（2026.V1）NCCN临床实践指南：小肠腺癌

指南综合与多学科· 未分类与其他 · 2026

NCCN Guidelines Version 1.2026

## Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

*AI B. Benson, III, MD/Chair †

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

* Alan P. Venook, MD/Vice-Chair ‡ ‡ UCSF Helen Diller Family Comprehensive Cancer Center

* Katrina Pedersen, MD, MS/Lead † Mayo Clinic Comprehensive Cancer Center

Mohamed Adam, MD ¶ UCSF Helen Diller Family Comprehensive Cancer Center

Manju Ambelil, MD # Fox Chase Cancer Center

George J. Chang, MD, MS, MHCM † The University of Texas MD Anderson Cancer Center

Kristen K. Ciombor, MD † Vanderbilt-Ingram Cancer Center

Stacey A. Cohen, MD † Fred Hutchinson Cancer Center

Madison Conces, MD ‡† Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Dustin Deming, MD † University of Wisconsin Carbone Cancer Center

Ignacio Garrido-Laguna, MD, PhD † Huntsman Cancer Institute at the University of Utah

Jean L. Grem, MD † Fred & Pamela Buffett Cancer Center

Carla Harmath, MD φ The UChicago Medicine Comprehensive Cancer Center

Paul Haste, MD $\phi$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

J. Randolph Hecht, MD † UCLA Jonsson Comprehensive Cancer Center

J. Kevin Hicks, PharmD, PhD, FCCP Σ Moffitt Cancer Center

Sarah Hoffe, MD § Moffitt Cancer Center

Steven Hunt, MD ¶ Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Hisham Hussan, MD ⏻ UC Davis Comprehensive Cancer Center Kimberly L. Johung, MD, PhD § Yale Cancer Center/Smilow Cancer Hospital

Nora Joseph, MD University of Michigan Rogel Cancer Center

Natalie Kirilcuk, MD ¶ Stanford Cancer Institute

Midhun Malla, MD, MS † O'Neal Comprehensive Cancer Center at UAB Rifat Mannan, MD ‡ City of Hope National Medical Center

Jennifer K. Maratt, MD, MS ⬒ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Wells A. Messersmith, MD † University of Colorado Cancer Center

Jeffrey Meyer, MD, MS § Johns Hopkins Kimmel Cancer Center

Jeffrey Meyerhardt, MD, MPH † Dana-Farber Brigham and Women's Cancer Center

Eric D. Miller, MD, PhD § The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Mary F. Mulcahy, MD ‡ †

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Steven Nurkin, MD, MS ¶ Roswell Park Comprehensive Cancer Center Hitendra Patel, MD † UC San Diego Moores Cancer Center

Leonard Saltz, MD ‡†‡ Memorial Sloan Kettering Cancer Center

Charles Schneider, MD † Abramson Cancer Center at the University of Pennsylvania

David Shibata, MD ¶ The University of Tennessee Health Science Center

Benjamin Shogan, MD ¶ The UChicago Medicine Comprehensive Cancer Center

Laurie Singer ¥ DoubleLL Productions

Constantinos T. Sofocleous, MD, PhD φ Memorial Sloan Kettering Cancer Center

Anna Tavakkoli, MD, MSc ⏻ UT Southwestern Simmons Comprehensive Cancer Center

Christopher G. Willett, MD § Duke Cancer Institute

Christina Wu, MD † Mayo Clinic Comprehensive Cancer Center

NCCN Lisa Gurski, PhD Frankie Jones

Φ Diagnostic/Interventional radiology § Grafoverterology ‡ Hematology/Hematology oncology

¥ Patient advocacy Σ Pharmacology/Pharmacy § Radiotherapy/Radiation onology

Surgery/Surgical oncology * Discussion Section Writing Committee

NCCN Guidelines Panel Disclosures

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

Version 1.2026, 01/22/26 © 2026 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.

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

NCCN Guidelines Index Table of Contents Discussion

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 Small Bowel Adenocarcinoma Panel Members

Summary of the Guidelines Updates

Clinical Presentations and Workup

• Workup for Small Bowel Adenocarcinoma (SBA-1)

Duodenum

• pMMR/MSS: Findings and Primary Treatment (SBA-2)

• dMMR/MSI-H: Findings and Primary Treatment (SBA-3)

Jejunum/Ileum

• pMMR/MSS: Findings and Primary Treatment (SBA-4)

• dMMR/MSI-H: Findings and Primary Treatment (SBA-5)

Adjuvant Treatment

• pMMR/MSS: Duodenum or Jejunum/Ileum Adjuvant Treatment (SBA-6)

• dMMR/MSI-H: Duodenum or Jejunum/Ileum Adjuvant Treatment (SBA-7)Metastatic and/or Recurrence

• Metastatic Adenocarcinoma and/or Serial Biomarker Elevation (SBA-8)Principles of Imaging and Endoscopy (SBA-A)

Principles of Pathologic Review (SBA-B)

Principles of Surgery (SBA-C)

Principles of Systemic Therapy (SBA-D)

Principles of Radiation Therapy (SBA-E)

Principles of Survivorship (SBA-F)

Staging (ST-1)

Abbreviations (ABBR-1)

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2026 of the NCCN Guidelines for Small Bowel Adenocarcinoma:Global

• Algorithm pages have been split by pMMR/MSS and dMMR/MSI-H for Duodenum and Jejunum/Ileum.

• Pages have been revised/added for dMMR/MSI-H (SBA-3, SBA-5, SBA-7) and for pMMR/MSS (SBA-2, SBA-4, SBA-6).

SBA-1

• Workup

Bullet 4 modified: EGD with EUS (duodenum only)

• Footnote c added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).

SBA-3

• Duodenum (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb])Resectable- Primary Treatment

◊ Treatment recommendation modified: Resection with en bloc removal of regional lymph nodes or Consider neoadjuvant checkpoint inhibitor immunotherapy (for T4 or bulky primary) (Also for Jejunum/Ileum on SBA-5)

Locally unresectable or medically inoperable- Primary Treatment

◊ Treatment recommendation removed: Fluorouracil/Leucovorin or Capecitabine (Also for Jejunum/Ileum on SBA-5)

Footnote j added: See SBA-D 2 of 12 for checkpoint inhibitor therapy options. (Also for Jejunum/Ileum on SBA-5)

SBA-6

• Duodenum or Jejunum/Ileum (pMMR/MSS)Adjuvant Treatment

◊ Footnote l modified: Enrollment in a clinical trial is encouraged. (eg, Phase III Trial Investigating the Potential Benefit of Adjuvant Chemotherapy for

Small Bowel Adenocarcinoma [BALLAD]: https://clinicaltrials.gov/ct2/show/NCT02502370). (Also for SBA-7)

◊ Footnote o modified: For duodenal cancers, if positive margin, consider sequential chemo/RT with capecitabine or infusional fluorouracil. See

Principles of Radiation Therapy (SBA-E). (Also for SBA-7)

◊ Footnote p modified: No studies have been performed to assess ideal surveillance intervals for SBA. The data in colorectal cancer surveillance is

generally currently accepted as appropriate for SBA. (Also for SBA-7)Surveillance

◊ Bullet 2 modified: CEA and/or CA 19-9 every 3–6 mo... (Also for SBA-7)

SBA-7

• Duodenum or Jejunum/Ileum (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb])Adjuvant Treatment

◊ Treatment recommendations added for T4, N0, M0 and T Any, N1–2:

– FOLFOX + Atezolizumab or CAPEOX + Atezolizumab

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

SBA-8

• Metastatic adenocarcinoma- Workup

Biomarker testing language modified:

◊ Molecular Biomarker testing performed as rapidly as possible following diagnosis, including:

– KRAS mutations and BRAF V600E mutations; HER2 (ERBB2) overexpression/amplifications; MMR or MSI status (if not previously done)

– Testing should be conducted as part of multigene panel testing (MGPT) broad molecular profiling, which would identify rare and actionable

mutations and gene fusions such as POLE/POLD1, RET, NTRK 1/2/3, and tumor mutational burden (TMB).

SBA-B

• Principles of Pathologic Review

Microsatellite Instability/Mismatch Repair Testing, language modified: Incidence of deficient MMR (dMMR)/MSI-high (MSI-H) and the possibility of

germline pathogenic variant (PV) mutation........Testing for MSI may be performed by validated MGPT next-generation sequencing (NGS) panels

• Text modified: For more information on biomarker molecular testing for NTRK 1/2/3, BRAF, KRAS, POLE/POLD1, RET, HER2 (ERBB2) overexpression/amplification, etc, see the Principles of Pathologic and Molecular Review in the NCCN Guidelines for Colon Cancer.

SBA-C

• Principles of Surgery- Principles for All Primary Sites

Bullet added: Diagnostic laparoscopy is not routinely indicated for clearly resectable early-stage disease. It may be considered when occult peritoneal

or metastatic disease is suspected—such as in locally advanced tumors, high-risk histology, elevated tumor markers, or discordant findings—and

when results would alter management.

SBA-D 1 of 12

• Principles of Systemic Therapy for Advanced or Metastatic Disease

• Qualifier headers for BRAF V600E, NTRK 1/2/3, RET, and KRAS G12C have been revised to remove the word 'positive'

Initial Therapy (pMMR/MSS)

◊ Intensive Therapy Recommended

– Regimen added: If BRAF V600E mutation: (FOLFOX/Encorafenib + [Cetuximab or Panitumumab])

◊ Initial Therapy if previous FOLFOX/CAPEOX in the adjuvant setting within past 12 months or contraindication

– Regimen added: If BRAF V600E mutation: (FOLFOX/Encorafenib + [Cetuximab or Panitumumab])

– Regimen and qualifier revised: If tissue TMB-high (>10 mut/Mb): Pembrolizumab has been changed from category 2B to a category 2A

recommendation for initial therapy and second-line and subsequent therapy

Second-Line and Subsequent Therapy (if not previously given)

◊ Regimen modified: Irinotecan ± Bevacizumab

◊ Qualifier modified for fam-trastuzumab deruxtecan-nxki: If HER2-amplified overexpression (IHC 3+)

◊ Treatment options added:

– If BRAF V600E mutation:

▪ Encorafenib + [Cetuximab or Panitumumab]

▪ (FOLFOX/Encorafenib + [Cetuximab or Panitumumab])

– If HER2 (ERBB2) overexpression/amplification and RAS and BRAF WT:

▪ (Pertuzumab or Tucatinib) + Trastuzumab

◊ Regimen modified: If KRAS G12C mutation: (Sotorasib or Adagrasib) ± (Cetuximab or Panitumumab)

Updates in Version 1.2026 of the NCCN Guidelines for Small Bowel Adenocarcinoma:

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

SBA-D 2 of 12

• New table and treatment recommendations added for checkpoint inhibitor therapy for any line of therapy

• The following agents have been added:

PD-1

◊ Penpulimab-kcqx

PD-L1

◊ Atezolizumab

◊ Avelumab

◊ Cosibelimab-ipdl

◊ Durvalumab

• Asterisk added: Some of these agents have not been specifically studied in SBA but are included in this Guideline based on the presumed class effect from data demonstrated in other cancer types. See Discussion section for more information.

SBA-D 3 of 12• Footnote d added: FDA added a Boxed warning to the capecitabine label, recommending to test patients for genetic variants of DPYD prior to initiating capecitabine unless immediate treatment is necessary. For information on DPYD testing and fluoropyrimidine-associated toxicity, see the NCCN

Guidelines for Colon Cancer.

• Footnote k added: Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

• Footnote l added: BRAF V600E regimen may be given with FOLFOX as subsequent line therapy if no previous treatment with oxaliplatin or BRAFtargeting regimen.

• Footnote m added: Principles of Pathologic Review (SBA-B).

• Footnote r added: Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and

hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab.

SBA-D 4 of 12 through SBA-D 9 of 12

• Dosing updated

SBA-D 10 of 12 through SBA-D 12 of 12

• References updated

SBA-F

• Lifestyle Modifications

Bullet 6: Link added to NCCN Guidelines for Smoking Cessation

Updates in Version 1.2026 of the NCCN Guidelines for Small Bowel Adenocarcinoma:

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Small bowel adenocarcinoma] --> A2[Workup: a,b,c]\n A2 --> A3[Abdomen/pelvis CT or MRI]\n A2 --> A4[Chest CT]\n A2 --> A5[FDG-positron emission tomography(PET)/CT is not indicated]\n A2 --> A6[EGD with EUS(duodenum only)]\n A2 --> A7[Complete blood count(CBC), chemistry profile]\n A2 --> A8[CA 19-9 and carcinoembryonic antigen(CEA)]\n A2 --> A9[Consider studies for celiac disease Biopsy with pathology review]\n A2 --> A10[Mismatch repair(MMR) or microsatellite instability(MSI) testing]\n A11[CLINICAL LOCATION] --> A12[Duodenum]\n A11 --> A17[Jejunum/ileum]\n A12 --> A13[pMMR/MSS]\n A12 --> A14[dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype]\n A13 --> A15[SBA-2]\n A14 --> A16[SBA-3]\n A17 --> A18[pMMR/MSS]\n A17 --> A19[dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype]\n A18 --> A20[SBA-4]\n A19 --> A21[SBA-5]\n](1/parseimages/figure97147651873b4ba9b762fe2177e48d69_0_4.png) Ampullary cancer $\rightarrow$ See NCCN Guidelines for Ampullary Adenocarcinoma

a Principles of Imaging and Endoscopy (SBA-A).

b FDA added a Boxed warning to the capecitabine label, recommending to test patients for genetic variants of DPYD prior to initiating capecitabine unless immediate treatment is necessary. For information on DPYD testing and fluoropyrimidine-associated toxicity, see the NCCN Guidelines for Colon Cancer.

c Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).

d EUS should be considered when needed to discern duodenal malignancy from ampullary, distal common bile duct, or pancreatic head malignancy. Also consider if other radiologic imaging is insufficient for clinical staging.

e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

f All patients with small bowel adenocarcinoma (SBA) should be counseled for familial malignancies and considered for risk assessment, including Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]), familial adenomatous polyposis (FAP), and other polypoid mutations. Refer to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL LOCATION$^{f}$

FINDINGS

PRIMARY TREATMENT

![graph TD\n A1[Duodenum(pMMR/MSS)] --> A2[Resectable]\n A1 --> A5[Locally unresctable or medically inoperable]\n A1 --> A8[Distant metastatic disease]\n A2 --> A3[Resection with en bloc removal of regional lymph nodes, g]\n A3 --> A4[Pathologic Stage, Adjuvant Therapy, and Surveillance(SBA-6)]\n A5 --> A6[Palliative diversion or stent(if obstructed) and/or FOLFOX or CAPEOX or Fluorouracil/Leucovorin or Capecitabine or FOLFIRINOX or Chemo/RT, h,i with Capecitabine or infusional Fluorouracil]\n A6 --> A7[Reevaluate for conversion to resectable disease]\n A7 --> A8\n A8 --> A9[Palliative diversion or stent(if obstructed) Metastatic Adenocarcinoma(SBA-8)]\n A8 --> A10[Survery or Systemic Therapy(SBA-D)]\n](1/parseimages/figure0ef6c264c8104710b834890370a33c82_0_7.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

f All patients with SBA should be counseled for familial malignancies and considered for risk assessment, including Lynch syndrome (HNPCC), FAP, and other polypoid mutations. Refer to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{9}$ Principles of Surgery (SBA-C).

h Principles of Radiation Therapy (SBA-E).

i Preoperative chemo/RT should be considered in patients who remain unresectable following a course of induction chemotherapy.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Duodenum (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb])] --> A2[Resectable]\n A1 --> A6[Locally unresectable or medically inoperable]\n A1 --> A10[Distant metastatic disease]\n A2 --> A3[Resection with en bloc removal of regional lymph nodes, or Consider neoadjuvant checkpoint inhibitor immunotherapy(for T4 or bulky primary)]\n A3 --> A4[Pathologic Stage, Adjuvant Therapy, and Surveillance(SBA-7)]\n A5[Locally unresectable or medically inoperable] --> A6\n A6 --> A7[Palliative diversion or stent(if obstructed) and/or Checkpoint inhibitor immunotherapy]\n A6 --> A8[FOLFOX or CAPEOX or FOLFIRINOX or Chem/RTwith Capcitabine or infusional Fluorouracil]\n A7 --> A8\n A8 --> A9[Reevaluate for conversion to resectable disease]\n A9 --> A10\n A9 --> A11[Resurgery or Systemic Therapy(SBA-D)]\n A10 --> A11\n A10 --> A12[• Palliative diversion or stent(if obstructed) • Metastatic Adenocarcinoma(SBA-8)]\n](1/parseimages/figure6c52024dd05f46ddbb1f6a52cc02e976_0_4.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

$^{f}$ All patients with SBA should be counseled for familial malignancies and considered for risk assessment, including Lynch syndrome (HNPCC), FAP, and other polypoid mutations. Refer to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric.

