC,grades 1-3)d	Preferred Regimens5-FU/leucovorin/oxaliplatinCapacitabine/oxaliplatinPaclitaxel/carboplatin every 3 weeks9,h	Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin	Useful in Certain Circumstances
Low-grade serous(stage IC)/Grade I endometrioid (stage IC)d,e,f	Preferred RegimensPaclitaxel/carboplatin every 3 weeks9,h± maintenance letrozole (category 2Bf)or other hormonal therapy (category 2Bf)Hormone therapy (aromataseinhibitors: anastrozole,letrozole,exemestane) (category 2Bf)	Other Recommended RegimensCarboplatin/liposomal doxorubicinDocetaxel/carboplatin	Useful in Certain CircumstancesPaclitaxel/cisplatin

表 5
High-grade serous Endometroidi (grade 2/3) Clear cell $carcinoma^{d}$ $Carcinosarcoma^{d}$	Preferred Regimens • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218)	Other Recommended Regimens • Paclitaxel/carboplatin weekly$^{g,h,k}$ • Docetaxel/carboplatin • Carboplatin/liposomal doxorubicin • Paclitaxel/carboplatin every 3 $weeks^{g}$ • Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab (GOG-218)	Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab • IV/IP paclitaxel/carboplatin • IV/IP paclitaxel/cisplatin (for optimally debulked stage II-III disease) • For carcinosarcoma: • Carboplatin/ifosfamide • Pisclatin/ifosfamide • Paclitaxel/ifosfamide (category 2B)$^{g}$ •
Mucinous $carcinoma^{d}$	Preferred Regimens • 5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab) • Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab) • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218)	Other Recommended Regimens • Paclitaxel/kyarboplatin • Docetaxel/carboplatin • Carboplatin/liposomal doxorubicin • Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab (GOG-218)	Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab
Low-grade serous/Grade I endometrioid$^{d,e,f}$	Preferred Regimens • Paclitaxel/carboplatin every 3 $weeks^{g,h}$ ± maintenance letrozole (category $2B^{1}$) or other hormonal therapy (category $2B^{1}$) • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{g}$ (ICON-7 & GOG-218) • Hormone therapy (aromatase inhibitors: anastrozole, letrozole, exemestane) (category 2B)	Other Recommended Regimens • Paclitaxel/kyarboplatin weekly$^{g,h,k}$ • Docetaxel/carboplatin ± maintenance letrozole (category $2B^{1}$) or other hormonal therapy (category $2B^{1}$) • Carboplatin/liposomal doxorubicin • Docetaxel/kyarboplatin.bevacizumab + maintenance bevacizumab	Useful in Certain Circumstances • Paclitaxel/cisplatin • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab (category $2B^{1}$)

表 6
Primary Systemic Therapy Recommended Dosing
Paclitaxel/carboplatin every 3 weeks$^{9,1}$	Docetaxel/carboplatin$^{1}$	Docetaxel/carboplatin$^{1}$
Paclitaxel 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1	Docetaxel 60–75 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1	Docetaxel 60–75 mg/m$^{2}$ AV followed by carboplatin$^{1}$ AUC 5–6 IV Day 1
Repeat every 21 days x 3–6 cycles$^{10,11}$	Recetaxel lip/liposomal doxorubicin$^{1}$	Recetaxel lip/liposomal doxorubicin$^{1}$
Paclitaxel/cisplatin every 3 weeks$^{10,11}$	Carboplatin AUC 5 IV + pegylated liposomal doxorubicin 30 mg/m$^{2}$ IV	Carboplatin AUC 5 IV + pegylated liposomal doxorubicin 30 mg/m$^{2}$ IV
Paclitaxel 175 mg/m$^{2}$ IV followed by cisplatin 75 mg/m$^{2}$ IV	Recetaxy 28 days for 3–6 cycles$^{1}$	Recetaxy 28 days for 3–6 cycles$^{1}$
Repeat every 21 days x 3–9 cycles	Acitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{9}$ (ICON-7)	Acitaxel/carboplatin/bevacizumab + maintenance bevacizumab$^{9}$ (ICON-7)
IV/IP Paclitaxel/cisplatin	Paclitaxel 135 mg/m$^{2}$ IV continuous infusion$^{1}$ Day 1; cisplatin 75–100 mg/m$^{2}$ IP Day 2 after IV paclitaxel; paclitaxel 60 mg/m$^{2}$ IP Day 8	Paclitaxel 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 5–6 IV, and bevacizumab 7.5 mg/kg IV Day 1
Repeat every 21 days x 6 cycles	Recetaxy 21 days x 6 cycles	Recetaxy 21 days x 5–6 cycles
IV/IP Paclitaxel/carboplatin$^{12}$	Paclitaxel 80 mg/m$^{2}$ IV on days 1, 8, and 15; carboplatin AUC 6 IP Day 1 after IV paclitaxel	Recetaxy 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 6 IV Day 1. Repeat every 21 days x 6 cycles
Paclitaxel 80 mg/m$^{2}$ IV on days 1, 8, and 15; carboplatin AUC 6 IP Day 1 after IV paclitaxel	Recetaxy 21 days x 6 cycles	Recetaxy 175 mg/m$^{2}$ IV followed by carboplatin$^{1}$ AUC 6 IV Day 1. Repeat every 21 days x 6 cycles
Repeat every 21 days x 6–8 cycles	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Paclitaxel weekly/carboplatin every 3 weeks$^{9}$	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Dose-dense paclitaxel 80 mg/m$^{2}$ IV Days 1, 8, and 15 followed by carboplatin$^{1}$ AUC 5–6 V IDV Day 1	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Repeat every 21 days x 6 cycles	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Paclitaxel 60 mg/m$^{2}$ IV followed by carboplatin AUC 2 IV	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Daclitaxel weekly/carboplatin $^{12}$	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Docetaxel 75 mg/m$^{2}$ IV followed by oxaliplatin 85 mg/m$^{2}$ IV, and bevacizumab 15 mg/kg IV	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Repeat every 21 days x 6 cycles	Recetaxy 19 days x 6 cycles	Recetaxy 19 days x 6 cycles
Continue bevacizumab 15 mg/kg IV every 21 days to complete 1 year of therapy
Individuals >70 Years and/or Those with Comorbidities
Paclitaxel 135 /carboplatin$^{9,13}$
Paclitaxel 135 mg/m$^{2}$ IV + carboplatin AUC 5 IV given every 21 days x 3–6 cycles$^{1}$
Paclitaxel weekly/carboplatin weekly$^{9}$
Paclitaxel 60 mg/m$^{2}$ IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes
Days 1, 8, and 15; repeat every 21 days x 6 cycles (18 weeks)