$^{9}$ Principles of Surgery (SBA-C).

h Principles of Radiation Therapy (SBA-E).

i Preoperative chemo/RT should be considered in patients who remain unresectable following a course of induction chemotherapy.

$^{j}$ See SBA-D 2 of 12 for checkpoint inhibitor therapy options.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL LOCATION$^{f}$

FINDINGS

PRIMARY TREATMENT

![graph TD\n A1[Jejunum/ileum （pMMR/MSS）] --> A2[Resectable]\n A1 --> A6[Locally unresectable or medically inoperable]\n A1 --> A11[Distant metastatic disease]\n A2 --> A3[Resection with en bloc removal of regional lymph nodesᠧe.g]\n A3 --> A4[Pathologic Stage, Adjuvant Therapy, and Surveillance （SBA-6）]\n A6 --> A7[Palliative diversion or bypass （if obstructed）and/or FOLFOX or CAPEOX or Fluorouracil/Leucovorin or Capecitabine or FOLFIRINOX]\n A7 --> A8[Reevaluate for conversion to resectable disease]\n A8 --> A9[Surgery or Systemic Therapy （SBA-D）]\n A11 --> A10[• Palliative diversion （if obstructed） • Metastatic Adenocarcinoma （SBA-8）]\n](1/parseimages/figure9dc86a5062514929b9713491fc12438f_0_7.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

$^{9}$ Principles of Surgery (SBA-C).

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Jejunum/ileum （dMMR/MSI-H or POLE/POLII mutation with ultra-hypermutated phenotype （eg.TMB>50 mut/Mb）】 --> A2[Resectable]\n A1 --> A4[Locally unresctable or medically inoperable]\n A1 --> A10[Distant metastatic disease]\n A2 --> A3[Resection with en bloc removal of regional lymph nodes ⁶⁹ or Consider neoadjuvant checkpoint inhibitor immunotherapy （for T₄ or bulky primary）]\n A3 --> A6[Pathologic Stage, Adjuvant Therapy, and Surveillance （SBA-7）]\n A4 --> A5[Palliative diversion or bypass （if obstructed） or Checkpoint inhibitor immunotherapy ⱼ or FOLFOX or CAPEOX or FOLFIRINOX]\n A5 --> A7[Reevaluate for conversion to resectable disease]\n A7 --> A8[Surgery or Systemic Therapy （SBA-D）]\n A10 --> A9[· Palliative diversion （if obstructed） · Metastatic Adenocarcinoma （SBA-8）]\n](1/parseimages/figurebd6459b9a7704f23857f13f7a5ee22ad_0_4.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

$^{g}$ Principles of Surgery (SBA-C).

$^{j}$ See SBA-D 2 of 12 for checkpoint inhibitor therapy options.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Duodenum or Jejunum/ileum (pMMR/MSS)] --> A2[T1-2, NO, MO]\n A1 --> A3[T3, NO, MO(no high-risk features)]\n A1 --> A4[T3, NO, MO with high-risk features or T4, NO, MO]\n A1 --> A5[T Any, N1-2]\n A2 --> A6[Observation]\n A3 --> A7[Observation or Consider Fluorouracil/Leucovorin or Capecitabine]\n A4 --> A8[Observation or FOLFOX or CAPEOX(3-6 mo) or Fluorouracil/Leucovorin or Capecitabine(6 mo)]\n A5 --> A9[FOLFOX or CAPEOX(3-6 mo) or Fluorouracil/Leucovorin or Capecitabine(6 mo)]\n A6 --> A10[• History and physical examination every 3-6 mo for 2 y, then every 6 mo for a total of 5 y • CEA and CA 19-9 every 3-6 mo for 2 y, then every 6 mo for a total of 5 y • Chest/abdomen/pelvis CT every 6-12 mo for 2 y, then every 12 mo for y 3-5 • FDG-PET/CT is not indicated • Routine capsule endoscopy is not indicated • Principles of Surveillance(SBA-F)]\n A7 --> A10\n A8 --> A10\n A9 --> A10\n](1/parseimages/figureb7bacd71e73145d29c345f57af234bd9_0_4.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

k High-risk features in stage II SBA include close or positive resection margins, <5 lymph nodes examined if duodenal location or <8 lymph nodes examined if jejunal/ ileal primary tumor location, and tumor perforation. Further consideration may be made for administering chemotherapy in patients with stage II disease who have lymphovascular or perineural invasion, or poorly differentiated histology due to data extrapolated from colorectal cancer studies.

$^{1}$ Enrollment in a clinical trial is encouraged.

$^{m}$ Principles of Systemic Therapy (SBA-D 4 of 12).

$^{n}$ No patients with SBA were included in the IDEA pooled analysis of adjuvant colon cancer trials. However, in the absence of any direct data regarding SBA, the finding of noninferior 3-year disease-free survival with 3 months of CAPEOX compared to 6 months of CAPEOX in colon cancer may be extrapolated.

° For duodenal cancers, if positive margin, consider sequential chemo/RT with capecitabine or infusional fluorouracil. See Principles of Radiation Therapy (SBA-E).

$^{p}$ No studies have been performed to assess ideal surveillance intervals for SBA. The data in colorectal cancer surveillance is currently accepted as appropriate for SBA.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

LOCATION

PATHOLOGIC STAGEe

ADJUVANT TREATMENT$^{1}$,m

SURVEILLANCE$^{P}$

![graph TD\n A1[Duodenum or Jejunum/ileum (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype[eg,TMB>50 mut/Mb])] --> A2[T1-3, NO, MO]\n A1 --> A4[T4, NO, MO]\n A1 --> A6[T Any, N1-2]\n A2 --> A3[Observation]\n A3 --> A10[•History and physical examination every 3–6 mo for 2 y, then every 6 mo for a total of 5 y •CEA and CA 19-9 every 3–6 mo for 2 y, then every 6 mo for a total of 5 y •Chest/abdomen/pelvis CT every 6–12 mo for 2 y, then every 12 mo for y 3–5 •FDG-PET/CT is not indicated •Routine capsule endoscopy is not indicated •Principles of Surveillance(SBA-F)]\n A4 --> A5[Observation or FOLFOX + Atezolizumab9 or CAPEOX + Atezolizumab9 or FOLFOX or CAPEOX(3-6 mo)n,0]\n A5 --> A10\n A6 --> A7[FOLFOX + Atezolizumab9 or CAPEOX + Atezolizumab9 or FOLFOX or CAPEOX(3-6 mo)n,0]\n A7 --> A10\n](1/parseimages/figurebd77c1259009400aa0814bc01dba6cc1_0_8.png) e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

$^{1}$ Enrollment in a clinical trial is encouraged.

$^{m}$ Principles of Systemic Therapy (SBA-D 4 of 12).

$\circ$ For duodenal cancers, if positive margin, consider sequential chemo/RT with capecitabine or infusional fluorouracil. See Principles of Radiation Therapy (SBA-E).

$^{9}$ No studies have been performed to assess ideal surveillance intervals for SBA. The data in colorectal cancer surveillance is currently accepted as appropriate for SBA. $^{9}$ The role of adjuvant immunotherapy for those who received neoadjuvant immunotherapy is not defined.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

METASTATIC AND/OR RECURRENCE

WORKUP

![graph TD\n A1[Metastatic adenocarcinoma] --> A2[Chest/abdomen/pelvis CTa\nCBC, chemistry profile\nCA 19-9, CEA\nBiomarker testing performed as rapidly as possible following diagnosis, includinge: >RAS and BRAF V600E mutations; HER2(ERBB2) overexpression/ amplification; MMR or MSI status(if not previously done)\n>Testing should be conducted as part of multigene panel testing(MGPT),which would identify rare and actionable mutations and gene fusions such as POLE/POLD1, RET, NTRK 1/2/3, and tumor mutational burden(TMB).]\n A2 --> A3[Principles of Systemic Therapy(SBA-D)]\n](1/parseimages/figure9da45550d55b4542960a6413ce4d5995_0_6.png) ![graph TD\n A1[Serial biomarker elevation] --> A2[Physical examination • Endoscopic evaluation(s) • Chest/abdomen/pelvis CT with contrast]\n A2 --> A3[Negative evaluation]\n A2 --> A5[Positive evaluation]\n A3 --> A4[Consider FDG-PET/CT • Reevaluate biomarker and CT with contrast in 3 months]\n A5 --> A6[See “Metastatic adenocarcinoma” above]\n](1/parseimages/figure6af44cfae1204dfcae7bc2a92317876a_0_7.png) a Principles of Imaging and Endoscopy (SBA-A).

e Principles of Pathologic Review (SBA-B). Depending on tumor location and patient history, celiac disease or Crohn's disease may need to be assessed.

「Potentially resectable visceral or peritoneal metastases are extremely rare for SBA. See Discussion for information on metastasectomy and cytoreductive surgery/intraperitoneal chemotherapy, which may be considered for select patients.

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

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-A 1 OF 2

PRINCIPLES OF IMAGING AND ENDOSCOPY

Initial Workup/Staging

• Chest, abdomen, pelvis CT

Evaluate local extent of tumor infiltration into surrounding structures.

Assess for distant metastatic disease to lungs, lymph node, liver, peritoneal cavity, and other organs.

Abdomen/pelvis CT should be performed with intravenous (IV) iodinated contrast and oral contrast agents unless contraindicated.

Chest CT does not require contrast (although it may be given if performed with abdominal CT).

Consider CT enterography for specific cases where primary tumor is poorly visualized by standard methods.

If IV iodinated contrast is contraindicated, then MR examination of the abdomen/pelvis with IV gadolinium-based contrast may be obtained instead.

In patients with chronic kidney failure (including patients on dialysis), IV gadolinium-based contrast may be administered in select cases using

gadobutrol, gadopentetate dimeglumine, gadobenate dimeglumine, or gadoteridol.1

• MRI

MR of the abdomen/pelvis or MR enterography may be considered where there is contraindication to CT.2,3,4

Consider MR of the abdomen with and without contrast for further evaluation of indeterminate liver lesions on CT.

Magnetic resonance cholangiopancreatography (MRCP) may need to be obtained in the initial workup of suspected duodenal malignancies to further

ascertain tumor site of origin, particularly in cases of biliary obstruction.

• FDG-PET/CT is not indicated as efficacy and clinical benefit have not been examined compared to CT or MR.5

Consider obtaining FDG-PET/CT in instances of equivocal CT or MR results, including the evaluation of potential peritoneal disease, particularly

where potential lesions are sized greater than the lower limits of FDG-PET detection.

1 Weinreb JC, Rodby RA, Yee J, et al. Use of intravenous gadolinium-based contrast media in patients with kidney disease: consensus statements from the American College of Radiology and the National Kidney Foundation. Radiology 2021;298:28-35.

2 Masselli G, Casciani E, Polettini E, et al. Magnetic resonance imaging of small bowel neoplasms. Cancer Imaging 2013;13:92-99.3 Cronin CG, Lohan DG, Browne AM, et al. Magnetic resonance enterography in the evaluation of the small bowel. Semin Roentgenol 2009;44:237-243.4 Masselli G, Di Tola M, Casciani E, et al. Diagnosis of small-bowel diseases: Prospective comparison of multi-detector row CT enterography with MR enterography. Radiology 2016;279:420-431.

5 Cronin CG, Scott J, Kambadakone A, et al. Utility of positron emission tomography/CT in the evaluation of small bowel pathology. Br J Radiol 2012;85:1211-1221.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF IMAGING AND ENDOSCOPY

Initial Workup/Staging

$\bullet$ Endoscopy

$\bullet$ Esophagogastroduodenoscopy (EGD)

$\bullet$ May be used for detection and pathologic sampling where duodenal malignancy is suspected. If simultaneous intestinal obstruction is detected, palliative stenting may be considered.$^{6}$

$\bullet$ Endoscopic ultrasound (EUS)

$\bullet$ Useful for enhanced pre-therapeutic clinical staging of proximal small intestinal malignancies and to discern duodenal from ampullary, biliary, or pancreatic primaries.$^{7}$

$\bullet$ Push- or device-assisted enteroscopy (double- or single-balloon enteroscopy)

$\bullet$ Not required for routine staging workup, although may be considered in patients with small intestinal strictures for diagnostic and/or palliative benefit. Biopsy may be performed during these procedures.$^{8-10}$

$\bullet$ Capsule endoscopy

$\bullet$ Consider when radiographic imaging and other forms of endoscopy fail to reveal a suspected primary lesion.$^{11,12}$ This is not the preferred primary method for diagnostic workup due to inability to obtain tissue for diagnosis.

$\bullet$ Contraindicated where small bowel obstruction or strictures exist.

Monitoring

* Chest, abdomen, pelvis CT with contrast

$\bullet$ Prior to adjuvant therapy to assess response to resection or primary therapy.

$\bullet$ During re-evaluation of conversion to resectable disease (neoadjuvant therapy).

$\bullet$ CT enterography is not routinely indicated for monitoring and should be reserved for instances of clinical necessity.

Surveillance

$\bullet$ Surveillance for recurrence should be judiciously applied. Recommended similar approach to colorectal surveillance due to lack of small bowel adenocarcinoma (SBA)-specific data.

$\bullet$ Patients with confirmed Lynch syndrome should have appropriate screenings commensurate with their genotype and family cancer history. This may include small intestinal screening moving forward.$^{13}$

$^{6}$ Hara AK, Leighton JA, Sharma VK, et al. Imaging of small bowel disease: comparison of capsule endoscopy, standard endoscopy, barium examination, and CT. Radiographics 2005;25:697-711; discussion 711-718.

$^{7}$ Nylund K, Odegaard S, Hausken T, et al. Sonography of the small intestine. World J Gastroenterol 2009;15:1319-1330.

$^{8}$ Cazzato IA, Cammarota G, Nista EC, et al. Diagnostic and therapeutic impact of double-balloon enteroscopy (DBE) in a series of 100 patients with suspected small bowel diseases. Dig Liver Dis 2007;39:483-487.

$^{9}$ Sunada K, Yamamoto H, Kita H, et al. Clinical outcomes of enteroscopy using the double-balloon method for strictures of the small intestine. World J Gastroenterol 2005;11:1087-1089.

$^{10}$ Chen WG, Shan GD, Zhang H, et al. Double-balloon enteroscopy in small bowel diseases: Eight years single-center experience in China. Medicine (Baltimore) 2016;95:e5104.

$^{11}$ Bailey AA, Debinski HS, Appleyard MN, et al. Diagnosis and outcome of small bowel tumors found by capsule endoscopy: a three-center Australian experience. Am J Gastroenterol 2006;101:2237-2243.

12 Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield of small bowel tumors with capsule endoscopy. Cancer 2006;107:22-27.

$^{13}$ Koornstra JJ. Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. Best Pract Res Clin Gastroenterol 2012;26:359-368.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF PATHOLOGIC REVIEW

Small Bowel Adenocarcinoma Appropriate for Resection

$\bullet$ Prefer pathologic confirmation of disease prior to resection, where possible

Discrimination of Duodenal Malignancy from Other Primary Sites

$\bullet$ To differentiate SBA from ampullary malignancies in duodenal cancers of the second portion, the epicenter of the tumor or precursor lesion should not be at the ampulla, and >75% of the mass should not be within the ampulla

Pathologic Stage

$\bullet$ The following parameters should be reported:

$\bullet$ Primary tumor site (ie, duodenum, jejunum, ileum, overlapping, not otherwise specified [NOS])

$\blacktriangleright$ Grade of cancer

* Tumor depth of invasion (T stage)

$\bullet$ Number of lymph nodes evaluated and number of lymph nodes positive (N)

$\bullet$ Status of proximal, distal, radial or mesenteric, uncinate, bile duct, pancreas, and other margins, as appropriate

$\bullet$ Specimen orientation and inking involves both the pathologist and surgeon as this will help to ensure accurate assessment of the size and extent of the tumor. There should be either direct communication between the surgeon and pathologist for proper orientation and margin identification, or the surgeon should identify the important margins with a clearly understood and documented method (eg, written on the pathology requisition); see above – Status of margins.

$\bullet$ Lymphovascular invasion

$\bullet$ MSI/MMR status

$\bullet$ Evidence of celiac disease

$\bullet$ Presence of Crohn's disease

$\bullet$ Presence of polyps

Lymph Node Evaluation

$\bullet$ The AJCC recommends a minimum evaluation of eight lymph nodes, although the College of American Pathologists notes no clear number of minimum lymph nodes to predict complete lymph node negativity has been established

* Regional lymph nodes differ by site of primary tumor:

$\bullet$ Duodenum: retropancreatic, hepatic artery, inferior pancreaticoduodenal, and superior mesenteric

$\blacktriangleright$ Jejunum/ileum: cecal (terminal ileum only), ileocolic (terminal ileum only), superior mesenteric, mesenteric, and NOS

Microsatellite Instability/Mismatch Repair Testing

$\bullet$ Universal MMR or MSI testing is recommended in all newly diagnosed patients with SBA

$\bullet$ Incidence of deficient MMR (dMMR)/MSI-high (MSI-H) and the possibility of germline pathogenic variant (PV) is enriched in patients with SBA compared to those with colon and rectal cancer, making this an important prognostic and/or predictive biomarker$^{1}$,$^{2}$

$\bullet$ Patients with stage II dMMR/MSI-H may have improved survival compared to patients with proficient MMR (pMR)/microsatellite stable (MSS); however, this has not been confirmed in the SBA population and is extrapolated from colorectal cancer data

$\bullet$ MMR or MSI testing should be performed only in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories

$\bullet$ Testing for MSI may be performed by validated MGPT

For more information on biomarker testing for NTRK 1/2/3, BRAF, KRAS, POLE/POLD1, RET, HER2 (ERBB2) overexpression/amplification, etc, see the Principles of Pathologic and Molecular Review in the NCCN Guidelines for Colon Cancer.

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-C

PRINCIPLES OF SURGERY

Principles for All Primary Sites

• Intraoperative staging of the abdomen, particularly including the mesentery, omentum, and peritoneum, should be completed in all cases.

• Adequate lymph node dissection, consisting of the resection and evaluation of at least eight lymph nodes, should be the goal for all resections.1,2

• Diagnostic laparoscopy is not routinely indicated for clearly resectable early-stage disease. It may be considered when occult peritoneal or metastatic

disease is suspected—such as in locally advanced tumors, high-risk histology, elevated tumor markers, or discordant findings—and when results would

alter management.

Duodenum

• Pancreaticoduodenectomy (Whipple)

Should be considered for all duodenal malignancies, particularly if arising in the second portion of the duodenum or invading any portion of the

ampulla or pancreas.

Pylorus preservation is acceptable in the absence of a hereditary condition.

Minimally invasive procedures should be used only by experienced surgeons.

Margins should be considered for frozen section at the time of resection if there are concerns about the margins. If margins <5 mm, the surgeon

should consider re-excision of involved margin.

• Limited segmentectomy

Although controversial, may be considered for select cases in the absence of a hereditary condition, particularly in lesions on the anti-mesenteric side

of the intestine that involve the third and fourth segments of the duodenum.

Due to reported lower yield of lymph nodes sampled during segmental resection, particular attention will need to be made for complete lymph node

dissection and evaluation.3

Case reports suggest segmentectomy and other limited resection methods may be considered for lesions of the first portion of the duodenum,4

particularly for lesions located on the mesenteric side of the intestine and for those <2 cm in size.

Jejunum/Ileum

• Segmentectomy

Lymph nodes should be identified and resected down to the origin of feeder vessels. Clinically suspicious nodes outside of the field of resection

should be biopsied or resected whenever possible.

Margins of at least 5–10 cm on either side of the tumor should be obtained.

Terminal ileal resection with right hemicolectomy should be used for distal ileal tumors.

1 Overman MJ, Hu CY, Kopetz S, et al. A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease. Ann Surg Oncol 2012;19:1439-1445.

2 Overman MJ, Hu CY, Wolff RA, Chang GJ. Prognostic value of lymph node evaluation in small bowel adenocarcinoma: analysis of the surveillance, epidemiology, and end results database. Cancer 2010;116:5374-5382.

3 Onkendi EO, Boostrom SY, Sarr MG, et al. 15-year experience with surgical treatment of duodenal carcinoma: a comparison of periampullary and extra-ampullary

duodenal carcinomas. J Gastrointest Surg 2012;16:682-691.

4 Hashimoto D, Arima K, Chikamoto A, et al. Limited resection of the duodenum for nonampullary duodenal tumors, with review of the literature. Am Surg 2016;82:1126-1132.

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-D 1 OF 12

PRINCIPLES OF SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASEa,b,c,d INITIAL THERAPY (pMMR/MSS)

Intensive Therapy Recommended

• CAPEOX (Capecitabine/Oxaliplatin)e ± Bevacizumabf

• FOLFIRI (Leucovorin/Fluorouracil/Irinotecan) ± Bevacizumabf,g

• FOLFIRINOX (Leucovorin/Fluorouracil/Irinotecan/Oxaliplatin)e ±Bevacizumabf

• FOLFOX (Leucovorin/Fluorouracil/Oxaliplatin)e ± Bevacizumabf

• If BRAF V600E mutation:

(FOLFOXe/Encorafenib + [Cetuximab or Panitumumab])

Intensive Therapy NOT Recommendedh

• Capecitabine ± Bevacizumabf

• Fluorouracil/Leucovorin ± Bevacizumabf

Initial Therapy if previous FOLFOX/CAPEOX in the adjuvant setting within past 12 months or contraindication

• FOLFIRI ± Bevacizumabf

• Taxane-based chemotherapy

• If BRAF V600E mutation:

Dabrafenib/Trametinib

(FOLFOXe/Encorafenib + [Cetuximab or Panitumumab])

• If tissue TMB-high (>10 mut/Mb)i,j:

Pembrolizumabk

SECOND-LINE AND SUBSEQUENT THERAPY (if not previously given)

• CAPEOXe ± Bevacizumabf

• FOLFIRI ± Bevacizumabf

• FOLFOXe ± Bevacizumabf

• Irinotecan ± Bevacizumabf

• Taxane-based chemotherapy

• If BRAF V600E mutation:

Dabrafenib/Trametinib

Encorafenib + [Cetuximab or Panitumumab]

(FOLFOXe/Encorafenib + [Cetuximab or Panitumumab])l

• If HER2 (ERBB2) overexpression/amplificationm and RAS and BRAF WT:(Pertuzumab or Tucatinib) + Trastuzumab

• If HER2 overexpression (IHC 3+)m,n:

Fam-trastuzumab deruxtecan-nxki

• If tissue TMB-high (>10 mut/Mb)i,j:

Pembrolizumabk

• If NTRK 1/2/3 gene fusion:

Entrectinib

Larotrectinib

Repotrectinibo

• If RET gene fusion:

Selpercatinib

• If KRAS G12C mutation:

(Sotorasib or Adagrasib)p ± (Cetuximab or Panitumumab)

• Best supportive care

Regimen Dosing Footnotes

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASEa,b,c,d

|CHECKPOINT INHIBITOR THERAPY FOR ANY LINE OF THERAPY$^{i,j,*}$||| |---|---|---| |PD-1|PD-L1|PD-1/CTLA-4| |Cemiplimab-rwlcDostarlimab-gxlyNivolumabqPembrolizumabkPenpulimab-kcqxRetifanlimab-dlwrTislelizumabjsgrToripalimab-tpzi|AtezolizumabrAvelumabCosibelimab-ipdlDurvalumab|• Ipilimumab + Nivolumabq,s|

* Some of these agents have not been specifically studied in SBA but are included in this Guideline based on the presumed class effect from data demonstrated in other cancer types. See Discussion section for more information.

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

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-D 3 OF 12

PRINCIPLES OF SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE – FOOTNOTES

a Many of the regimens recommended in these guidelines are extrapolated from data for colorectal cancer.b For infection risk, monitoring, and prophylaxis recommendations for targeted therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of CancerRelated Infections.

c An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.d FDA added a Boxed warning to the capecitabine label, recommending to test patients for genetic variants of DPYD prior to initiating capecitabine unless immediate

treatment is necessary. For information on DPYD testing and fluoropyrimidine-associated toxicity, see the NCCN Guidelines for Colon Cancer.

e Discontinuation of oxaliplatin should be strongly considered after 3 to 4 months of therapy (or sooner for unacceptable neurotoxicity) while maintaining other agents

until time of progression. Oxaliplatin may be reintroduced if it was discontinued for neurotoxicity rather than for disease progression.

f Bevacizumab has been shown to be safe in advanced SBA, although efficacy has not been proven. g The majority of data on first-line treatment of metastatic SBA are for oxaliplatin-based regimens.h For patients who are older, please complete geriatric assessment to aid appropriate prediction of treatment risks. See NCCN Guidelines for Older Adult Oncology,

OAO-2.

i NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities.j If no previous treatment with a checkpoint inhibitor.k Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

l BRAF V600E regimen may be given with FOLFOX as subsequent line therapy if no previous treatment with oxaliplatin or BRAF-targeting regimen.m Principles of Pathologic Review (SBA-B).n May not be indicated in patients with underlying lung issues due to lung toxicity (3.5% report of drug-related deaths from interstitial lung disease on the DESTINYCRC01 trial).

o On the TRIDENT-1 trial, repotrectinib showed activity both in NTRK TKI naïve and NTRK TKI-pretreated patients.p Sotorasib and adagrasib have showed activity as monotherapy, but have not been tested in combination with EGFR inhibitors in SBA.q Nivolumab and hyaluronidase-nvhy is not approved for concurrent use with IV ipilimumab; however, for nivolumab monotherapy, nivolumab and hyaluronidase-nvhy

subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV

nivolumab. This applies to all areas of the Guideline where nivolumab is listed.

r Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and

administration instructions compared to IV atezolizumab.

s Nivolumab + ipilimumab may be considered as subsequent therapy if checkpoint inhibitor monotherapy was previously received.

Regimen Dosing

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

NEOADJUVANT OR ADJUVANT THERAPY REGIMENSa,c,t

FOLFOX$^{1}$⁻$^{3}$ Oxaliplatin 85 mg/m$^{2}$ IV Day $^{1}$u Leucovorin 400 mg/m$^{2}$ IV Day $^{1}$v Fluorouracil 400 mg/m$^{2}$ IV bolus on Day 1, then 1200 mg/m$^{2}$/day x 2 Days (total 2400 mg/m$^{2}$ over 46–48 Hours) continuous infusion Repeat every 2 Weeks Fluorouracil/Leucovorin$^{1}$⁻$^{3}$ Leucovorin 500 mg/m$^{2}$ given as a 2-hour infusion and repeated Weekly x 6

Fluorouracil 500 mg/m$^{2}$ given bolus 1 Hour after the start of Leucovorin and repeated Weekly x 6 Every 8 Weeks for 4 cycles

Simplified biweekly infusional Fluorouracil/Leucovorin (sLV5FU2)$^{1}$⁻$^{3}$ Leucovorin 400 mg/m$^{2}$ IV Day 1, V followed by Fluorouracil bolus 400 mg/m$^{2}$ and then 1200 mg/m$^{2}$/day x 2 Days (total 2400 mg/m$^{2}$ over 46-48 Hours) continuous infusion Repeat every 2 Weeks

* Capecitabine$^{1}$⁻$^{3}$ * Capecitabine 1000–1250 mg/m$^{2}$ PO twice Daily for 14 Days every 3 Weeks

* Capecitabine + RT$^{4}$ Capecitabine 825 mg/m$^{2}$ PO twice daily Monday-Friday, on days of radiation treatment only, throughout the duration of RT (typically 28–30 treatment Days)

Fluorouracil + RT$^{4}$

Fluorouracil 225 mg/m$^{2}$ IV over 24 Hours (continuous infusion) daily on Days 1–5 or 1–7 for 5 Weeks with RT

CAPEOX$^{1-3}$ Oxaliplatin 130 mg/m$^{2}$ IV day 1$^{u}$ Capecitabine 1000 mg/m$^{2}$ twice daily for 14 Days every 3 Weeks$^{W}$

FOLFOX + Atezolizumab$^{5}$ Atezolizumab 840 mg IV every 2 Weeks for 12 cycles (6 Months) then maintenance Atezolizumab 840 mg IV every 2 Weeks for 13 cycles (12 Months total)

CAPEOX + Atezolizumab$^{5}$ Atezolizumab 1200 mg IV every 3 Weeks for 8 cycles (6 Months) then maintenance Atezolizumab 1200 mg IV every 3 Weeks for 8 cycles (12 Months total)

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

Abstract

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

NCCN Guidelines Index Table of Contents Discussion

SBA-D 5 OF 12 ADVANCED OR METASTATIC THERAPY REGIMENS a,c

a Many of the regimens recommended in these guidelines are extrapolated from data for colorectal cancer. c An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. u Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1 mg/m 2 /min. Leucovorin infusion should match infusion time of oxaliplatin. Cerek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1 mg/m 2 /min. J Oncol Pract 2016;12:e548-553. v Leucovorin 400 mg/m 2 is the equivalent of levoleucovorin 200 mg/m 2 . w The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m 2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, and may require a lower dose of capecitabine. x Bevacizumab may be safely given at a rate of 0.5 mg/kg/min (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes).