表 7
Preferred Regimens	Other Recommended Regimens$^{5}$	Useful in Certain Circumstances
Carboplatin/ gemcitabine$^{14}$	Capecitabine	For mucinous carcinoma:
± bevacizumab	$Carboplatin^{14}$	1.5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab)$^{9}$
Carboplatin/liposomal	Carboplatin/docetaxel^{23,24}$	• Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab)$^{9}$
doxorubicin$^{16}$	Carboplatin/pacitaxel (weekly)$^{9,25}$	• Carboplatin/paclitaxel (for age >70)$^{9,9}$
± bevacizumab$^{q,17}$	$Cisplatin^{18}$	• Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)
Carboplatin/paclitaxel$^{g,18}$	Doxorubicin	• Iranotecan/cisplatin (for clear cell carcinoma)$^{31}$
± bevacizumab$^{q,19}$		Targeted Therapy$^{X}$
Cisplatin/gemcitabine$^{20}$		Dabrafenib + trametinib (for BRAF V600E-positive tumors)$^{32}$
Targeted Therapy (single-agents)	Niraparib/bevacizumab (category 2B)$^{q,26}$	Entretinib$^{33}$ or larrotectinib$^{34}$ or reprotectinib$^{35}$ (for NTRK gene fusion-positive tumors)
Bevacizumab$^{q,21,22}$	Niraparib (category 3)$^{1,27}$	Fam-trastuzumab deruxtecan-nxki (for HER2-positive tumors) [ICH 3+ 2+](category 2B)$^{36}$ Mirvetuximab soratvansine-gynx$^{1}$ (for FRα-expressing tumors [≥575 positive tumor cells])$^{37}$
	Olaparib (category 3)$^{1,28}$	Mirvetuximab soratvansine-gynx$^{1}$ (for FRα-expressing tumors [≥50% positive tumor cells])$^{39}$
	Pazopanib (category 2B)$^{29}$	Selpercatinib (for RET gene fusion-positive tumors)$^{39}$
	Rucaparib (category 3)$^{7,30}$	For low-grade serous carcinoma:
	Fluzoparib [c]*, u	• Avutometinib/defactinib (for KRAS-mutated tumors)$^{40}$
	Pamiparib [c]*, u	• Trametinib$^{41}$
	Hormone Therapy	• Binimetinib (category 2B)$^{42,43}$
	Aromatase inhibitors (anastrozole, exemestane, letrozole)	Hormone Therapy
	Goserelin acetate	Fulvestrant (for low-grade serous carcinoma)
	Leuprolide acetate	• Immunotherapy$^{X}$
	Megestrol acetate	Dostarlimab-gxly (for dMMR/MSI-H recurrent or advanced tumors)$^{44}$
	Tamoxifen$^{1}$	Pembrolizumab (for MSI-H or dMMR solid tumors, or patients with TMB-H tumors ≥10 mutations/megabase)$^{45}$
		• Vnsinabab (for dMMR/MSI-H recurrent or advanced tumors)$^{†}$
		Tisleizumab (for dMMR/MSI-H recurrent or advanced tumors)$^{‡}$
		Serpliulimab (for dMMR/MSI-H recurrent or advanced tumors)$^{§}$
		Pucotenlimab (for dMMR/MSI-H recurrent or advanced tumors)$^{§}$

表 8
Preferred Regimens	Other Recommended Regimens	Useful in Certain Circumstances
Cytotoxic Therapy	Cytotoxic Therapys	Carboplatin/paclitaxel (for age >70)g,w,* Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)
Cyclophosphamide (oral)/ bevacizumabq4,46	Capecitabine	Carboplatin/paclitaxel, albumin bound (for confirmed taxane hypersensitivity)
Docetaxel47	Carboplatin/docetaxel*	Immunotherapyx
Etoposide (oral)48	Carboplatin/paclitaxel (weekly)q,9,*	Dostarlimab-gxly (for dMMR/MSI-H recurrent or advanced tumors)43
Gemcitabine49,50	Carboplatin/gemcitabine14	Pembrolizumab (for patients with MSI-H or dMMR solid tumors, or TMB-H tumors ≥10 mutations/megabase)44
Liposomal doxorubicin/ bevacizumabq5,41	± bevacizumabq,7,15,*	Envafolimab (for dMMR/MSI-H recurrent or advanced tumors)† Tisleizumab (for dMMR/MSI-H recurrent or advanced tumors)‡ Serplulimab (for dMMR/MSI-H recurrent or advanced tumors)§ Pucotlenimab (for dMMR/MSI-H recurrent or advanced tumors)¶
Laiplasol doxorubicin/ bevacizumabq5,42	Carboplatin/paclitaxel, 58,59	Serplulimab (for dMMR/MSI-H recurrent or advanced tumors)§ Pucotlenimab (for dMMR/MSI-H recurrent or advanced tumors)¶
Laiplasol doxorubicin/ bevacizumabq5,42	Ammotherapy	Hormone Therapy Fulvestrant (for low-grade serous carcinoma)
Laiplasol doxorubicin/ bevacizumabq5,42	Ixabepilone/bevacizumab (category 2B)z,61	Targeted Therapyx Dabrafenib + trametinib (for BRAF V600E-positive tumors)32
Laiplasol doxorubicin/ bevacizumabq5,42	Niraparib (category 3)z,27 Olaparib (category 3)z,28	Entrectinib33 or larrotectinib34 or raportectinib35 (for NTRK gene fusion-positive tumors)Fam-trastuzumab deruxtecan-nxki (for HER2-positive tumors [IHC 3+ or 2+])36 Mirvetuximab soravtansine-gynx/bevacizumab (for FRa-expressing tumors [≥25% positive tumor cells])q,38,62,83 Selpercatinib (for RET gene fusion-positive tumors)39 For low-grade serous carcinoma: Avutometinib/defactinib (for KRAS-mutated tumors)40 Trametinib41 Binimetinib (category 2B)42,43 For mucinous carcinoma: FOLFIRI ± bevacizumab (category 2B)64-67
Laiplasol dotorubicin/ bevacizumabq5,42

表 9
Serous Tumors
• Serous cystadenoma NOS	0
• Serous surface papilloma	0
• Serous adenofibroma NOS	0
• Serous cystadenofibroma NOS	0
• Serous borderline tumor NOS	1
• Serous borderline tumor, micropapillary variant	2
• Serous carcinoma, non-invasive, low-grade	2
• Low-grade serous carcinoma	3
• High-grade serous carcinoma	3
Mucinous Tumors
• Mucinous cystadenoma NOS	0
• Mucinous adenofibroma NOS	0
• Mucinous borderline tumor	1
• Mucinous adenocarcinoma	3
Endometrioid Tumors
• Endometrioid cystadenoma NOS	0
• Endometrioid adenofibroma NOS	0
• Endometrioid tumor, borderline	1
• Endometrioid adenocarcinoma NOS	3
• Seromucinous carcinoma	3
Clear Cell Tumors
• Clear cell cystadenoma	0
• Clear cell cystadenofibroma	0
• Clear cell borderline tumor	1
• Clear cell adenocarcinoma NOS	3

表 10
Brenner Tumors
Brenner tumor, NOS	0
Brenner tumor, borderline malignancy	1
Brenner tumor, malignant	3
Seromucinous Tumors
Seromucinous cystadenoma	0
Seromucinous adenofibroma	0
Seromucinous borderline tumor	1
Other carcinomas
Mesonephric-like adenocarcinoma	3
Carcinoma, undifferentiated, NOS	3
Dedifferentiated carcinoma	3
Carcinosarcoma NOS	3
Mixed cell adenocarcinoma	3
Mesenchymal Tumors
Endometrioid stromal sarcoma, low-grade	3
Endometrioid stromal sarcoma, high-grade	3
Leiomyoma NOS	0
Leiomyosarcoma NOS	3
Smooth muscle tumor of uncertain malignant potential	1
Myxoma NOS	0
Mixed Epithelial & Mesenchymal TumorsAdenosarcoma	3

表 11
Sex Cord-Stromal Tumors: Pure Stromal Tumors	0
• Fibroma NOS	0
• Cellular fibroma	1
• Thecoma NOS	0
• Thecoma, luteinized	0
• Sclerosing stromal tumor	0
• Microcystic stromal tumor	0
• Signet-ring stromal tumor	0
• Leydig cell tumor of the ovary NOS	0
• Steroid cell tumor NOS	0
• Steroid cell tumor, malignant	3
• Fibrosarcoma NOS	3
Sex Cord-Stromal Tumors: Pure Sex Cord Tumors	0
• Adult granulosa cell tumor of the ovary	3
• Granulosa cell tumor, juvenile	1
• Sertoli cell tumor NOS	1
• Sex cord tumor with annular tubules	1
Mixed Sex Cord-Stromal Tumors	1
• Sertoli-Leydig cell tumor NOS	1
• Sertoli-Leydig cell tumor, well differentiated	0
• Sertoli-Leydig cell tumor, moderately differentiated	1
• Sertoli-Leydig cell tumor, moderately differentiated	1
• Sertoli-Leydig cell tumor, retiform	1
• Sex cord tumor NOS	1
• Gynandroblastoma	1

表 12
Germ Cell Tumors	0
• Teratoma, benign	0
• Immature teratoma NOS	3
• Dysgerminoma	3
• Yolk sac tumor NOS	3
• Embryonal carcinoma NOS	3
• Choriocarcinoma NOS	3
• Mixed germ cell tumor	3
Monodermal Teratoma & Somatic-type
Tumors from Dermoid Cyst
• Struma ovarii, NOS	0
• Struma ovarii, malignant	3
• Struma carcinoid	1
• Teratoma with malignant	3
• transformation
• Cystic teratoma NOS	0
Germ Cell- Sex Cord-Stromal Tumors
• Gonadoblastoma	1
• Dissecting gonadoblastoma
• Undifferentiated gonadal tissue
• Mixed germ cell- sex cord-stromal tumor, NOS	1
Metastases to the ovary

表 13
Miscellaneous Tumors
• Adenoma of rete ovarii	0
• Adenocarcinoma of rete ovarii	3
• Wolffian tumor	1
• Solid pseudopapillary tumor of ovary	1
• Small cell carcinoma, hypercalcaemic type	3
• Small cell carcinoma, large cell variant
• Wilms tumor	3
Tumor-like Lesions
• Follicle cyst	0
• Corpus luteum cyst	0
• Large solitary luteinized follicle cyst	0
• Hyperreactio luteinalis	0
• Pregnancy luteoma	0
• Stromal hyperplasia and hyperthecosis	0
• Fibromatosis and massive oedema	0
• Leydig cell hyperplasia	0
Metastases to the ovary

表 14
TNM	FIGO	TNM	FIGO
TX	Primary tumor cannot be assessed	T2	II
T0	No evidence of primary tumor
T1	I	Tumor limited to ovaries (one or both) or fallopian tube(s)	T2a	IIA Extension and/or implants on the uterus and/or fallopian tube(s) and/or ovaries
T1a	IA	Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings	T2b	IIB Extension to and/or implants on other pelvic tissues
T1b	IB	Tumor limited to both ovaries; (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings	T3	Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes
T1c	IC	Tumor limited to one or both ovaries or fallopian tubes, with any of the following:	T3a
T1c1	IC1	Surgical spill	T3b IIIB
T1c2	IC2	Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface	T3c IIIC Macroscopic peritoneal metastasis beyond pelvis
T1c3	IC3	Malignant cells in ascites or peritoneal washings	T3c IIIC Macroscopic peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)

表 15
TNM	FIGO
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N0(i+)	Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm
N1	IIIA1 Positive retroperitoneal lymph nodes only (histologically confirmed)
N1a	IIIA1 Metastasis up to and including 10 mm in greatest dimension
N1b	IIIA1ii Metastasis more than 10 mm in greatest dimension

表 16
	T	N	M
Stage I	T1	N0	M0
Stage IA	T1a	N0	M0
Stage IB	T1b	N0	M0
Stage IC	T1c	N0	M0
Stage II	T2	N0	M0
Stage IIA	T2a	N0	M0
Stage IIB	T2b	N0	M0
Stage IIIA1	T1/T2	N1	M0
Stage IIIA2	T3a	NX/N0/N1	M0
Stage IIIB	T3b	NX/N0/N1	M0
Stage IIIC	T3c	NX/N0/N1	M0
Stage IV	Any T	Any N	M1
Stage IVA	Any T	Any N	M1a
Stage IVB	Any T	Any N	M1b

表 17
ACLS	advanced cardiovascular life support	HCT	hematopoietic cell transplant	PARPi	PARP inhibitor
AUC	area under the curve	HIPEC	hyperthermic intraperitoneal chemotherapy	PCS	primary cytoreductive surgery
BSO	bilateral salpingo-oophorectomy	HR	homologous recombination	PR	partial response
β-hCG	beta-human chorionic gonadotropin	HRD	homologous recombination deficiency	REI	reproductive endocrinology and infertility
CAP	College of American Pathologists	IDS	interval debulking surgery	RRSO	risk-reducing salpingo-oophorectomy
CBC	complete blood count	IHC	immunohistochemistry
CEA	carcinoembryonic antigen	IM	intramuscular	SEE-FIM	sectioning and extensively examining the fimbriated end
CLIA	Clinical Laboratory Improvement Amendments	IP	intraperitoneal	STIC	serous tubal intraepithelial carcinoma
CR	complete response	LCOC	less common ovarian cancers
ctDNA	circulating tumor DNA	LDH	lactate dehydrogenase
C/A/P	chest/abdomen/pelvis	LFT	liver function test	TMB	tumor mutational burden
dMMR	mismatch repair deficient	LMP	low malignant potential	TMB-H	tumor mutational burden-high tumor node metastasis
FIGO	International Federation of Gynecology and Obstetrics	LOH	loss of heterozygosity		USO
FNA	fine-needle aspiration	MMMT	malignant mixed Müllerian tumor	USO	unilateral salpingo-oophorectomy
GI	gastrointestinal	MSI	mismatch repair
		MSI-H	microsatellite instability
			microsatellite instability-high

表 18
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 19
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

表 20
Trial, Primary Report	Patients	Arms	Follow-up, Median
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) NCT00058032 Jacobs et al, 2016$^{165}$	Age: 50-74 yearsNo prior bilateral oophorectomyPersonal cancer history: no history of ovarian cancer, no active non-ovarian malignancyFamily cancer history of breast or ovarian cancer: 6.4%breast, 1.6%; excluded if elevated risk of familial breast or ovarian cancer	Annual screening with CA-125, with TVUS as a second-line test (n=50,640)Annual screening with TVUS (n=50,359)No screening (n=101,359)	11.1 years
Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial NCT00002540 Pinsky et al, 2016$^{156}$	Age: 55-74 yearsNo prior bilateral oophorectomyPersonal cancer history: no prior lung, colorectal, or ovarian; 3.6% had prior breast cancer; no current treatment for other cancer (except nonmelanoma skin cancer)Family cancer history of breast or ovarian cancer: ~17%	Screening: annual TVUS and CA-125; bimanual palpitation offered (n=39,105)Usual care (n=39,111)	14.7 years
Jacobs et al, 1999$^{168}$	Age: ≥45 yearsNo prior bilateral oophorectomyPersonal cancer history: no history of ovarian cancer, no active malignancyFamily cancer history: NR	Screening: offered 3 annual CA-125, with pelvic US as second-line test (n=10,977)No screening (n=10,958)	6.8 years