References

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

FOLFIRINOX or Modified FOLFIRINOX + Bevacizumab$^{10}$,$^{11}$,$^{16}$, y Bevacizumab 5 mg/kg IV, Day$^{x}$ Repeat every 2 Weeks

* Capecitabine + RT$^{4}$ Capecitabine 825 mg/m$^{2}$ PO twice daily Monday-Friday, on days of radiation treatment only, throughout the duration of RT (typically 28–30 treatment Days)

Fluorouracil + RT$^{4}$ Fluorouracil 225 mg/m$^{2}$ IV over 24 Hours (continuous infusion) Daily on Days 1–5 or 1–7 for 5 Weeks with RT

Fluorouracil/Leucovorin Roswell Park regimen$^{18}$ Leucovorin 500 mg/m$^{2}$ IV over 2 Hours, Days 1, 8, 15, 22, 29, and 36 Fluorouracil 500 mg/m$^{2}$ IV bolus 1 Hour after start of Leucovorin, Days 1, 8, 15, 22, 29, and 36 Repeat every 8 Weeks

Simplified Biweekly infusional Fluorouracil/LV (sLV5FU2)$^{19}$ Leucovorin 400 mg/m$^{2}$ IV over 2 Hours on Day 1, followed by Fluorouracil bolus 400 mg/m$^{2}$ and then 1200 mg/m$^{2}$/day x 2 Days (total 2400 mg/m$^{2}$ over 46–48 Hours) continuous infusion Repeat every 2 Weeks

Weekly$^{20}$ Leucovorin 20 mg/m$^{2}$ IV over 2 Hours on Day 1 Fluorouracil 500 mg/m$^{2}$ IV bolus injection 1 Hour after the start of Leucovorin Repeat every Week or Fluorouracil 2600 mg/m$^{2}$ by 24-hour infusion on Day 1

Leucovorin 500 mg/m$^{2}$ over 2 hours on Day 1 Repeat every Week

Bolus or infusional Fluorouracil + Bevacizumab Bevacizumab 5 mg/kg IV Day 1x Repeat every 2 Weeks

Capecitabine$^{21}$ Capecitabine 850–1250 mg/m$^{2}$ PO twice Daily, for 14 Days Repeat every 3 Weeks

Capecitabine + Bevacizumab$^{21}$ Bevacizumab 7.5 mg/kg IV Day $1^x$ Repeat every 3 Weeks

Irinotecan$^{22,23}$ Irinotecan 125 mg/m$^{2}$ IV over 30–90 Minutes, Days 1 and 8 Repeat every 3 Weeks or Irinotecan 180 mg/m$^{2}$ IV over 30–90 Minutes, Day 1 Repeat every 2 Weeks or Irinotecan 300–350 mg/m$^{2}$ IV over 30–90 Minutes, Day 1 Repeat every 3 Weeks Repeat every 3 Weeks

References

ª Many of the regimens recommended in these guidelines are extrapolated from data for colorectal cancer. $^{c}$ An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. $^{v}$ Leucovorin 400 mg/m$^{2}$ is the equivalent of levoleucovorin 200 mg/m$^{2}$.

$\bullet$ Bevacizumab may be safely given at a rate of 0.5 mg/kg/min (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes). $\bullet$ FOLFIRINOX is recommended instead of FOLFOXIRI because FOLFOXIRI uses a high dose of fluorouracil (3200 mg/m$^{2}$ over 48 hours). Patients in the United States have been shown to have greater toxicity with fluorouracil. The dose of fluorouracil (2400 mg/m$^{2}$ over 46 hours) is a starting dose consistent with the dose recommended in FOLFOX or FOLFIRI and should be strongly considered for U.S. patients.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

Irinotecan + Bevacizumab$^{24}$ Irinotecan 180 mg/m$^{2}$ IV Day 1 Bevacizumab 5 mg/kg IV Day 1 Repeat every 2 Weeks or Irinotecan 300–350 mg/m$^{2}$ IV Day 1 Bevacizumab 7.5 mg/kg IV Day 1 Repeat every 3 Weeks

Pembrolizumab$^{25,26}$ (dMMR/MSI-H or TMB-high [≥10 mut/Mb] or POLE/ POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) Pembrolizumab 2 mg/kg IV every 3 Weeks or Pembrolizumab 400 mg IV every 6 Weeks or Pembrolizumab 4 mg/kg IV every 6 Weeks

Nivolumab$^{27}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hermutated phenotype [eg, TMB>50 mut/Mb]) Nivolumab 3 mg/kg every 2 Weeks or Nivolumab 480 mg IV every 4 Weeks or Nivolumab 480 mg IV every 4 Weeks or Nivolumab 6 mg/kg IV every 4 Weeks

Ipilimumab + Nivolumab$^{28}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hermutated phenotype [eg, TMB>50 mut/Mb]) Nivolumab 3 mg/kg (30-Minute IV infusion) Ipilimumab 1 mg/kg (30-Minute IV infusion) Once every 3 Weeks for 4 doses, then Nivolumab 3 mg/kg IV or Nivolumab 240 mg IV every 2 Weeks

Dostarlimab-gxly$^{29}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) Dostarlimab-gxly 500 mg IV every 3 Weeks for 4 doses followed by 1000 mg IV every 6 Weeks

Cemiplimab-rwlc$^{30}$,$^{31}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) 350 mg IV Day 1 Repeat every 3 Weeks

Retifanlimab-dlr$^{32}$,$^{33}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) 500 mg IV Day 1 Repeat every 4 Weeks

Tislelizumab.jsgr$^{34}$⁻$^{37}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) 200 mg IV Day 1 Repeat every 3 Weeks

Toripalimab-tpzi$^{38}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hermutated phenotype [eg, TMB>50 mut/Mb]) 3 mg/kg IV Day 1 Repeat every 2 Weeks

Penpulimab-kcxq$^{39}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hermutated phenotype [eg, TMB>50 mut/Mb]) 200 mg IV Day 1 Repeat every 2 Weeks

Atezolizumab$^{40}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) 840 mg IV Day 1 every 14 Days 1200 mg IV Day 1 every 21 Days 1680 mg IV Day 1 every 28 Days

Avelumab$^{41,42}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb]) 800 mg IV Day 1 Every 14 Days

References

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

Cosibelimab-ipd143 (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb])

1200 mg IV Day 1

Every 21 Days

Durvalumab$^{44}$ (dMMR/MSI-H or POLE/POLD1 mutation with ultra-hypermutated phenotype [eg, TMB>50 mut/Mb])

1500 mg IV Day 1

Every 28 Days

Albumin-bound Paclitaxel$^{45}$

Albumin-bound Paclitaxel 220-260 mg/m$^{2}$ IV every 21 Days

Docetaxel$^{46}$

Docetaxel 75–100 mg/m$^{2}$ IV on Day 1 every 21 Days

* Paclitaxel$^{46}$

Paclitaxel 135-250 mg/m$^{2}$ IV on Day 1 every 21 Days or

* Paclitaxel 80 mg/m$^{2}$ IV Weekly

Paclitaxel 80 mg/m$^{2}$ IV on Days 1, 8, and 15 every 28 Days

Albumin-bound Paclitaxel/Gemcitabine$^{46}$

Albumin-bound Paclitaxel 125 mg/m$^{2}$ IV on Days 1, 8, and 15

Gemcitabine 1000 mg/m$^{2}$ IV on Days 1, 8, and 15

Every 28 Days

Docetaxel/Gemcitabine$^{46}$

Gemcitabine 1000 mg/m$^{2}$ IV Days 1 and 8

Docetaxel 75 mg/m$^{2}$ IV Day 8

Every 21 Days

Gemcitabine/Paclitaxel$^{46}$

Gemcitabine 1000 mg/m$^{2}$ IV Days 1, 8, and 15

Paclitaxel 110 mg/m$^{2}$ Days 1, 8, and 15

Every 28 Days

Carboplatin/Paclitaxel$^{46}$

Paclitaxel 175 mg/m$^{2}$ IV Day 1

Carboplatin AUC 5 IV Day 1

Every 21 Days

GTX (Gemcitabine Fixed-Dose Rate/Docetaxel/Capecitabine)$^{46}$

Gemcitabine 750 mg/m$^{2}$ IV at a rate of 10 mg/m$^{2}$/min

on Days 4 and 11

Docetaxel 30 mg/m$^{2}$ IV Days 4 and 11

* Capecitabine 750 mg/m$^{2}$ PO twice Daily for 14 Days

Every 21 Days for 2-6 cycles

Larotrectinib$^{47}$ (NTRK 1/2/3 gene fusion) 100 mg PO twice Daily

Entrectinib$^{48}$ (NTRK 1/2/3 gene fusion) 600 mg PO once Daily

Repotrectinib$^{49}$ (NTRK 1/2/3 gene fusion) 160 mg PO Daily for first 14 Days,

Then increase to 160 mg PO twice Daily

Selpercatinib$^{50}$ (RET gene fusion)

Patients ≥50 kg: 160 mg PO twice Daily

Patients <50 kg: 120 mg PO twice Daily

Dabrafenib/Trametinib$^{51}$ (BRAF V600E mutation)

Dabrafenib 150 mg PO twice Daily

Trametinib 2 mg PO Daily

Every 28 Days

Fam-trastuzumab deruxtecan nxki$^{52}$ (HER2 overexpression, IHC 3+)

5.4 mg/kg IV on Day 1 every 21 Days

References

ªMany of the regimens recommended in these guidelines are extrapolated from data for colorectal cancer.

$^{c}$ An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

ADVANCED OR METASTATIC THERAPY REGIMENSª,c

Pertuzumab + Trastuzumab$^{53}$ (HER2 [ERBB2] overexpression/amplification and RAS and BRAF WT) Trastuzumab 8 mg/kg IV loading dose on Day 1 of cycle 1, followed by 6 mg/kg IV every 21 Days Pertuzumab 840 mg IV loading dose on Day 1 of cycle 1, followed by 420 mg IV every 21 Days

Tucatinib + Trastuzumab$^{54}$ (HER2 [ERBB2] overexpression/amplification and RAS and BRAF WT) Trastuzumab 8 mg/kg IV loading dose on Day 1 of cycle 1, followed by 6 mg/kg IV every 21 Days Tucatinib 300 mg PO twice Daily

Adagrasib$^{55}$ (KRAS G12C mutation) 600 mg PO BID

Sotorasib$^{56}$ (KRAS G12C mutation) 960 mg PO daily

FOLFOX/Encorafenib + Cetuximab$^{57}$ (BRAF V600E mutation) Encorafenib 300 mg PO Daily Cetuximab 500 mg/m$^{2}$ IV Day 1 Oxaliplatin 85 mg/m$^{2}$ IV Day 1 Leucovorin 400 mg/m$^{2}$ IV Day 1 Fluorouracil 400 mg/m$^{2}$ IV bolus on Day 1, followed by 1200 mg/m$^{2}$/day x 2 Days (total 2400 mg/m$^{2}$ over 46–48 hours) IV continuous infusion Repeat every 2 Weeks

FOLFOX/Encorafenib + Panitumumab$^{57}$ (BRAF V600E mutation) Encorafenib 300 mg PO Daily Panitumumab 6 mg/kg IV every Day 1 Oxaliplatin 85 mg/m$^{2}$ IV Day 1 Leucovorin 400 mg/m$^{2}$ IV Day 1 Fluorouracil 400 mg/m$^{2}$ IV bolus on Day 1, followed by 1200 mg/m$^{2}$/day x 2 Days (total 2400 mg/m$^{2}$ over 46–48 Hours) IV continuous infusion Repeat every 2 Weeks

Adagrasib + Cetuximab58 (KRAS G12C mutation) Adagrasib 600 mg PO BID Cetuximab 500 mg/m$^{2}$ IV every 2 Weeks

Adagrasib + Panitumumab (KRAS G12C mutation) Adagrasib 600 mg PO BID Panitumumab 6 mg/kg IV every 2 Weeks

Sotorasib + Cetuximab (KRAS G12C mutation) Sotorasib 960 mg PO Daily Cetuximab 500 mg/m$^{2}$ IV every 2 Weeks

Sotorasib + Panitumumab$^{59}$ (KRAS G12C mutation) Sotorasib 960 mg PO Daily Panitumumab 6 mg/kg IV every 2 Weeks

Encorafenib + Cetuximab$^{60-62}$ (BRAF V600E mutation) Encorafenib 300 mg PO Daily Cetuximab 400 mg/m$^{2}$ IV followed by 250 mg/m$^{2}$ IV weekly or Cetuximab 500 mg/m$^{2}$ IV every 2 Weeks

Encorafenib + Panitumumab$^{60-62}$ (BRAF V600E mutation) Encorafenib 300 mg PO Daily Panitumumab 6 mg/kg IV every 14 Days

References

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

$^{1}$ Evans TRJ, Aparicio T, Malicot KL, et al. GLOBAL BALLAD: An International Rare Cancers Initiative trial to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma (IRCI 002) [abstract]. J Clin

6.2 Ecker BL, McMillan MT, Datta J, et al. Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: A propensity score-matched analysis. Cancer 2016;122:693-701.

$^{3}$ Overman MJ, Kopetz S, Lin E, et al. Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine. Acta Oncol 2010;49:474-479.

4. Allegra CJ, Yothers G, O'Connell MJ, et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: A phase III randomized clinical trial. J Natl Cancer Inst 2015;107:djv248.

5. Sinicrope F, Ou FS, Arnold D, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC) [abstract]. J Clin Oncol 2025;43:LBA1.

6 Horimatsu T, Nakayama N, Moriwaki T, et al. A phase II study of 5-fluorouracil/L-leucovorin/oxalipatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. Int J Clin Oncol 2017;22:905-912.

$^{7}$ Tushima T, Taguri M, Honma Y, et al. Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated with chemotherapy. Oncologist 2012;17:1163-1170.

$^{8}$ Zaanan A, Costes L, Gauthier M, et al. Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study. Ann Oncol 2010;21:1786-1793.

$^{9}$ Xiang XJ, Liu YW, Zhang L, et al. A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma. Anticancer Drugs 2012;23:561-566.

$^{10}$ Aydin D, Sendur MA, Kefeli U, et al. Evaluation of bevacizumab in advanced small bowel adenocarcinoma. Clin Colorectal Cancer 2017;16:78-83.

$^{11}$ Takayoshi K, Kusaba H, Uenomachi M, et al. Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer. Cancer Chemother Pharmacol 2017;80:333-342.

$^{12}$ Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009;27:2598-2603.

13 Gulhati P, Raghav K, Shroff RT, et al. Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater: A single-center, open-label, phase 2 study. Cancer 2017;123:1011-1017.

14 Zaanan A, Gauthier M, Malka D, et al. Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study. Cancer 2011;117:1422-1428.

15 Conroy T, Bosset JF, Etienne PL, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:702-715.

16. Lamarca A, Foster L, Valle JW, et al. FOLFIRINOX or FOLFOXIRI in locally advanced duodenal adenocarcinoma: are we missing out? ESMO Open 2020;5:e000633.

17 Bennouna J, Andre T, Campion L, et al. Rationale and design of the IROCAS study: multicenter, international, randomized phase 3 trial comparing adjuvant modified (m) FOLFIRINOX to mFOLFOX6 in patients with high-risk stage III (p74 and/or N2) colon cancer-A UNICANCER GI-PRODIGE Trial. Clin Colorectal Cancer 2019;18:e69-e73.

18 Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879-1887.

$^{19}$ Andre 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 metastatic colorectal cancer. Eur J Cancer 1999;35:1343-1347.

$^{20}$ Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluoracuril in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Cancer Study Protocol 1. J Clin Oncol 1996;14:2274-2279.

$^{21}$ Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancer Oncol 2013;14:1077-1085.

$^{22}$ Polyzos A, Kouraklis G, Giannopoulos A, et al. Irinotecan as salvage chemotherapy for advanced small bowel adenocarcinoma: a series of three patients. J Chemother 2003;15:503-506.

23 Suenaga M, Mizunuma N, Chin K, et al. Chemotherapy for small-bowel adenocarcinoma at a single institution. Surg Today 2009;39:27-31.