表 21
Cancer Type	Pathologic Staginga	Recommended Options (category 2A unless otherwise noted)
Cancer Type	Pathologic Staginga	Observation	Standard IV Platinum-Based $Chemotherapy^{b}$	Other Adjuvant Systemic Therapy
High-grade serous carcinoma	Stage IA/B/C	--	Yes	--
Grade 2 endometrioid	Stage IA/IB	Yes	Yes	--
Grade 3 endometrioid	Stage IA/B/C	--	Yes	--

表 22
Carcinosarcoma	Stage IA/B/C	--	Yes	Carboplatin/ifosfamide Cisplatin/ifosfamide Paclitaxel/ifosfamide (category 2B)
Clear cell carcinoma	Stage IA	Yes	Yes	--
Clear cell carcinoma	Stage IB/IC	--	Yes	--
Mucinous carcinoma	Stage IA/IB	Yes	--	--
Mucinous carcinoma	Stage IC	Yes	Yes	5-FU/leucovorin/oxaliplatin Capecitabine/oxaliplatin
Grade 1 endometrioid	Stage IA/IB	Yes	--	--
Grade 1 endometrioid	Stage IC	Yes (category 2B)	Yes	Hormone therapy (category 2B)$^{c}$
Low-grade serous carcinoma	Stage IA/IB	Yes	--	--
Low-grade serous carcinoma	Stage IC	Yes (category 2B)	Yes	Hormone therapy (category 2B)$^{c}$

表 23
Cancer Type	Recommended Options (category 2A unless otherwise noted)
Cancer Type	Standard IV Platinum-based Chemotherapy ± Bevacizumab	Other	Other
High-grade serous	Yes	IP/IV paclitaxel/cisplatin (optimally debulked stage III only)
Grade 2/3 endometrioid	Yes	IP/IV paclitaxel/cisplatin (optimally debulked stage III only)
Carcinosarcoma	Yes	IP/IV paclitaxel/cisplatin (optimally debulked stage III only) Carboplatin/ifosfamide Cisplatin/ifosfamide Paclitaxel/ifosfamide (category 2B)
Clear cell carcinoma	Yes	IP/IV paclitaxel/cisplatin (optimally debulked stage III only)
Mucinous carcinoma	Yes	5-FU/leucovorin/oxaliplatin ± bevacizumab (category 2B for bevacizumab) Capecitabine/oxaliplatin ± bevacizumab (category 2B for bevacizumab)
Low-grade serous	Yes	Hormone therapy (aromatase inhibitors [anastrozole, letrozole, exemestane], leuprolide acetate, tamoxifen) (category 2B)
Grade 1 endometrioid	Yes	Hormone therapy (aromatase inhibitors [anastrozole, letrozole, exemestane], leuprolide acetate, tamoxifen) (category 2B)

表 24
Regimen Short Name	Detailed Dosing per $Cycle^{c}$	Cycle Length, Weeks	# Cycles	$Category^{d}$	Preference Category	Randomized Trials
Paclitaxel 175/ carboplatin	Paclitaxel 175 mg/$m^{2}$ IV over 3 hours followed by carboplatin AUC 5–6e IV over 30–60 minutes on Day 1	3	6	2A	Preferred	See Table 5 and 6
Paclitaxel weekly/ carboplatin weekly	Paclitaxel 60 mg/$m^{2}$ IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes, weekly	3	6 (18 weeks)	2A	Other Recommended	MITO-7757 $ICON8^{758,759}$

表 25
Paclitaxel weekly/ carboplatin q3weeks	Dose-dense paclitaxel, 80 mg/m² IV over 1 hour on days 1, 8, and 15 followed by carboplatin AUC 5-6° IV over 30-60 minutes on Day 1	3	6	2A	Other Recommended	$ICON8^{758,759}$ $JGOG-3016^{760-762}$ $GOG-0262^{763}$
Carboplatin/ liposomal doxorubicin	Carboplatin AUC 5 IV over 30-60 minutes + pegylated liposomal doxorubicin 30 mg/m² IV over 1 hourf	4	6	2A	Other Recommended	$MITO-2^{764}$
Docetaxel/ carboplatin	Docetaxel 60-75 mg/m² IV over 1 hour followed by carboplatin AUC 5-6 IV over 30-60 minutes on Day 1	3	6	2A	Other Recommended	$SCOTROC1^{765}$

表 26
Trial	Stage	$N^{c}$	First-Line Systemic $Therapy^{d}$	Efficacy^{e}	Safety/QOL^{f}
Trial	Stage	$N^{c}$	Dosing per Cycle	Efficacy^{e}	Safety/QOL^{f}	Cycle Length Weeks	# Cycles
Dutch/Danish $RCT^{766,767}$	IIB-IV	208	Paclitaxel 175 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1	3	6	NS	More nausea, vomiting, peripheral neurotoxicityLess granulocytopenia and thrombocytopenia
$GOG-158^{f},$ 768	III	792	Paclitaxel 135 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1	3	6	NS	More GI, renal, and metabolic toxicity;Less thrombocytopenia
AGO-OVAR-3769-771	IIB-IV	798	Paclitaxel 185 mg/$m^{2}$ D1 + cisplatin 75 mg/$m^{2}$ D1	3	6	NS	More nausea/vomiting, appetite loss, fatigue, and neurotoxicityLess hematologic toxicityWorse overall QOL, physical functioning, role functioning, cognitive functioning
ChiCTR-TRC-11001333772	II-IV	182	Paclitaxel 175 mg/$m^{2}$ D1 + nedaplatin 80 mg/$m^{2}$ D1	3	6	ITT: NS Stage III-IV: better PFS (P = .02); NS OS	Less grade 3-4 leukopenia

表 27
Trial	Stage	$N^{b}$	First-Line Systemic Therapy^{c}$	Efficacy^{d}	Safety/$QOL^{e}$
Trial	Stage	$N^{b}$	Dosing per Cycle	Efficacy^{d}	Safety/$QOL^{e}$	Cycle Length, Weeks	# Cycles
$ICON3^{773}$	IC-IV	653	Cyclophosphamide 500 mg/m² D1 + doxorubicin 50 mg/m² D1 + cisplatin 50 mg/m² D1	3	6	NS	More nausea/vomiting, feverLess sensory neuropathy
HeCOG $RCT^{774}$	IIC-IV	247	Paclitaxel 175 mg/m² D1 + carboplatin AUC 7 D1 cycles 1, 3, $5^{h}$ + cisplatin at 75 mg/m² D1 cycles 2, 4, 6	3	6	NS	More severe nausea/vomiting
AGO-OCSG $RCT^{775}$	IIB-IV	1282	Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + epirubicin 60 mg/m² D1	3	6	NS	More nausea/emesis, mucositis, infections, and grade 3-4 hematologic toxicitiesWorse QOL
NCT00102375776	IIB-IV	1308	Paclitaxel 175 mg/m² D1 cycles 1-6 + carboplatin AUC 5 D1 cycles 1-6 + topotecan 1.25 mg/m² D1-5 cycles 7-10	3	≤10	NS	More grade 3-4 hematologic toxicities and grade 3-4 infections
GOG-0182- $ICON5^{777,778}$	III-IV	4312	Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + gemcitabine 800 mg/m² D1	3	8i	NS	More neutropenia, thrombocytopenia, anemia, fever/infection, hepatic toxicity, peripheral neuropathy, GI toxicity
GOG-0182- $ICON5^{777,778}$	III-IV	4312	Paclitaxel 175 mg/m² D1 + carboplatin AUC 5 D1 + pegylated liposomal doxorubicin 30 mg/m² D1 cycles 1, 3, 5, 7	3	8i	NS	More neutropenia, thrombocytopenia, anemia, fever/infection, GI toxicity
GOG-0182- $ICON5^{777,778}$	III-IV	4312	Paclitaxel 175 mg/m² D1 cycles 5-8 + carboplatin AUC 5 D3 cycles 1-4, AUC 6 D1 cycles 5-8 + topotecan 1.25 mg/m²/d D1-3 cycles 1-4	3	8i	NS	More anemia, hepatic toxicityLess peripheral neuropathy
GOG-0182- $ICON5^{777,778}$	III-IV	4312	Paclitaxel 175 mg/m² D1 cycles 5-8 + carboplatin AUC 6 D8 cycles 1-4, D1 cycles 5-8 + gemcitabine 1000 mg/m²/d D1,8 cycles 1-4	3	8i	NS	More thrombocytopenia, anemia, hepatic toxicity, pulmonary toxicityLess peripheral neuropathy
Bolis et al, $2010^{779}$	III-IV	326	Topotecan 1.0 mg/m² D1-3 + paclitaxel 175 mg/m² D3 + carboplatin AUC 5 D3	3	6	NS	More fatigue, anemia, leukopenia, neutropenia