Continued

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

SBA-D 10 OF 12

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

24 Yildiz R, Buyukberber S, Uner A, et al. Bevacizumab plus irinotecan-based therapy in metastatic colorectal cancer patients previously treated with oxaliplatin-based regimens. Cancer Invest 2010;28:33:37. 25 Le DT, Uran JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520. 26 Pedersen KS, Foster NR, Overman MJ, et al. ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma. Clin Cancer Res 2021;27:3641-3648. 27 Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:1182-1191. 28 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-779. 29 André T, Berton D, Curigliano G, et al. Antitumor activity and safety of dosarlimab monotherapy in patients with mismatch repair deficient solid tumors: A nonrandomized controlled trial. JAMA Netw Open 2023;6:e62341165. 30 Paccaly AJ, Migden MR, Papadopoulos KP, et al. Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis. Adv Ther 2021;38:2365-2378. 31 Migden MR, Khushalani NI, Chang ALS, et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 2020;21:294-305. 32 Berton D, Pautier P, Lorusso D, et al. Antitumor activity and safety of the PD-1 inhibitor retifanlimab in patients with recurrent microsatellite instability-high or deficient mismatch repair endometrial cancer: Final safety and efficacy results from cohort H of the POD1UM-101 phase I study. Gynec Oncol 2024;186:191-198. 33 Lakhani N, Cosman R, Banerji U, et al. A first-in-human phase I study of the PD-1 inhibitor, retifanlimab (INCMGA00012), in patients with advanced solid tumors (POD1UM-101). ESMO Open 2024;9:102254. 34 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;36:257-269. 35 Pang K, Yang Y, Tian D, et al. Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial). BMJ Open 2023;13:e069499.

36 Yang Z, Zhang X, Zhang J, et al. Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tisleizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial). BMC Cancer 2022;22:462. 37 Zhang L, Geng Z, Hao B, Geng Q. Tisleizumab: A Modified Antitumor Programmed Death Receptor 1 Antibody. Cancer Control 2022;29:1073274822111296.

38 Hu H, Kang PL,

38 Hu H, Kang PL, Zhang J,

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

45 Overman MJ, Adam L, Raghav K, et al. Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer. Ann Oncol 2018;29:139-144. 46 Aldrich JD, Raghav KPS, Varadhachary GR, et al. Retrospective analysis of taxane-based therapy in small bowel adenocarcinoma. Oncologist 2019;24:e384-e386.

$^{47}$ 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.

48 Doebere 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.

49 Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial. Annals of Oncology 2023;34:S755-S851.

50 Subbiah V, Wolf J, Konda B, et al. Tumour agnostic efficacy and safety of spercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid: a global, phase 1/2, multicentre, open-label trial (LIBRETTO-001). Lancet Oncol 2022;23:161-1273.

51 Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med 2023;29:1103-1112.

52 Raghav KPS, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol 2023;41:3501.

53 Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2019;20:518-530.

54 Strickler JH, Cercek A, Siena S, et al. Additional analyses of MOUNTAINEER: A phase II study of tucatinib and trastuzumab for HER2-positive mCRC [abstract]. Ann Oncol 2022;33:S808-S869.

55 Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54.

56 Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 2022;23:115-124.

57 Kopetz S, Yoshino T, Cutsem EV, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025;31:901-908.

58 Yaeger R, Weiss J, Pelster M, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54.

59 Kuboki Y, Yaeger R, Fakih MG, et al. 45MO Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort [abstract]. Ann Oncol 2022;33:S1445-S1446.

60 Van Cutsem E, Huijberts S, Grothey A, et al. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E-mutant metastatic colorectal cancer: Safety lead-in results from the phase III BEACON colorectal cancer study. J Clin Oncol 2019;37:1460-1469.

61 Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 2019;381:1632-1643.

62 Kopetz S, Grothey A, Van Cutsem E, et al. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open 2022;7:100477.

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

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-E

PRINCIPLES OF RADIATION THERAPY

Duodenum

• Database analysis suggests no survival benefit from the addition of adjuvant chemo/RT versus chemotherapy alone in patients with surgically resected duodenal adenocarcinoma.1 A separate retrospective study showed mixed results regarding the efficacy of either preoperative or postoperative chemo/RT for the management of locally advanced or margin-positive duodenal adenocarcinomas.2 Therefore, chemo/RT following chemotherapy should be

considered only in patients with positive margins.

• Preoperative chemo/RT should be considered in patients who remain unresectable following a course of induction chemotherapy.

• Patients should be evaluated by multidisciplinary teams at high-volume centers in cases where either preoperative or postoperative RT is being

considered.

• Treatment Information:

Fluoropyrimidine-based chemotherapy should be delivered concurrently with RT.

Treatment can be delivered using 3D conformal RT (3D-CRT). When appropriate, advanced treatment planning, such as intensity-modulated RT

(IMRT), should be considered to limit toxicity to adjacent normal organs.

Image-guided RT (IGRT) with kilovoltage (kV) imaging, MR-guided imaging, and cone beam CT imaging should be routinely used during the course of

treatment with IMRT.

Target Volumes:

◊ The primary site and regional lymph node basins should be included in the RT fields.

RT Dosing:

◊ Doses of 45–54 Gy in 1.8–2 Gy daily fractions should be used based on tolerance limits of adjacent normal tissues.

◊ Adjacent small bowel dose should be limited to Dmax 55 Gy, V45 Gy should be ≤150 cc, or V50 should be ≤30 cc for individual small bowel loops, if possible.3

Jejunum/Ileum

• RT is not generally indicated for lesions arising in these sites. Any consideration for such therapy must be made on a highly selected basis by a multidisciplinary team.

1 Ecker BL, McMillan MT, Datta J, et al. Adjuvant chemotherapy versus chemoradiotherapy in the management of patients with surgically resected duodenal

adenocarcinoma: A propensity score-matched analysis of a nationwide clinical oncology database. Cancer 2017;123:967-976.

2 Kelsey CR, Nelson JW, Willett CG, et al. Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;69:1436-1441.

3 Alvarez JA, Shi Q, Dasari A, et al. Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus

doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer. Supplement 2. Protocol update to Alliance A022104. BMC Cancer 2024;24:901.

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

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

SBA-F

PRINCIPLES OF SURVIVORSHIP

Surveillance

• Surveillance recommendations on SBA-6 and SBA-7

Survivorship Care Planning

• Should have defined roles for the oncologist and the primary care provider following curative-intent therapy

• Overall summary, including dates, of all diagnostic and surgical procedures, chemotherapy received (including drug and number of cycles), and RT(including dose) should be provided to the patient at end of treatment

• Description of long-term toxicities and when they may resolve, as well as potential delayed toxicity

• Surveillance recommendations and schedule

• Health behavior recommendations

• Fertility counseling

Management of Late/Long-term Sequelae of Treatment

• For issues related to distress, pain, neuropathy, fatigue, or sexual dysfunction, see NCCN Guidelines for Survivorship

Oxaliplatin-Related Neuropathy

• Only consider duloxetine, pregabalin, or gabapentin in cases where pain is present, as these are ineffective in treating numbness or tingling associated with the long-term use of oxaliplatin

• Consider non-pharmacologic interventions, including balanced physical activity, acupuncture, heat or ice, or other methods

Lifestyle Modifications

• Avoid gluten in patients with confirmed celiac disease

• Eat a plant-based diet

• Maintain healthy body weight throughout life

• Engage in regular physical activity

• Undergo all age- and gender-appropriate preventive health and cancer screenings at recommended intervals with primary care provider

• Avoid the use of alcohol or tobacco, see NCCN Guidelines for Smoking Cessation

Crohn’s Disease

• Patients with Crohn’s disease and history of SBA remain at elevated risk for developing further SBAs. Surveillance screening should be considered for these individuals.1,2

1 Grolleau C, Pote NM, Guedj NS, et al. Small bowel adenocarcinoma complicating Crohn's disease: a single-centre experience emphasizing the importance of screening for dysplasia. Virchows Arch 2017;471:611-617.

2 Cahill C, Gordon PH, Petrucci A, Boutros M. Small bowel adenocarcinoma and Crohn's disease: any further ahead than 50 years ago? World J Gastroenterol 2014;20:11486-11495.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

American Joint Committee on Cancer (AJCC) TNM Staging Classification for Small Intestine Adenocarcinoma 8th ed., 2017

Table 1. Definitions for T, N, M

T T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis High-grade dysplasia/carcinoma in situ

T1 Tumor invades the lamina propria or submucosa

T1a Tumor invades the lamina propria

T1b Tumor invades the submucosa

T2 Tumor invades the muscularis propria

T3 Tumor invades through the muscularis propria into the subserosa, or extends into nonperitonealized perimuscular tissue (mesentery or retroperitoneum) without serosal penetration

T4 Tumor perforates the visceral peritoneum or directly invades other organs or structures (e.g., other loops of small intestine, mesentery of adjacent loops of bowel, and abdominal wall by way of serosa; for duodenum only, invasion of pancreas or bile duct)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in one or two regional lymph nodes

N2 Metastasis in three or more regional lymph nodes

M Distance Metastasis

M0 No distant metastasis

M1 Distant metastasis present

Table 2. AJCC Prognostic Stage Groups

||T|N|M| |---|---|---|---| |Stage 0|Tis|N0|M0| |Stage I|T1-2|N0|M0| |Stage IIA|T3|N0|M0| |Stage IIB|T4|N0|M0| |Stage IIIA|Any T|N1|M0| |Stage IIIB|Any T|N2|M0| |Stage IV|Any T|Any N|M1|

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.

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

NCCN Guidelines Index Table of Contents Discussion

AUC

area under the curve

CBC

complete blood count

CEA

carcinoembryonic antigen

CLIA Clinical Laboratory Improvement Amendments dMMR mismatch repair deficient

EGD

esophagogastroduodenoscopy

EUS

endoscopic ultrasound

FAP

familial adenomatous polyposis

HNPCC hereditary non-polyposis colorectal cancer

IGRT image-guided radiation therapy

IMRT intensity-modulated radiation therapy

MGPT multigene panel testing

MMR mismatch repair

MRCP magnetic resonance cholangiopancreatography MSI

microsatellite instability

MSI-H microsatellite instability-high MSS

microsatellite stable

NOS

not otherwise specified

ABBREVIATIONS

ABBR-1

pMMR repair proficient mismatch PV

pathogenic variant

SBA

small bowel adenocarcinoma

TKI

tyrosine kinase inhibitor

TMB

tumor mutational burden

3D-CRT three-dimensional conformal radiation therapy

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

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.

Discussion

Table of Contents

Overview ......................................................................................... MS-2

Literature Search Criteria and Guidelines Update Methodology. MS-2

Sensitive/Inclusive Language Usage…………………………..........MS-3

Risk Factors for Small Bowel Adenocarcinoma ........................... MS-3

Lifestyle Factors ........................................................................... MS-3

Inflammatory Bowel Disease and Celiac Disease ......................... MS-3

Familial Syndromes ...................................................................... MS-3

Clinical Presentation and Workup................................................. MS-5

Imaging and Endoscopy ............................................................... MS-5

Pathology and Staging .................................................................. MS-6

Lymph Node Evaluation................................................................ MS-6

Treatment of Stage I–III Small Bowel Adenocarcinoma ............... MS-7

Surgical Management of Localized Resectable Disease ............... MS-7

Adjuvant Therapy ......................................................................... MS-7

Primary Treatment of Unresectable Disease................................. MS-9

Treatment of Distant Metastatic (Stage IV) Small Bowel

Adenocarcinoma .......................................................................... MS-10

Metastasectomy ......................................................................... MS-10

Peritoneal Carcinomatosis.......................................................... MS-10

Systemic Therapy for Metastatic Disease ................................... MS-11

Posttreatment Surveillance ......................................................... MS-18

Survivorship................................................................................. MS-19

Summary ...................................................................................... MS-19

References ................................................................................... MS-21

This discussion corresponds to the NCCN

Guidelines for Small Bowel Adenocarcinoma. Last updated September 13, 2024

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Overview

In 2024, an estimated 12,440 new cases of small bowel cancer will occur, and 2090 patients will die of this disease.$^{1}$ Compared to cancers of other organs in the gastrointestinal tract, small bowel cancers are relatively rare, accounting for only about 3% of cancers occurring in this organ system. Small bowel cancers affect males and females relatively equally, with an incidence of 2.6 per 100,000 for males and 2.0 per 100,000 for females.$^{2}$ The median age at diagnosis is 66 years. The incidence of small bowel cancers is increasing, with an annual percent increase of 1.8 between 2006 and 2015. This trend is in contrast to other gastrointestinal malignancies, including esophageal, gastric, colon, and rectal, which decreased in incidence across the same timeframe.$^{2}$ The four most common cancer histologies originating in the small bowel are adenocarcinomas, neuroendocrine tumors, gastrointestinal stromal tumors (GISTs), and lymphomas.$^{3,4}$ The treatment recommendations in this guideline only refer to small bowel adenocarcinoma (SBA), which comprise an estimated 30% to 40% incidence of small intestinal cancer diagnoses.$^{4}$ Due to the rarity of this disease, there are very few established guidelines for SBA management. In 2018, a French intergroup published the first clinical practice guidelines for SBA.$^{5}$ These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Bowel Adenocarcinoma are the second.

This Discussion summarizes the NCCN Guidelines® for Small Bowel Adenocarcinoma. These guidelines begin with the clinical presentation of the patient and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. When reviewing these guidelines, clinicians should be aware of several things. First, these guidelines adhere to the TNM (tumor, node, metastases) staging system(Table 1 in the algorithm).$^{6}$ Furthermore, all recommendations are classified as category 2A except where noted in the text or algorithm.

Although the guidelines are believed to represent the optimal treatment strategy, participation in a clinical trial is especially encouraged for patients with SBA based on the dearth of clinical trial data on which to base treatment decisions for this disease.

Literature Search Criteria and Guidelines Update Methodology

Prior to the development of the NCCN Guidelines for Small Bowel Adenocarcinoma, an electronic search of the PubMed database was performed to obtain key literature in the field of small bowel cancer, using the following search terms: (small bowel cancer) OR (small intestine cancer) OR (jejunum cancer) OR (duodenum cancer) OR (ileum cancer). The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.$^{7}$ The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial; Multicenter Study; Practice Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.

The data from key PubMed articles and 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. NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. When citing published studies and recommendations from other organizations, the terms used (eg, male, female) reflect the cited sources.

The complete details of the Development and Update of the NCCN Guidelines are available on the NCCN website at www.NCCN.org.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation.$^{8}$ NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Risk Factors for Small Bowel Adenocarcinoma

Risk factors for SBA are similar to those for colorectal cancer (CRC), including lifestyle factors, inflammatory bowel disease (IBD), and certain familial syndromes such as Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer [HNPCC]), Peutz-Jeghers syndrome (PJS), and familial adenomatous polyposis (FAP). Therefore, it is recommended that all patients with small bowel cancer be queried regarding their family history and considered for risk assessment, as detailed in the NCCN Guidelines for Colorectal Cancer Screening.

Lifestyle Factors

Although data on the role of lifestyle factors in relation to the risk of developing SBA are very limited due to low incidence of disease, lifestyle factors that have been reported as raising the risk of SBA generally agree with known risk factors for CRC. A systematic review of the literature has reported that high levels of alcohol consumption, smoking, and dietary factors, including low intake of fiber and high intake of red/processed meat and sugary drinks, may increase the risk of SBA.$^{9}$ Additionally, the results of a pooled analysis of more than 500,000 individuals in the Asia Cohort Consortium reported that elevated body mass index (BMI) and high alcohol consumption were associated with a non-significant trend towards an increased risk of SBA, although this analysis did not identify smoking as a risk factor.$^{10}$

Inflammatory Bowel Disease and Celiac Disease

It is well recognized that individuals with IBD (ulcerative colitis or Crohn's disease) are at increased risk for CRC. Several studies have also reported an increased risk of distal SBA in patients with IBD.$^{11-16}$ The results of a retrospective, multicenter observational cohort study of 9100 patients with IBD found that the relative risk of small bowel cancer was 3.70 (95% CI, 1.23–11.13). The rate of death and cancer remission did not differ between patients who maintained treatment for IBD compared to those who stopped IBD treatment.$^{11}$ Additionally, in a cohort study of 48,119 individuals with celiac disease (CD), 0.06% (n = 29) patients were diagnosed with SBA within 1 year of a CD diagnoses, suggesting a possible link between these conditions.$^{17}$ The association with celiac disease is poorly understood and a distinct difference from CRC, for which celiac disease is not a risk factor.