表 28
Trial	Stage	$N^{b}$	First-Line Systemic Therapy $^{c}$	Efficacy $^{d}$	Safety/$QOL^{e}$
Trial	Stage	$N^{b}$	Dosing per Cycle	Efficacy $^{d}$	Safety/$QOL^{e}$	Cycle Length, Weeks	# Cycles
du Bois et al, $2010^{780}$	I-IV	1742	Paclitaxel 175 mg/$m^{2}$ D1+ carboplatin AUC 5 D1+ gemcitabine 800 mg/$m^{2}$ D1, D8	3	6	Worse PFS (P=.0044) NS OS	• More grade 3-4 hematologic toxicity, fatigue • Worse QOL
OV-16/ EORTC-55012/ GEICO-0101781	IIB-IV	819	Cisplatin 50 mg/$m^{2}$ D1 cycles 1-4+ topotecan 0.75 mg/$m^{2}$ D 1-5 cycles 1-4+ paclitaxel 175 mg/$m^{2}$ D1 cycles 5-8+ carboplatin AUC 5 D1 cycles 5-8+ epirubicin 75 mg/$m^{2}$	3	8j	NS	• More hematologic toxicities, thromboembolic events, nausea, vomiting, and hospitalizations • Less neurosensory effects and allergic reactions
NSGO, EORTC GCG and NCIC CTG782	IIB-IV	887	Paclitaxel 175 mg/$m^{2}$ D1+ carboplatin AUC 5 D1+ epirubicin 75 mg/$m^{2}$	3	6-9	NS	• More anemia, febrile neutropenia, use of G- SCF, nausea, vomiting, mucositis • Less allergic reactions, arthralgia, myalgia • Worse QOL

表 29
Trial	Stage	$N^{b}$	First-Line Systemic $Therapy^{c}$	Efficacy^{d}$ HR [95% CI]	Safety/QOL^{e}$
Trial	Stage	$N^{b}$	Dosing per Cycle	Efficacy^{d}$ HR [95% CI]	Safety/QOL^{e}$	Cycle Length, Weeks	# Cycles
$ICON3^{773}$	IC-IV	943	Carboplatin AUC ≥$5^{f}$ D1	3	6	NS	• Less alopecia grade 3-4, fever grade 3-4, sensory neuropathy grade 2-3, motor neuropathy grade 3-4
SCOTROC1765	IC-IV	1077	Docetaxel 75 mg/m² D1 + carboplatin AUC 5 D1	3	$6^{g}$	NS	• More GI, peripheral edema, allergic reactions, nail changes • Less neurosensory and neuromotor toxicity, arthralgia, alopecia, abdominal pain • QOL: Global NS
MITO-2 NCT00326456764	IC-IV	820	Carboplatin AUC 5 D1 + pegylated liposomal doxorubicin 30 mg/m² D1	3	$3-6^{i}$	NS	• More anemia, thrombocytopenia, skin toxicity, stomatitis • Less neuropathy, alopecia, diarrhea • QOL: less diarrhea after 3 cycles and loss of appetite after 3 cycles
MITO-7 NCT00660842757	IC-IV	822	Paclitaxel 60 mg/m² D1, D8, D15 + carboplatin AUC 2 D1, D8, D15	3	6	NS	• More pulmonary toxicity • Less neutropenia, febrile neutropenia, thrombocytopenia, neuropathy, hair loss, vomiting • Better QOL
JGOG-3016 NCT00226915760,761	II-IV	637	Paclitaxel 80 mg/m² D1, 8, $15^{h}$ + carboplatin AUC 6 D1	3	6	Better PFS: 0.76 [0.62-0.91]; P=.0037 Better OS: 0.79, [0.63-0.99]; P=.039	• More grade 3-4 anemia • Global QOL NS; worse QOL on FACT-T subscale
GOG-0262 NCT01167712763	II-IV	112	Paclitaxel 80 mg/m² D1, 8, 15 + carboplatin AUC 6 D1	3	6	Better PFS: 0.62 [0.40-0.95]; P=.03	• More anemia and sensory neuropathy • Less neutropenia • Worse QOL on FACT-O TOI
GOG-0262 NCT01167712763	II-IV	580	Paclitaxel 80 mg/m² D1, 8, 15 + carboplatin AUC 6 D1 + bevacizumab 15 m/kg D1 cycles 2-6	3	6	NS	• More grade 3-4 AEs, including uncomplicated neutropenia, anemia • Worse Global QOL
ICON8 NCT01654146758,759	IC-IV	1566	Paclitaxel IV 80 mg/m² D1, D8, D15 + carboplatin IV AUC 5-6 D1	3	6	NS	• More grade 3-4 AEs, including uncomplicated neutropenia, anemia • Worse Global QOL
ICON8 NCT01654146758,759	IC-IV	1566	Paclitaxel IV 80 mg/m² D1, D8, D15 + carboplatin IV AUC 2 D1, D8, D15	3	6	NS	• More grade 3-4 AEs, including uncomplicated neutropenia, carboplatin hypersensitivity reaction • Worse Global QOL

表 30
Regimen Short Name	Detailed Dosing per $Cycle^{c}$	Cycle Length, Weeks	# Cycles	$Category^{d}$	Preference Category	Randomized Trials
Paclitaxel 175/ carboplatin	Paclitaxel 175 mg/$m^{2}$ IV over 3 hours followed by carboplatin AUC 5–6° IV over 30–60 minutes on Day 1	3	High-grade serous: 6 All other: 3	2A	Preferred	$ICON3^{773}$ GOG-$157^{801,802}$ du Bois, $2010^{780}$ SCOTROC1765 MITO-$2764$ MITO-$757$ MITO-$758,759$ ICON$8^{758,759}$
Carboplatin/ liposomal doxorubicin	Carboplatin AUC 5 IV over 30–60 minutes + pegylated liposomal doxorubicin 30 mg/$m^{2}$ IV over 1 $hour^{f}$	4	High-grade serous: 6 All other: 3	2A	Other Recommended	$MITO-2^{764}$
Docetaxel/ carboplatin	Docetaxel 60–75 mg/$m^{2}$ IV over 1 hour followed by carboplatin AUC 5–6 IV over 30–60 minutes on Day 1	3	High-grade serous: 6 All other: 3	2A	Other Recommended	$SCOTROC1^{765}$

表 31
A. Summary of Results
Trial	$Patients^{a}$	First-Line Chemotherapy^{b}$ → Maintenance	n	F/u, $mo^{c}$	PFS Median (months), HR [95% CI], P-$value^{d}$	OS Median (months), HR [95% CI], P-$value^{d}$	AEs G3-4	AEs G5	Dc'd $AE_{s}^{e}$
GOG-0218 NCT00262847 Burger $2011^{817}$	Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%	Arm 1: carbo/pac/placebo → placebo	625	19.$4^{f}$	10.3	39.3	NR	1.0%	12%
GOG-0218 NCT00262847 Burger $2011^{817}$	Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%	Arm 2: carbo/pac/bev → placebo	623	11.2 [0.795-1.040]	0.908 [0.795-1.040]	38.7 [0.827-1.297]	NR	1.6%	15%
GOG-0218 NCT00262847 Burger $2011^{817}$	Stage III incompletely resected (34% ≤1 cm, 40% >1) or stage IV (26%) Residual disease, R0/>0-≤1 cm/>1 cm:$^{528}$ 5%/41%/54% Cancer type: 85% serous Tumor grade 3: 73%	Arm 3: carbo/pac/bev → bev	625	11.2 [0.795-1.040]	14.1 [0.625-0.824]	39.7 [0.727-1.152]	NR	2.2%	17%
GCIG ICON7 Perren $2011^{818}$ Oza $2015^{819}$	High-risk early stage (I-IIA and clear cell or Grade 3; 9%), IIB-IIIB (21%) or IIIC-IV (70%) Residual disease, R0/>0-≤1 cm/>1 cm: 48%/24%/26% Cancer type: 69% serous Tumor grade 3: 72%	Arm 1: carbo/pac → none	Arm 1: carbo/pac → none	764	48.6	17.5	58.6	54%	1%
GCIG ICON7 Perren $2011^{818}$ Oza $2015^{819}$	High-risk early stage (I-IIA and clear cell or Grade 3; 9%), IIB-IIIB (21%) or IIIC-IV (70%) Residual disease, R0/>0-≤1 cm/>1 cm: 48%/24%/26% Cancer type: 69% serous Tumor grade 3: 72%	Arm 2: carbo/pac/bev → bev	764	48.8	19.9 [0.83-1.05]	0.$93^{g}$ P=.25	58.0 [0.85-1.14]	65%	1%

表 32
B. Treatment Regimens
Trial	Treatments
GOG-0218	Arm 1: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 Arm 2: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 + bevacizumab 15 mg/kg q3weeks x cycles 2-6 Arm 3h: Carboplatin AUC 6 + paclitaxel 175 mg/m² IV, q3weeks x cycles 1-6 + bevacizumab 15 mg/kg q3weeks x cycles 2-6 → maintenance bevacizumab 15 mg/kg q3weeks x cycles 7-22
GCIG ICON7	Arm 1: Carboplatin AUC 5-6 + paclitaxel 175 mg/m², q3weeks x 6 cycles Arm 2h: Carboplatin AUC 5-6 + paclitaxel 175 mg/m², q3weeks x 6 cycles + bevacizumab 7.5 m/kg q3weeks x 5-6 cycles (omitted cycle 1 if <4 weeks from surgery) → maintenance bevacizumab 7.5 m/kg q3weeks x 12 cycles

表 33
Regimen Short Name	Detailed Dosing per Cycle	Cycle Length, Weeks	# $Cycles^{c}$	$Category^{d}$	Preference Category	Supporting References
Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(ICON-7)	Paclitaxel 175 mg/m² IV over 3 hours, followed by carboplatin AUC 5-6 IV over 1 hour, and bevacizumab 7.5 mg/kg IV over 30-90 minutes Day 1	3	5-6	2A	Preferred	ICON-7Perren 2011818Oza 2015819
Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(ICON-7)	(Maintenance) bevacizumab 7.5 mg/kg IV over 30-90 minutes Day 1	3	≤12	BRCA1/2 wild-type/unknown: 2Ae BRCA1/2 mutation: bevacizumab alone not $recommended^{f}$		ICON-7Perren 2011818Oza 2015819
Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(GOG-218)	Paclitaxel 175 mg/m² IV over 3 hours, followed by carboplatin AUC 6 IV over 1 hour, plus bevacizumab (cycles 2-6) 15 mg/kg IV over 30-90 minutes Day 1	3	6	2A	Preferred	GOG-0218Burger 2011817Tewari,2019821
Paclitaxel/carboplatin/bevacizumab+maintenancebevacizumab(GOG-218)	(Maintenance) bevacizumab 15 mg/kg IV over 30-90 minutes Day 1	3	≤16	BRCA1/2 wild-type/unknown: 2Ae BRCA1/2 mutation: bevacizumab alone not $recommended^{f}$		GOG-0218Burger 2011817Tewari,2019821

表 34
Trial	$Patients^{a}$	First-Line Systemic $Therapy^{b}$	n	Median (months), HR [95% CI], P-$value^{d}$	AEs G5	Dc'd $AEs^{e}$
Trial	$Patients^{a}$	First-Line Systemic $Therapy^{b}$	n	PFS	AEs G5	Dc'd $AEs^{e}$	OS
GOG-0104863	Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/10%/23% Tumor grade, 1/2/3: 12%/30%/58% Residual disease, R0/>0-≤1 cm/>1 cm: 26%/73%/0	IP/IV: Cyclophosphamide 600 mg/$m^{2}$ IV + cisplatin 100 mg/$m^{2}$ IP, Q3W x 6 cycles	279	NR	49, 0.76 [0.61- 0.96], P=.02	1%	9%
GOG-0104863	Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/10%/23% Tumor grade, 1/2/3: 12%/30%/58% Residual disease, R0/>0-≤1 cm/>1 cm: 26%/73%/0	IV: Cyclophosphamide 600 mg/$m^{2}$ IV + cisplatin 100 mg/$m^{2}$ IV, Q3W x 6 cycles	267	NR	41	0	5%
GOG-0114864	Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/12%/21% Tumor grade, 1/2/3: 12%/40%/48% Residual disease, R0/>0-≤1 cm/>1 cm: 35%/65%/0	IP/IV: Carboplatin AUC 9 IV Q4W x 2 cycles; then paclitaxel 135 mg/$m^{2}$ IV, then cisplatin 100 mg/$m^{2}$ IP, Q3W x 6 cycles	227	18, 0.78, P=.01	63; 0.81, P=.05	1%	NR
GOG-0114864	Stage III OC/FTC/PPC: 100%, 0, 0 Cancer type, serous/endometrioid/other: 67%/12%/21% Tumor grade, 1/2/3: 12%/40%/48% Residual disease, R0/>0-≤1 cm/>1 cm: 35%/65%/0	IV: Paclitaxel 135 mg/$m^{2}$ IV + cisplatin 75 mg/$m^{2}$ IV, Q3W x 6 cycles	235	22	52	1%	NR
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	IP/IV: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 100 mg/$m^{2}$ IP D2 + paclitaxel 60 mg/$m^{2}$ IP D8, Q3W x 6 cycles	214	23.8, 0.80 [0.64-1.00], P=.05	65.6, 0.75 [0.58-0.97], P=.03	2.4%	NR
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	IV: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 75 mg/$m^{2}$ IV D2, Q3W x 6 cycles	215	18.3	49.7	1.9%	NR
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	IV/IP pac/carbo bev: paclitaxel 80 mg/$m^{2}$ IV D1, D8, D15	518	27.4, 0.925 [0.802-1.07]	78.9, 0.949 [0.799- 1.128]	1.4%	28%
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	• carboplatin AUC 6 IP D1, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22	• 0.925 [0.802-1.07]	• 0.949 [0.799- 1.128]	• 0.949 [0.799- 1.128]	• 2%	NR
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	IV/IP pac/cis/bev: Paclitaxel 135 mg/$m^{2}$ IV D1 + cisplatin 75 mg/$m^{2}$ IP D2 + paclitaxel 60 mg/$m^{2}$ IP D8, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22	521	26.2, 0.977 [0.847-1.13]	72.9, 1.05 [0.884-1.24]	2.0%	29%
GOG-172 (NCT0003322)$^{724,867}$	Stage III OC/FTC/PPC: 88%, 0, 12% Cancer type, serous/endometrioid/other: 79%/7%/14% Tumor grade, 1/2/3: 10%/37%/51% Residual disease, R0/>0-≤1 cm/>1 cm: 63%/37%/0	IV pac/carbo/bev: Paclitaxel 80 mg/$m^{2}$ IV D1, D8, D15 + carboplatin AUC 6 IV D1, Q3W x 6 cycles; + bevacizumab 15 mg/kg IV Q3W cycles 2-22	521	24.9	75.5	1.6%	24%