Familial Syndromes

Due to the relative rarity of SBA, and the disease's association with several genetic syndromes, the NCCN Panel recommends that all patients

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

with SBA should be counseled for familial malignancies and considered for risk assessment of various genetic syndromes, including Lynch syndrome, PJS, FAP, and other polypoid mutations. A brief description of some of these syndromes is included below. See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric for more information.

Familial Adenomatous Polyposis

FAP is an autosomal dominant condition characterized by a germline mutation in the APC gene, located on chromosome 5q21.$^{18,19}$ Patients with FAP develop large numbers of adenomatous polyps in the large bowel, beginning as early as adolescence, and most patients with classic FAP will develop polyps by the age of 25. Patients with attenuated FAP due to a germline MUTYH mutation develop fewer numbers of polyps, generally at a later age than those with classic FAP.$^{18,19}$ While the incidence of SBA in patients with FAP has not been well established, the lifetime risk has been estimated as 3% to 5%.$^{20}$ The duodenum and periampullary region are the most common locations for SBA in patients with FAP.$^{20}$

Peutz-Jeghers Syndrome

PJS is an autosomal dominant condition mainly characterized by multiple hamartomatous and adenomatous gastrointestinal polyps, predominantly located in the jejunum and ileum.$^{20,21}$ A majority of PJS cases occur due to mutations in the STK11 (LKB1) gene.$^{22,23}$ However, other genetic mutations may be involved, as an estimated half of patients with PJS do not have detectable STK11/LKB1 mutations.$^{24}$ SBA can arise from either hamartomatous or adenomatous polyps, predisposing patients with PJS to SBA. The relative risk of developing SBA has been estimated as 520 compared to the general population,$^{25}$ and the lifetime risk of SBA has been estimated between 1.7% to 13% for individuals with PJS.$^{20,25,26}$

Lynch Syndrome

Lynch syndrome is a hereditary syndrome resulting from germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). Individuals with Lynch syndrome are estimated to have a lifetime risk of 4% of developing SBA, representing a relative risk of >100 compared to the general population.$^{27,28}$ Although identifying a mutation in an MMR gene through germline sequencing is definitive for Lynch syndrome, patients usually undergo selection for screening by considering family history and performing an initial test on tumor tissue before sequencing. One of two (or both) different initial tests can be performed on SBA specimens to identify individuals who might have Lynch syndrome: 1) immunohistochemical analysis for MMR protein expression, which is often diminished because of mutation; or 2) polymerase chain reaction (PCR) analysis for microsatellite instability (MSI), which results from MMR deficiency and is detected as changes in the length of repetitive DNA elements in tumor tissue caused by the insertion or deletion of repeated units.$^{29}$

Many NCCN Member Institutions and other comprehensive cancer centers perform immunohistochemistry (IHC) and sometimes MSI testing on all newly diagnosed CRC and endometrial cancers regardless of family history to determine which patients should have genetic testing for Lynch syndrome.$^{7,30-33}$ This approach may also be applied to patients with SBA, particularly since it has been reported that SBA has a higher percentage of MSI-high (MSI-H)/MMR-deficient (dMMR) tumors compared to CRC.$^{34,35}$ The NCCN Colon/Rectal/Anal Cancers Panel endorses universal MMR or MSI testing of all newly diagnosed patients with SBA to identify individuals with Lynch syndrome. This testing is also relevant for treatment selection in stage IV disease (see Pembrolizumab, Nivolumab ± Ipilimumab, or Dostarlimab-gxly [for dMMR/MSI-H tumors], below). A more detailed discussion is available in the NCCN Guidelines for Colorectal Cancer Screening.

NCCN

National Comprehensive Cancer Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026 Cancer Small Bowel Adenocarcinoma

Clinical Presentation and Workup

The treatment recommendations in this guideline only refer to SBA. For GISTs, see the NCCN Guidelines for Soft Tissue Sarcoma; for neuroendocrine tumors, see the NCCN Guidelines for Neuroendocrine and Adrenal Tumors; and for small bowel lymphomas see the NCCN Guidelines for B-Cell Lymphomas.

Most cases of SBA arise in the duodenum, accounting for approximately 52% to 58% of cases. The remainder arise in the jejunum (15%–29%), ileum (10%–13%), or in an unspecified location of the small bowel (4%–16%).$^{36}$⁻$^{39}$ Patients with SBA tend to be younger at diagnosis and often present with a higher stage and grade compared to those with CRC.$^{40}$ SBA often presents with a local complication of the tumor, most often gastric outlet obstruction in the case of a duodenal SBA or cramping abdominal pain in the case of a jejunal or ileal SBA.$^{36}$,$^{41}$,$^{42}$ Occult gastrointestinal bleeding is another common presentation for SBA, occurring in approximately one-quarter to one-third of cases.

Patients who present with small bowel cancer require a complete staging workup, including biopsy (if appropriate), pathologic tissue review, imaging studies (see Imaging and Endoscopy, below), complete blood count (CBC), chemistry profile, carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and MMR or MSI testing. In addition, patients with metastatic and/or recurrent disease should also be tested for BRAF V600E mutation and HER2 amplification. Testing for tumor mutational burden (TMB) and POLE/POLD1 mutation should be considered for these patients. Depending on the tumor's location and the patient's history, studies for celiac disease or IBD may be indicated. As discussed above, MMR or MSI testing is recommended for all patients with SBA as MMR/MSI status can function as a prognostic and/or predictive marker and can help identify patients who should be tested for

Lynch syndrome (see Risk Factors for Small Bowel Adenocarcinoma, above).

For more information on molecular testing for NTRK, BRAF, POLE/POLD1, RET, HER2 amplifications, and TMB, see the Principles of Pathologic and Molecular Review in the NCCN Guidelines for Colon Cancer.

Imaging and Endoscopy

Esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) is recommended during initial workup and staging for detection and pathologic sampling when a duodenal malignancy is suspected. If obstruction is detected during imaging, palliative diversion or stenting may be considered.$^{43}$ EUS is useful for pre-therapeutic staging of proximal small bowel malignancies and may be used to discern duodenal lesions from ampullary, biliary, or pancreatic primaries.$^{44}$

Other endoscopic techniques that are not required for routine staging, but may be useful in certain circumstances, include double balloon endoscopy and capsule endoscopy. A number of studies, both prospective and retrospective, have reported on the effectiveness and safety of double balloon endoscopy for workup of patients with small bowel cancer.$^{45}$⁻$^{47}$ Specifically, the use of this method may be of particular benefit for patients with small bowel strictures.$^{48}$ While capsule endoscopy allows for a more detailed examination of the entire small bowel mucosa, possibly resulting in the diagnosis of SBA when other imaging methods have failed to reveal a primary lesion, it is not the preferred method for initial workup due to its inability to biopsy tissue for diagnosis.$^{49}$⁻$^{51}$ In the case of a small bowel obstruction or stricture, the capsule may not be excreted naturally, requiring surgical removal. Therefore, capsule endoscopy is contraindicated for these conditions.$^{43}$

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

CT or magnetic resonance (MR) imaging may be used during initial workup of SBA to evaluate the extent of local tumor invasion and to assess for distant metastases. CT or MR enterography, techniques involving administration of enteric contrast agent to the gastrointestinal system via oral intake or nasogastric tube, respectively, may improve imaging of the small bowel and, therefore, may be considered when conventional CT or MR with contrast have failed to discern a tumor.$^{52-55}$ A prospective study comparing CT enterography to MR enterography in 150 patients with suspected small bowel disease, but negative findings on endoscopy, reported that MR enterography was more accurate than CT enterography, particularly for neoplastic diseases (P = .0412).$^{56}$

While FDG-PET/CT has not been formally evaluated for ability to detect metastatic SBA, or compared to MR or CT, there have been reports describing its usefulness for this disease.$^{57}$ Therefore, while FDG-PET/CT is not routinely indicated, it may be considered when CT or MR results are equivocal.

See Posttreatment Surveillance, below, for the use of these imaging methods for posttreatment surveillance and for use in individuals with inflammatory bowel disease, celiac disease, or familial syndromes.

Pathology and Staging

SBA staging is based on the TNM staging system.$^{6}$ In the 8th edition of the AJCC Staging Manual, T1 tumors involve the lamina propria or submucosa; T2 tumors penetrate through the submucosa into the muscularis propria; T3 tumors penetrate through the muscularis propria into the subserosa or extend into nonperitonealized perimuscular tissue; and T4 tumors perforate the visceral peritoneum or directly invade other organs or structures. Regional lymph node classification includes N0 (no regional lymph node metastasis), N1 (1-2 positive lymph nodes), and N2

(3 or more positive nodes). SBA is classified as M1 when distant metastasis is present.$^{6}$

SBA is staged as I or II when a tumor is present without regional lymph node or distant metastases (any T, N0, M0). Stage III disease includes disease with regional lymph node, but not distant, metastasis (any T, N1-2, M0). Stage IV is distant metastatic disease (any T, any N, M1).$^{6}$ A number of sources have reported stage III or IV SBA as having significantly worse outcomes compared to earlier stage disease.$^{6,58,59}$

Other factors that may be useful for prognostication, but not used for staging, include the primary tumor site (ie, duodenum, jejunum, ileum); histologic grade; number of lymph nodes evaluated; margin status; lymphovascular invasion; MSI/MMR status; evidence/presence of celiac or IBD; and presence of polyps.$^{6}$ The NCCN Panel recommends reporting of these parameters during pathologic review.

Lymph Node Evaluation

Regional lymph nodes differ based on the site of the primary tumors: retropancreatic, hepatic artery, inferior pancreaticodudenal, and superior mesenteric nodes are regional to the duodenum; cecal or ileocolic (terminal ileum only, superior mesenteric, or mesenteric [not otherwise specified]) nodes are regional to the jejunum and ileum.

Multiple analyses of patients with SBA in the SEER database have found that longer survival following resection is strongly associated with a lower ratio of positive-to-negative lymph nodes as well as with a higher number of regional lymph nodes assessed during surgery.$^{40,60-62}$ Two of these analyses, which considered duodenal and jejunoileal adenocarcinomas separately, concluded that, for adequate staging, a minimum of 5 lymph nodes should be retrieved for duodenal tumors and a minimum of 9 lymph nodes for jejunal or ileal tumors.$^{61,62}$ Analyses that pooled duodenal and jejunoileal tumors found that 8 regional lymph nodes should be assessed

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

for adequate staging,$^{40,60}$ although some data have suggested that harvesting even higher numbers of lymph nodes may better predict SBA survival outcomes.$^{63}$ Based on these studies, NCCN recommends that a goal for all SBA resections should be the retrieval of at least 8 regional lymph nodes for evaluation.

Treatment of Stage I-III Small Bowel Adenocarcinoma

Surgical Management of Localized Resectable Disease

For local (stage I-III) SBA, primary treatment consists of surgical resection with en bloc removal of the regional lymph nodes. While there have been no prospective randomized trials to inform surgical technique, retrospective reviews on the subject have been published.$^{64}$⁻$^{67}$ Intraoperative staging of the abdomen—particularly including the mesentery, omentum, and peritoneum—should be completed in all cases.

The type of resection used to treat localized SBA depends on the location of the primary tumor. Segmental resection of the small bowel is often the mainstay of treatment, although duodenal tumors may require either pancreaticoduodenectomy or segmental duodenal resection. For tumors of the jejunum or ileum, segmentectomy is the preferred method of resection.

Pancreaticoduodenectomy, also known as the Whipple procedure, should be considered for all duodenal cancers, and is particularly appropriate for those arising in the second portion of the duodenum or invading into any portion of the ampulla or pancreas. Minimally invasive procedures, such as laparoscopic surgery, may be considered for pancreaticoduodenectomy, but should only be used by experienced surgeons. Limited segmentectomy may be considered in SBA involving the third and fourth segments of the duodenum and on the anti-mesenteric side of the intestine, although this approach is controversial based on reports of lower lymph node yields.$^{66}$ However, a retrospective study of 1611 patients with duodenal adenocarcinoma found that patients who

were treated with radical resection did not show an improvement in overall survival (OS) or disease-specific survival compared to a simple removal of the primary site, after controlling for confounding factors.$^{68}$ This finding was despite greater lymph node retrieval with radical resection. Another systematic review and meta-analysis of observational studies including 6438 patients with duodenal cancer also reported that both segmental resection and pancreaticoduodenectomy allowed adequate assessment of lymph nodes and no difference in OS was observed between the two techniques with distal duodenal primary tumors.$^{67}$ Limited resection may also produce more favorable rates of overall morbidity and postoperative pancreatic fistula.$^{69}$ Case reports have suggested that segmentectomy and other limited resection methods may be considered for lesions in the first portion of the duodenum, particularly for those <2 cm in size and located on the mesenteric side of the intestine.$^{65}$

NCCN recommends that a goal for all SBA resections should be the retrieval of at least 8 regional lymph nodes for evaluation based on the strong prognostic impact of lymph node metastases and studies showing improved outcomes with higher numbers of lymph nodes assessed during surgery.$^{60-62}$ See Lymph Node Evaluation, above, for more information on pathologic review of dissected lymph nodes.

Adjuvant Therapy

Localized SBAs are treated with surgical resection, but local and distant recurrences are common and optimal perioperative therapy is unknown.$^{70}$ Therefore, participation in a clinical trial is preferred for all patients with SBA who are considering adjuvant therapy. For discussion of neoadjuvant therapy, see Primary Treatment of Unresectable Disease, below.

The ongoing, international phase III BALLAD trial is the first prospective trial investigating the role of adjuvant 5-FU/leucovorin (5-FU/LV) or 5-FU/LV plus oxaliplatin (FOLFOX) compared to observation alone for

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

patients with stage I–III SBA.$^{71}$,$^{72}$ Until the results of BALLAD have been reported, the potential benefits of adjuvant therapy for SBA can be estimated only through retrospective reports. The data from retrospective studies or meta-analyses that have sought to assess the efficacy of adjuvant therapy (either chemotherapy or chemoradiotherapy) for SBA have been mixed, with some showing a benefit to adjuvant therapy,$^{39,73-75}$ some showing no benefit,$^{37,76,77}$ and some showing an equivocal or non-significant benefit.$^{78,79}$

The IDEA collaboration was a large trial of patients with colon cancer that investigated whether limiting adjuvant treatment to 3 months of FOLFOX or CAPEOX—which would markedly decrease the incidence of neuropathy—would compromise oncologic outcomes.$^{80,81}$ While the non-inferiority of 3 months versus 6 months of CAPEOX was not proven, 3 months of CAPEOX numerically appeared similar to 6 months of CAPEOX for 5-year OS (82.1% vs. 81.2%; HR, 0.96), with considerably less toxicity. These results support the use of 3 months of adjuvant CAPEOX over 6 months for patients with stage III colon cancer. For stage II disease, the duration of therapy was associated with a small (and not statistically significant) difference in disease-free survival (DFS) between 3 and 6 months of CAPEOX.$^{82}$ There were significantly less grade 3–5 toxicities with 3 months versus 6 months. While the IDEA trial enrolled no patients with SBA, extrapolation from these colon cancer data are reasonable in the absence of any direct data regarding adjuvant treatment of SBA with the caveat that, stage-for-stage, survival is worse for SBA than for colon cancer.$^{58,59}$

Data supporting the use of adjuvant chemoradiation are especially limited, with a retrospective review of patients with resected, nonmetastatic duodenal adenocarcinoma showing that patients who received adjuvant chemoradiotherapy (n = 550) had no significant improvement in survival compared to those who received chemotherapy alone (n = 694), even in

high-risk cases.$^{83}$ Therefore, chemoradiation should be considered only in highly selected patients.

MSI/MMR Status for Adjuvant Therapy

MSI/MMR is an important piece of information to consider when deciding whether to use adjuvant chemotherapy in patients with stage II SBA. Mutation of MMR genes or modifications of these genes (eg, methylation) can result in MMR protein deficiency and MSI.$^{84}$ Tumors showing the presence of MSI are classified as either MSI-H or MSI-low (MSI-L), depending on the extent of instability in the markers tested, whereas tumors without this characteristic are classified as microsatellite-stable (MSS).$^{85}$ Patients determined to have dMMR status are biologically the same population as those with MSI-H status.

Data from several large studies in colon cancer have shown that MSI-H (ie, dMMR) tumors have a decreased likelihood to metastasize and that MSI-H/dMMR may function as a prognostic marker for favorable outcomes in stage II disease.$^{86-88}$ Some of these same studies also show that a dMMR/MSI-H tumor status may be a predictive marker of decreased benefit and possibly a detrimental impact from adjuvant therapy in patients with stage II colon cancer.$^{87-89}$ However, a study of 1913 patients with stage II CRC from the QUASAR study, half of whom received adjuvant chemotherapy, showed that although dMMR was prognostic, it did not predict benefit or detrimental impact of chemotherapy.$^{90}$ A study of patients in the CALGB 9581 and 89803 trials came to a similar conclusion, though notably this used older, non-standard chemotherapy regimens.$^{91}$ Extrapolating from these colon cancer data, patients with stage II MSI-H/dMMR SBA may have a good prognosis and the benefit from adjuvant therapy is unclear.

NCCN Recommendations for Adjuvant Therapy

Based on the limited data available from retrospective studies of SBA, and extrapolation from studies of colon cancer the NCCN Panel recommends:

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

$\bullet$ Three to 6 months of adjuvant treatment with capecitabine plus oxaliplatin (CAPEOX) or 6 months of adjuvant treatment with FOLFOX, 5-FU/LV, or capecitabine for any locally advanced SBA with positive lymph nodes (stage III). Following adjuvant systemic therapy, sequential chemoradiation with capecitabine or infusional 5-FU may be considered for stage III duodenal cancer that is margin-positive following resection.

$\bullet$ Observation or adjuvant treatment with 3 to 6 months of CAPEOX or 6 months of FOLFOX, 5-FU/LV, or capecitabine for stage II tumors that are MSS or MMR proficient (pMMR) and have high-risk features. High-risk features include T4 stage, close or positive surgical margins, few lymph nodes examined (<5 for duodenal or <8 for jejunal/ileal primary tumor location), or tumor perforation.$^{40,60,76}$ Studies in CRC, and a retrospective report in SBA, have identified lymphovascular or perineural invasion and poorly differentiated histology as poor prognostic factors.$^{76,92-94}$ Therefore, adjuvant therapy may be considered for patients with these factors as well. Following adjuvant systemic therapy, sequential chemoradiation with capecitabine or infusional 5-FU may be considered for high-risk stage II duodenal cancer that is margin-positive following resection.

$\bullet$ Observation or 6 months of adjuvant treatment with 5-FU/LV or capecitabine for T3, N0, M0 (stage IIA) tumors that are MSS or pMMR and have no high-risk features.

$\bullet$ Observation following surgical treatment for all stage I tumors and for stage II tumors that are MSI-H or dMMR.

Primary Treatment of Unresectable Disease

For some patients with locally unresectable or medically inoperable SBA, conversion to resectable disease may be a goal. A limited amount of data

has demonstrated that neoadjuvant therapy may be beneficial in converting unresectable SBA to resectable disease. A retrospective study of patients with unresectable or recurrent duodenal adenocarcinoma who were treated with neoadjuvant chemotherapy or chemoradiation found that 9 out of 10 patients showed conversion to resectable disease following neoadjuvant therapy. At the time of data collection, 5 patients were still alive (ranging from 18-83 months postoperatively), suggesting prolonged survival following conversion to resectable disease.$^{95}$ In addition, neoadjuvant chemoradiation was studied in two small prospective trials. A phase II trial including patients with duodenal or pancreatic adenocarcinomas reported that 4 of 5 patients with tumors in the duodenum were able to undergo resection following neoadjuvant chemoradiation.$^{96}$ Another small prospective study of patients with duodenal or pancreatic adenocarcinomas reported that 4 all patients with duodenal cancer underwent curative resection following neoadjuvant chemoradiation and experienced a complete pathologic response.$^{97}$

Since many small bowel cancers present at an advanced stage, malignant small bowel obstruction is a common complication. One retrospective Eastern European study reported that most patients with small bowel cancer presented due to an emergency situation,$^{41}$ with obstruction being a common complication for SBA, accounting for 22% to 57.9% of these cases.$^{41,98-100}$ Malignant small bowel obstruction may be treated palliatively with either surgical diversion or stenting. While most of the literature on palliative treatment of malignant small bowel obstruction comes from pancreatic cancer, there are a few studies that include SBA cases.$^{41,101-104}$ One retrospective study concluded that there was no difference in post- stent survival between patients with pancreatic and nonpancreatic cancers, and that patients with nonpancreatic cancers (including SBA) showed a longer OS.$^{101}$

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Based on these data, the Panel recommends that patients with locally unresectable or medically inoperable SBA may undergo neoadjuvant therapy, during which they should be routinely monitored for conversion to resectable disease. Neoadjuvant chemoradiation may be indicated for duodenal disease that remains unresectable following a course of induction chemotherapy, but degree of benefit is controversial and should be considered on an individual case basis. Alternatively, in cases where conversion to resectable disease is not feasible, palliative chemotherapy may be considered. Palliative diversion or stenting is recommended if a small bowel obstruction is present.

Treatment of Distant Metastatic (Stage IV) Small Bowel Adenocarcinoma

Approximately 32% of patients diagnosed with SBA have stage IV (distant metastatic) disease.$^{40}$ The most common sites for metastatic spread include the peritoneal cavity and liver, consistent with other gastrointestinal malignancies.$^{6}$ While 5-year survival is relatively high (85%) for localized disease, patients with stage IV SBA have a 5-year relative survival of only 42%.$^{105}$ In addition, recurrence rates of localized SBA treated with surgery are high, with many of these patients developing distant metastases.$^{36}$ The NCCN recommendations for treatment of stage IV SBA are discussed below.

Metastectomy

While resectable metastases are rare for SBA and the data supporting metastasectomy for SBA are limited, a retrospective analysis of patients with non-CRC, nonendocrine liver metastases (including 28 patients with small bowel cancers and 12 patients with duodenal cancers) showed promising survival rates following resection of liver metastases.$^{106}$ The 5-year survival rate for small bowel cancers was 49% with a median survival of 58 months. For duodenal cancers, the 5-year survival rate was 21% with a median survival of 34 months. In addition, another retrospective

study of 34 patients undergoing resection of SBA metastases reported a median OS of 28.2 months and a relapse-free survival of 18.7 months.$^{107}$ In total, 44.1% of patients in this study survived >3 years and 88.2% of patients in this study received perioperative chemotherapy. Poor differentiation, invaded margins, and lymphatic invasion of the primary tumor were identified as poor prognostic factors. Therefore, certain patients with SBA and limited metastasis to visceral organs may be candidates for metastasectomy. If metastasectomy is being considered, a multidisciplinary team, including a surgeon experienced in the resection of metastases, should be consulted.

Peritoneal Carcinomatosis

Peritoneal carcinomatosis (peritoneal metastases) has been shown to affect 25% to 50% of patients with stage IV SBA. Peritoneal carcinomatosis occurs more frequently in tumors arising from the jejunum or ileum and less commonly in duodenal tumors.$^{108}$ Peritoneal carcinomatosis generally carries a poor prognosis with a reported median OS of 5.9 months.$^{109}$ The goal of treatment for unresectable peritoneal metastases is palliative and primarily consists of systemic therapy (see Systemic Therapy for Metastatic Disease).

For resectable peritoneal carcinomatosis, surgical cytoreduction may be considered. For peritoneal metastases that present synchronously with the primary tumor, resection of the primary and cytoreduction of peritoneal metastases may be carried out concurrently. A multidisciplinary team evaluation at an experienced center is important if considering this treatment approach. Data supporting the use of hyperthermic intraperitoneal chemotherapy (HIPEC) for SBA with peritoneal carcinomatosis are extremely limited, consisting entirely of small, retrospective studies.$^{109-114}$ In addition, a phase III PRODIGE 7 study showed no benefit of oxaliplatin-based HIPEC in patients with CRC compared to cytoreduction alone.$^{115}$ Significant morbidity and mortality are

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

associated with this procedure. Various studies have reported morbidity rates ranging from 19% to 31% for serious adverse events (AEs) and mortality rates ranging from 0% to 4%.$^{110-114}$ Furthermore, recurrences after the procedure are common.$^{113,114}$ Based on this lack of evidence, HIPEC cannot be recommended for this population unless more robust data become available.

Systemic Therapy for Metastatic Disease

Data supporting systemic therapy for advanced adenocarcinoma of the small bowel were also almost entirely limited to retrospective reports,$^{116}$⁻$^{119}$ although recently several small phase II trials for SBA have been reported. Based on the results from these studies, several systemic therapy regimens are recommended for treatment of metastatic SBA. However, participation in clinical trials is especially encouraged for patients with SBA based on the lack of data.

The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, and the differing toxicity profiles of the constituent drugs. Furthermore, an evaluation of the efficacy and safety of these regimens for an individual patient must take into account the performance status of the patient. As initial therapy for advanced disease where intensive therapy is recommended (ie, a patient with a good tolerance for this therapy and for whom a high tumor response rate would be potentially beneficial), the Panel recommends a choice of combination chemotherapy regimens: FOLFOX, CAPEOX, FOLFIRI (infusional 5-FU plus irinotecan), or FOLFIRINOX (infusional 5-FU, LV, oxaliplatin, irinotecan); any of which may be combined with bevacizumab. For patients for whom intensive therapy is not recommended, treatment options would exclude the more toxic components of these regimens with 5-FU/LV or capecitabine with or without bevacizumab recommended as first-line therapy for these patients. For both intensive and non-intensive therapy, the checkpoint inhibitors pembrolizumab or nivolumab, with or without

ipilimumab, are recommended as initial therapy options for tumors that are dMMR/MSI-H.

For subsequent lines of therapy, many of the chemotherapy regimens recommended as first-line options may be given as subsequent line, if not given previously. In addition, taxane-based chemotherapies are also options for non-first line therapy. Checkpoint inhibitors are an option for dMMR/MSI-H disease or POLE/POLD1 mutation with ultra-hypermutated phenotype if a checkpoint inhibitor was not previously given. Larotrectinib, entrectinib, or repotrectinib are options in subsequent lines of therapy for metastatic SBA with neurotrophic tyrosine receptor kinase (NTRK) gene fusion and no satisfactory alternative treatments. Finally, selpercatinib is an option in subsequent lines of therapy for rearranged during transfection (RET) gene fusion-positive metastatic SBA and no satisfactory alternative treatments.

Genetic Alterations in SBA

Emerging research has shown that SBA has a distinct genetic profile, which sets it apart from CRC or gastroesophageal cancers, the two cancer types SBA is most often likened to. While KRAS and TP53 alterations are frequently identified in both SBA and CRC, APC mutations are significantly less common in SBA (27% in SBA vs. 76% in CRC; P < .001).$^{35}$

Considering the near ubiquity of APC mutation and its well-established role in CRC carcinogenesis, this suggests that neoplastic transformation in SBA is unique compared to CRC.$^{34,35}$

SMAD4 and CDKN2A mutations are more commonly seen compared to gastroesophageal cancers and CRC. Though BRAF mutations occur at a similar rate as seen in CRC, only 10% of BRAF-mutant SBAs have a V600E alteration, compared with >70% in BRAF-mutant CRC.$^{35}$ Importantly, human epidermal growth factor receptor 2 (HER2) alterations, MSI-H/dMMR, programmed death-ligand 1 (PD-L1) expression, and tumor mutational burden-high (TMB-H) are enhanced in SBA compared to

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

CRC,$^{35,120-122}$ and may reveal greater importance of targeted or immunotherapeutic treatments compared to current CRC treatment algorithms. One study showed higher rates of PD-L1 positivity in SBA associated with Crohn's or celiac disease, compared with sporadic SBA.$^{123}$

Regimens Not Recommended for SBA

While many of the systemic therapy regimens recommended for treatment of metastatic SBA are extrapolated from data for CRC, there are several regimens commonly used for metastatic CRC that are not recommended for SBA based either on a lack of data supporting their use or data suggesting that these regimens do not work for metastatic SBA.

A 2017 retrospective analysis reported that the efficacy of cetuximab-containing chemotherapy for RAS wild-type SBA was inconclusive.$^{124}$ Subsequently, a phase II trial published in 2018 showed that panitumumab has no clinically meaningful activity in RAS wild-type SBA$^{125}$; therefore, cetuximab or panitumumab should not be used for treatment of SBA.

While trifluridine-tipiracil or regorafenib are recommended as subsequent therapy options for metastatic CRC, there are no data to support their use for SBA and are, therefore, not recommended.

FOLFOX or CAPEOX

Both FOLFOX and CAPEOX have been evaluated prospectively for first-line treatment of advanced SBA in phase II clinical trials. One of these trials evaluated CAPEOX in 30 patients with advanced adenocarcinomas of the small bowel and ampulla of Vater. The overall response rate (ORR) (the primary endpoint) was 50%, with 10% achieving a complete response.$^{126}$ A similar response rate of 48.5% (95% CI, 31%–67%) was seen in another small phase II study of 33 patients that assessed the efficacy of FOLFOX in first-line treatment of advanced SBA.$^{127}$ Likewise, another phase II study reported an ORR of 45% for 24 patients with metastatic or unresectable SBA who were treated with FOLFOX, with a

median progression-free survival (PFS) and OS of 5.9 and 17.3 months, respectively.$^{128}$ These response rates to CAPEOX and FOLFOX were much higher than the 18% response rate seen in another small phase II study that evaluated 5-FU/doxorubicin/mitomycin C in patients with metastatic SBA.$^{129}$ AEs reported across these three trials were similar, with neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, peripheral neuropathy, and fatigue reported most frequently.$^{126-128}$ Retrospective studies have supported the results of these trials, reporting that the combination of a fluoropyrimidine with oxaliplatin was the most effective first-line therapy for advanced SBA.$^{118,130,131}$ Based on these data, FOLFOX or CAPEOX are recommended as first-line therapy options for treatment of patients with advanced SBA who are appropriate for intensive therapy. FOLFOX or CAPEOX may also be appropriate as subsequent therapy if not given as first-line therapy, although there is a lack of data for their use in this setting.