表 35
Regimen Short Name	Detailed Dosing per Cycle		Cycle Length, Weeks	# Cycles	Category	Preference Category	Trials with Supporting Data
IV/IP Paclitaxel/cisplatin	Paclitaxel 135 mg/m² IV continuous infusion over 3 or 24 hours Day 1; + Cisplatin 75-100 mg/m² IP Day 2 after IV paclitaxel; + Paclitaxel 60 mg/m² IP Day 8	3	6	2A	Useful in Certain Circumstances	GOG-0172724

表 36
Trial	$Patients^{a}$	Treatment Arms	Arm A Versus B	Arm A Versus B	Arm A Versus B
Trial	$Patients^{a}$	Treatment Arms	n	Surgical Outcomes	Median PFS/OS, months
EORTC 55971 NCIC-CTG OV13 NCT00003636 Phase III Vergote $2010^{483}$ N = 670	FIGO Stage IIIC, IV: 76%, 24% Poor differentiation: 41%$^{b}$ Entry criteria: Diagnosis by $biopsy^{b}$	Arm 1: NACT x 3 cycles →IDS if response/SD →Chemo x ≥ 3 cycles →Second look allowed Arm 2: PDS →Chemo x 3 cycles →IDS option if response/SD and >1 cm after PDS →Chemo x ≥ 3 cycles →Second look allowed	334 vs. 336	Operative time, minutes: median 180 vs. 165 Residual disease: •R0: 51% vs. 19% •≤1 cm: 81% vs. 42% Death <28 days postop: 0.7% vs. 2.5%	PFS: 12 vs. 12; NS OS: 30 vs. 29; P = .01° •Hemorrhage: 4.1% vs. 7.4% •Infections: 1.7% vs. 8.1% •Venous complications: 0 vs. 2.6%
CHORUS ISRCTN74802813 Phase III Kehoe $2015^{481}$ N = 550	FIGO stage IIIC, IV: 72%, $16^{d}$ Poor differentiation: 77% Entry criteria: diagnosis by imaging, CA- 125:CEA > $25^{d}$	Arm 1: NACT x 3 cycles →IDS →Chemo x 3 cycles Arm 2: PDS →Chemo x 3 cycles →IDS option for >1 cm residual after PDS →Chemo x 3 cycles	274 vs. 276	Operative time, minutes: median 120 vs. 120 Residual disease: •R0: 39% vs. 17%; P = .0001 •<1 cm: 73% vs. 41%; P = .0001 Hospital stay ≤14 days: 93% vs. 80%; P < .0001 Death <28 days postop: <1% vs. 6%; P = .001	PFS: 12.0 vs. 10.7; HR, 0.91 (95% CI, 0.76–1.09) OS: 24.1 vs. 22.6; HR, 0.87 (95% CI, 0.72–1.05)$^{e}$

表 37
Trial	Patientsa	Treatment Arms	Arm A Versus B	Arm A Versus B	Arm A Versus B
Trial	Patientsa	Treatment Arms	n	Surgical Outcomes	Median PFS/OS, months
SCORPION NCT01461850 Phase III Fagotti $2016^{639,886}$ N = 110	FIGO stage IIIC, IV: 89%, $11\%^{f}$ Poor differentiation: $NR^{f}$ Entry criteria: diagnosis by $S-LPS^{f}$	Arm 1: NACT x 3-4 cycles →IDS if response/SD →Chemo to a total of 6 cycles Arm 2: PDS →Chemo x 6 cycles	55 vs. 55	Operative time, minutes: median 275 vs. 451; P = .0001 Residual disease: • R0: 58% vs. 46%; NS • ≤1 cm: 85% vs. 91% Hospital stay, days: median 6 vs. 12; P = .0001 Death ≤30 days postop: 0 vs. 4%; NS PDS associated with more extensive and complex procedures and $blood loss^{g}$	NR
JCOG0602 Phase III Onda $2016^{482}$ N = 301	FIGO stage III, IV: 68%, 32% (IIIC NR) Poor differentiation: NR Entry criteria: diagnosis by imaging plus cytology, h CA-125 >200 U/mL, CEA <20 ng/mL	Arm 1: NACT x 4 cycles →IDS if response/SD →Chemo x 4 cycles Arm 2: PDS →Chemo x 4 cycles →IDS option if residual >1 cm after $PDS^{i}$ →Chemo x 4 cycles	152 vs. 149	Operative time, minutes: median 273 vs. $341; P < .001^{i}$ Residual disease: • R0: 55% vs. 31% • <1 cm: 71% vs. $63^{i}$ Surgery-related death: 0 vs. 0.7%; NS PDS associated with more extensive surgery and blood/ascites $loss^{i}$	NR
Liu $2017^{640}$ N = 108	FIGO stage III, IV: 68%, 32% Grade 2-3: 55% Entry criteria: diagnosis by imaging, serum CA-125; confirmed by LPS biopsy or laparotomy	Arm 1: NACT IP/IV x 2 cycles →IDS →Chemo IV x 6 cycles Arm 2: PDS →Chemo IV x 6–8 cycles	58 vs. 50	Operative time, hours: 2.36 vs. 3.63; P < .001 Successful cytoreduction: 74% vs. 46%; P = .0054 PDS associated with greater blood loss (P < .001)	PFS: 26 vs. 22; NS OS: 62 vs. 51; NS^{i}$

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图示：NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12,19:17在医脉通平台下载,仅供个人使用,严禁分发。2026 美国国家综合癌症网络版权所有。 NCCN Guidelines Index Table of Contents NCCN Guide #NCCN Guide ##Low-Grade DIAGNOSISa ###ADJUVANT TREATMENT ###MONITORING/FOLLOW-UP ####LOW-grade serous carcinoma$^{g,h}$ Stage IA-IB Observe g (category 2B) Systemic therapy (OV-C, 5 of 12)$^{f}$ Observe or Systemic therapy (OV-C, 5 of 12)$^{f}$ Observe or Maintenance letroz or Other hormonal therapy category 2B)$^{n}$ Monitoring/ Follow-up for Recurrent Disease (LOC-7) Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage II-IV Stage

图示：NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2026/01/12 19:17在医脉通平台下载，仅供个人使用，严禁分发。2026 美国国家综合癌症网络版权所有。 NCCN Guidelines Index Table of Contents Discussion PATHOLOGIC DIAGNOSISª PATHOLOGIC DIAGNOSISª Ovarian serous borderline epithelial tumors (LMP)a Prior complete surgical resectionc,d Low-grade serous carcinoma See adjuvant options (LCOC-6) Monitoring/ Follow-up (LCOC-10) Ovarian serous borderline epithelial tumors (LMP)a Prior incomplete surgical resectionc,d LCOC-9

图示：Ovarian serous borderline epithelial tumor (LMP), incomplete surgical staging, or tumor reductive surgery Imagingp if not previously done - eg, C/A/P CT, chest CT, A/P MRI, PET/ CT, PET/ MRI No residual disease remaining after first procedure and/or on imaging Fertility-sparing surgery (if fertility desired) and resection of residual disease$^{y,z}$ Corridor surgical intervention for select patients$^{a}$ Dissection Borderline on final pathology Monitoring/(LCOC-10) LOCC-6 Consider no surgical intervention for select patients$^{a}$ NCCN Guidelines Index Table of Contents Discussion

图示：Visits every 3-12 mo for up to 5 y, then as clinically indicated Physical exam including pelvic exam as clinically indicated CA-125$^{q}$ or other tumor markers every visit if initially elevated CBC, chemistry profile as indicated Imaging$^{p}$ as clinically indicated: eg C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI (skull base to mid-thigh) Ultrasound as indicated for patients with fertility-sparing surgery Clinical relapse Surgical evaluation + debulking if appropriate Noninvasive disease Observe Low-grade invasive carcinoma See appropriate LCOC page based on histology™ (LCOC-1) High-grade invasive carcinoma Treatment as epithelial ovarian cancer™ (OV-4)

图示：CLINICAL PRESENTATION/ DIAGNOSIS TREATMENTX Fertility desired Fertility not desired Malignant germ cell tumors Prior surgery$^{99}$ Dysgerminoma or Grade 1 immature teratoma Pior imaging of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI) Embryonal, endodermal sinus tumor (yolk sac tumor), grade 2-3 immature teratoma, nongestational choriocarcinoma, or mixed histology Positive imaging and positive tumor markers Pert of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI) Positive imaging and positive tumor markers Pert of non-merg (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI) Embronyal, endodermal sinus tumor (yolk sac tumor), grade 2-3 immature teratoma, nongestational choriocarcinoma, or mixed histology PCT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast. Note: This is the NCCN Guidelines for China. For definitions, see page DEF-1. Note: All recommendations are category 2A unless otherwise indicated. Lococ-12

图示：PATHOLOGIC DIAGNOSISª AJDUVANT TREATMENT MONITORING/FOLLOW-UP THERAPY FOR RECURRENT/PERSISTENT DISEASEff Stage I dysgerminomaII or Stage I, grade 1 immature teratomaII Observe Surveillance (LCOC-B) Any stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumor) or Stage II-IV dysgerminoma or Stage I, grade 2 or 3 or Stage II-IV immature teratoma or Any stage nongestational choriocarcinoma ImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, and, A/P MRI, PET/ CT, or PET/ MRI (skull base to mid-thigh) ImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh) Residual tumor on imaging; markers normalkk Observe�evillance (LCOC-B) Complete clinical response LCOC-14 NCCN Guidelines Index Table of Contents Discussion PATHOLOGIC DIAGNOSISA ADJUVANT TREATMENT MONITORING/FOLLOW-UP THERAPY FOR RECURRENT/PERSISTENT DISEASEff Stage I dysgerminomaII or Stage I, grade 1 damage in immature teratoma II Observeávillance (LCOC-B) Any stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumor) or Chemotherapyji Chemotherapyji ImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh) ImagingP as clinically indicated: eg, C/A/P CT, chest, CT, chest, CT, or PET/ MRI (skull base to mid-thigh) Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or Consider surgical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reteratoma Biospy or consider musical reterat

图示：Any stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumorii) or Stage II–IV dysgerminoma or 3 or Stage II–IV immature teratoma or Any stage nongestational choriocarcinoma Complete clinical response Observe (LCOC-B) Abnormal markers, definitive recurrent disease Second-line chemotherapy$^{ee}$ (category 2B) or High-dose chemotherapy$^{II}$ + HCT (category 2B) or Consider surgery for select patients Complete clinical response Second-line chemotherapy$^{ee}$ (category 2B) or High-dose chemotherapy$^{II}$ + HCT (category 2B) or Consider surgery for select patients LCOC-A

图示：DRUG REACTION TO PLATINUM AGENTS REACTION | | | | | | |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|--

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引用 / 出处

（2025.V3）NCCN临床实践指南—中国版：卵巢癌包括输卵管癌和原发性腹膜癌. 2025.

（2025.V3）NCCN临床实践指南—中国版：卵巢癌包括输卵管癌和原发性腹膜癌

Version 3.2025

Hematology/ Hematology oncology # Patient advocacy

D Internal medicine † Medical oncology

Hematology/ — Pathology

CHINESE EDITORIAL COMMITTEE — OVARIAN CANCER EXPERT

PANEL MEMBERS

NCCN

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines for China

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

POOR SURGICAL CANDIDATE OR LOW LIKELIHOOD OF OPTIMAL CYTOREDUCTION

NEOADJUVANT THERAPY

NCCN Guidelines for China

DIAGNOSIS BY PREVIOUS SURGERY

FINDINGS

NCCN Guidelines for China

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines for China

Version 3.2025

Epithelial Ovarian Cancer/Fallopian Tube Cancer/

Primary Peritoneal Cancer

NCCN Guidelines for China

NCCN Guidelines for China

NCCN Guidelines for China

NCCN Guidelines for China

Version 3.2025

Mucinous Carcinoma of the Ovary

NCCN Guidelines for China

NCCN Guidelines for China

NCCN Guidelines for China

MONITORING/FOLLOW-UP FOR RECURRENCE

NCCN Guidelines for China

Version 3.2025

Ovarian Serous Borderline Epithelial Tumors

NCCN Guidelines for China

Version 3.2025

Malignant Sex Cord-Stromal Tumors

NCCN Guidelines for China

NCCN Guidelines for China

NCCN Guidelines for China

Malignant Germ Cell Tumors

NCCN Guidelines for China

Version 3.2025

Malignant Germ Cell/Sex Cord-Stromal Tumors

SYSTEMIC THERAPY REGIMENSª

MALIGNANT GERM CELL TUMORS<sup>a,b,c</sup>

Preferred Regimens

Other Recommended Regimens

Useful in Certain Circumstances

Preferred Regimens

Other Recommended Regimens

MALIGNANT SEX CORD-STROMAL TUMORS$^{a,c}$

Other Recommended Regimens

Useful in Certain Circumstances

Useful in Certain Circumstances

SURVEILLANCE

PRINCIPLES OF SURGERY$^{1}$

NCCN Guidelines for China

Version 3.2025

Ovarian Cancer/Fallopian Tube Cancer/Primary

Peritoneal Cancer

PRINCIPLES OF PATHOLOGY

General

Tumor molecular analyses

PRINCIPLES OF SYSTEMIC THERAPY

General