Results of the OPTIMOX1 study showed that a “stop-and-go” approach using oxaliplatin-free intervals resulted in decreased neurotoxicity but did not affect OS in patients with CRC receiving FOLFOX as initial therapy for metastatic disease.$^{132}$ Other trials have also addressed the question of treatment breaks, with or without maintenance therapy, and found that toxicity can be minimized with minimal or no effect on survival.$^{133,134}$ Therefore, the Panel recommends adjusting the schedule/timing of oxaliplatin as a means of limiting AEs. Discontinuation of oxaliplatin from FOLFOX or CAPEOX should be strongly considered after 3 months of therapy, or sooner for unacceptable neurotoxicity, with other drugs in the regimen maintained for the entire 6 months or until time of tumor progression. Patients experiencing neurotoxicity on oxaliplatin should not receive subsequent oxaliplatin therapy until and unless they experience near-total resolution of that neurotoxicity.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

FOLFIRINOX

While the role of FOLFIRINOX for treatment of SBA has not been formally evaluated, CAPIRINOX (capecitabine, irinotecan, oxaliplatin) has been tested as first-line treatment in a phase II trial of 33 patients with advanced SBA.$^{135}$ In this trial, CAPIRINOX—dose-adjusted according to UGT1A1 genotype—showed a response rate of 37.5% (95% CI, 21%–56%), with a median PFS and OS of 8.9 and 13.4 months, respectively. Neither hematologic toxicity nor tumor response rate differed significantly by UGT1A1 genotype, supporting the feasibility of genotype-directed dosing for CAPIRINOX. The NCCN Panel does not recommend use of CAPIRINOX for SBA due to concerns about toxicity, but the recommendation for FOLFIRINOX is extrapolated from the results of this study.

FOLFOX, CAPEOX, or FOLFIRINOX Plus Bevacizumab

While data supporting the addition of biologics to FOLFOX, CAPEOX, or FOLFIRINOX are currently extremely limited, a single-phase II trial has reported that CAPEOX in combination with bevacizumab is safe and efficacious in patients with SBA.$^{136}$ Retrospective analyses have supported these results, reporting favorable outcomes in patients treated with bevacizumab-containing chemotherapy regimens without adding significant toxicity.$^{124,137}$ Based on these data, FOLFOX, CAPEOX, or FOLFIRINOX may be given with or without bevacizumab for treatment of advanced SBA.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing biologic therapy. Several biosimilars are now available in the U.S. market, including biosimilars to bevacizumab.$^{138,139}$ The NCCN Panel has agreed that an U.S. Food and Drug Administration (FDA)-approved biosimilar may be substituted for bevacizumab wherever it is recommended within the NCCN Guidelines for Small Bowel Adenocarcinoma.

Pembrolizumab, Nivolumab ± Ipilimumab, or Dostarlimab-gxly (for dMMR/MSI-H tumors or POLE/POLD1 mutation with ultra-hypermutated phenotype)

Pembrolizumab is a PD-1 inhibitor that was evaluated as a subsequent-line therapy for treatment-refractory metastatic cancers in a phase 2 study that included 3 cohorts: 1) dMMR colorectal adenocarcinomas; 2) MMR-proficient colorectal adenocarcinomas; and 3) dMMR cancers of types other than CRC.$^{140}$ This third cohort included 2 patients with small bowel cancers. The immune-related objective response rate and immune-related PFS rate were 40% and 78%, respectively, for patients with dMMR CRC and 71% and 67% for patients with dMMR non-CRC. Common AEs of clinical interest included rash or pruritus; thyroiditis, hypothyroidism, or hypophysitis; and asymptomatic pancreatitis.$^{140}$ Based on the results of this study, the FDA granted accelerated approval to pembrolizumab in May 2017 for patients with unresectable or metastatic dMMR or MSI-H solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.$^{141}$

More recently, other phase II studies of pembrolizumab have included patients with previously treated SBA. The KEYNOTE-158 study enrolled 233 patients with dMMR/MSI-H advanced non-CRC, including 19 patients with SBA.$^{142}$ For the whole study population, ORR was 34.3%, with a median PFS of 4.1 months and median OS of 23.5 months. For SBA specifically, ORR was 42.1%, including three complete responses, median PFS was 9.2 months, and the median duration of response and OS had not been reached at the time of publication. The ZEBRA study evaluated the efficacy of pembrolizumab in 40 patients with previously treated, advanced SBA, regardless of MMR/MSI status.$^{143}$ While pembrolizumab did not achieve the goal ORR for this study, 50% of patients with MSI-H tumors (n=4) had a partial response to therapy and remained alive without progression at the time of data collection. One patient with MSS disease showed a partial response while a second patient achieved an unconfirmed partial response, both of whom were TMB-H. The disease

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

control rate was 38%. On this study, 63% of patients had grade ≥3 AEs and 28% had AEs of grade 4 or 5.

Another PD-1 inhibitor, nivolumab—alone or in combination with the CTLA-4 inhibitor, ipilimumab—has been studied in patients with dMMR metastatic CRC in the phase II, multi-cohort CheckMate-142 trial.$^{144,145}$ One cohort of this trial included 74 patients with dMMR CRC who were treated with nivolumab. ORR for these patients was 31.1% (95% CI, 20.8-42.9), with 69% of patients having disease control for at least 12 weeks.

Median duration of response had not yet been reached at the time of data collection. PFS and OS were 50% and 73%, respectively, at 1 year. Grade 3 or 4 drug-related AEs occurred in 20% of patients, with increased amylase and increased lipase being the most common.$^{144}$ Another cohort of the CheckMate-142 trial included 119 patients with dMMR CRC who were treated with nivolumab in combination with ipilimumab. For this cohort, ORR was 55% (95% CI, 45.2–63.8) and the disease control rate for at least 12 weeks was 80%. PFS and OS were 71% and 85%, respectively, at 1 year. In addition, significant, clinically meaningful improvements were observed in patient-reported outcomes of functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related AEs occurred in 32% of patients, but were manageable.$^{145}$ The phase II DART SWOG S1609 trial, which tested nivolumab plus ipilimumab in rare tumors, has published an abstract reporting results for a cohort of patients with small bowel cancer (n = 25).$^{146}$ For the 23 patients who received treatment on this cohort, ORR was 8% (with 1 complete and 1 partial response).

tumors was evaluated in the KM-06 open-label, multicenter, single-arm, phase II trial for tumors harboring genetic alterations in DNA damage response and repair (DDR) genes leading to MSI and TMB-H. The trial consisted of 48 patients mostly with colorectal cancer (41.7%) and with an MSI score of >2.5 in addition to a TMB of >12 mutations/Mb.$^{147}$ Partial

response was achieved by 8 patients resulting in a 17.8% ORR, median progression-free survival was 2.9 months, and a disease control rate of 60%; however, most patients (91.7%) experienced a treatment related adverse event of ≥3.$^{147}$ It is important to note that nivolumab monotherapy is not currently recommended in MSS/TMB-H setting.

A third humanized IgG4 PD-1 blocking antibody, dostarlimab-gxly, has been FDA-approved for the treatment of adult patients with dMMR recurrent or advanced solid tumors that have progressed on or following treatment and who have no satisfactory alternative treatment options.$^{148}$ The safety and efficacy of dostarlimab-gxly was evaluated in the ongoing phase I GARNET study of patients with advanced solid tumors who had previously received systemic therapy for advanced disease.$^{149,150}$ In the entire efficacy population for patients with dMMR and MSI-H or POLE mutated tumors (n = 327). Of 327 patients, 23 had small-intestinal solid tumors, of which 21.7% (n = 5) achieved a complete response; 17.4% (n = 4) achieved a partial response; the ORR for these patients was 39.1% (95% CI, 19.7–61.5); mDOR was not reached; mPFS was 8.1 months (95% CI, 2.5–16.5); and mOS was 31.6 months (95% CI, 8.2–not reached).$^{149,150}$ The most common immune-related adverse events were hypothyroidism (6.9%), increase in alanine aminotransferase (5.8%), and arthralgia (4.7%). Additionally, the GARNET trial contained 11 patients with POLE mutated advanced tumors and dostarlimab monotherapy showed promising anti-tumor activity within this small population; ORR of 54.5% and a PFS of ≥ 1 year.$^{149,150}$

Extrapolating from positive data on first-line use of checkpoint inhibitors in CRC, pembrolizumab monotherapy and nivolumab combination therapy, with or without ipilimumab, are also initial therapy options for dMMR/MSI-H disease or POLE/POLD1 mutation with ultra-hypermutated phenotype. $^{151}$,$^{152}$ Data suggests that POLE/POLD1 short variant mutations are associated with an ultra-hypermutated phenotype, and this patient

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

population has a significant benefit with checkpoint inhibitors. 152-154 Moreover, certain SBA patients could also benefit from ICI treatment as emerging data has resulted in a higher incidence of dMR/MSI-H and higher rates of PD-L1 IHC positivity compared to CRC.34,35,120 Additionally, in 2017 a prospective analysis was performed to compare genomic profiles of SBA (n = 317) to CRC (n = 6353) and gastric carcinomas (GC) (n = 889), data from this analysis resulted in a POLE mutation incidence rate of 0.3% in both SBA and CRC.35 The same incidence rates of POLE mutation for both SBA and CRC further support the use of similar treatment options for both patient populations in this setting. Based on these positive results for CRC, and the data showing benefit of pembrolizumab in SBA, the NCCN Panel recommends pembrolizumab; nivolumab, with or without ipilimumab; or dostarlimab-gxly as subsequent-line treatment options for dMMR/MSI-H or POLE/POLD1 mutation positive advanced SBA.

Pembrolizumab for Tumor Mutational Burden (TMB)-High (>10 mut/Mb)

Pembrolizumab has also been FDA-approved as a treatment for unresectable or metastatic, TMB-H solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.$^{141}$ TMB-H is defined in the label as ≥10 mutations/megabase by an FDA-approved test. Multiple studies have demonstrated TMB-H in approximately 9% to 11% of SBA solid tumors samples, which was significantly higher than CRC (4.3%) suggesting treatment implications with checkpoint inhibitors in the SBA population.$^{35,155}$ The approval of pembrolizumab was based off results of the phase 2, KEYNOTE-158 study that enrolled patients with advanced solid tumors.$^{156}$ Patients with TMB-H tumors who were treated with pembrolizumab had an ORR of 29% compared to 6% of those with non-TMB-H tumors. However, of the 796 patients who were evaluated for efficacy in this study, none had small bowel or colorectal cancers. Additionally, the ZEBRA study had one

patient achieve a PR with low MSS and a high TMB.$^{143}$ The phase II TAPUR basket study reported results for 27 patients with TMB-H advanced CRC who were treated with pembrolizumab.$^{157}$ One partial response and seven cases with stable disease for at least 16 weeks were reported, for a disease control rate of 28% and an ORR of 4%. A retrospective, single-center study that included three patients with TMB-H small intestine or duodenal cancer reported that only one of these three cases demonstrated a partial response to pembrolizumab.$^{158}$

Furthermore, in 2017 a prospective analysis performed by Schrock et al. compared genomic profiles of SBA (n = 317) to CRC (n = 6353) and gastric carcinomas (GC) (n = 889). Of the entire cohort, 9.5% (n = 30) of SBA samples had a TMB of >20 mutations/Mb compared to 4.3% (n = 276) of CRC samples (P = .001) and 5.6% (n = 50) of GC samples (P = .03). Although, MSS was not specified in the TMB-H population; of the entire cohort, 49% (n = 156) of SBA samples were MSS.$^{35}$ Based on emerging data for SBA, the NCCN Panel believes TMB biomarker testing should be considered for all patients with metastatic disease.

Pembrolizumab monotherapy is an NCCN category 2B recommended treatment option for patients with TMB-H (>10 mut/Mb) advanced SBA solid tumors.

Dabrafenib plus Trametinib (for BRAF V600E-positive tumors)

Treatment combination of dabrafenib plus trametinib blocks MAPK pathway signaling while inhibiting growth and survival of BRAF-V600E mutated cells, in addition to enforcing anti-tumor activity.$^{159}$ Data suggests the prevalence of BRAF V600E mutated solid tumors in SBA is consistent with that of mCRC and is detected in 5% to 10% of patients.$^{160}$ A prospective analysis by Schrock et al. reported BRAF mutation in 9.1% (n = 29 of 317) and of those 29 patients 10.3% (n = 3 of 29) were BRAF V600E mutation positive.$^{35}$

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

Additionally, in the phase II basket trial, ROAR, safety and efficacy of dabrafenib in combination with trametinib was analyzed in 8 cohorts of patients with a BRAF V600E mutation and an advanced rare cancer.$^{159}$ Out of the 8 cohorts within the trial, 3 patients had adenocarcinoma of the small intestine.$^{159}$ The primary endpoint of the ROAR trial was investigator-assessed overall response rate (ORR) supported by independent radiology assessment that resulted in an ORR of 67% in the small intestine cohort.$^{159}$ The secondary endpoint assessed median duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The median DoR in the small intestine cohort was 7.7 months while median PFS was not evaluable, and OS was 21.8 months.$^{159}$

Additionally, adverse events (AEs) related to the study treatment of either dabrafenib or trametinib were reported in 87.9% (n = 181) across all 8 cohorts. Commonly reported AEs were pyrexia (n = 84; 40.8%), fatigue (n = 53; 25.7%), chills (n = 52; 25.7%), nauesa (n = 49; 23.8%) and rash (n = 42; 20.4%). Serious AEs possibly linked to the study treatment were observed in 46 patients (22.3%) and fatal SAEs were reported in 9 patients (4.4%).$^{159}$

The data represented in the ROAR trial supported the FDA approval of dabrafenib (BRAF kinase inhibitor) in combination with trametinib (MEK inhibitor) for unresectable or metastatic solid tumors with BRAF V600E mutations for patients whose disease has progressed following prior treatment and have no satisfactory alternative treatment options.$^{161}$ The NCCN Panel recommends these therapies as options for subsequent-line treatment of advanced or metastatic SBA that is BRAF V600E mutation positive.

Fam-trastuzumab Deruxtecan-nxki [HER2 amplified (IHC 3+)]

The safety and efficacy of fam-trastuzumab deruxtecan-nxki was evaluated in the multicenter studies, DESTINY-PanTumor02 and

DESTINY-CRC02, for HER2 amplified solid tumors with confirmed immunohistochemistry (IHC) of (3+/2+).$^{162}$⁻$^{164}$ Patient enrollment criteria included previously treated locally advanced or metastatic disease and/or no available alternative treatment options. In the DESTINY-PanTumor02 trial, 267 patients received treatment with trastuzumab deruxtecan (5.4 mg/kg once every 3 weeks) across 7 cohorts of solid tumors, including 1 patient in the rare solid tumor cohort with intestinal adenocarcinoma. The objective response rate (ORR) in all patients was 37.1% (n = 99; [95% CI, 31.3 to 43.2]); median DOR was 11.3 months (95% CI, 9.6–17.8); median PFS was 6.9 months (95% CI, 5.6–8.0); and the median OS was 13.4 months (95% CI, 11.9–15.5).$^{162}$ In comparison, patients with HER2 amplified IHC 3+ expressed tumors (n = 75) had an ORR of 61.3% (95% CI, 49.4–72.4); a median DOR of 22.1 months (95% CI, 9.6–not reached), a median PFS of 11.9 months (95% CI, 8.2–13.0), and a median OS of 21.1 months (95% CI, 15.3–29.6). The highest response rates and longest DOR, PFS, and OS; regardless of prior treatment, were observed in those with HER2 IHC 3+ expression profiles.$^{162}$

Investigator-assessed drug-related adverse events were observed in 84.6% (n = 226) patients, most commonly, nausea (55.1%) anemia (27.7%), diarrhea (25.8%), vomiting (24.7%), and fatigue (24.7%). Drug-related AEs grade ≥3 were observed in 40.8% (n = 109) with the most common being neutropenia and anemia. AEs leading to discontinuation of treatment occurred in 8.6% (n = 23) and dose reduction in 20.2% (n = 54). There were four deaths and ILD/pneumonitis was observed in 20.5% (n = 28) of patients.$^{162}$

In the DESTINY-CRC02 trial, the safety and efficacy of trastuzumab deruxtecan was evaluated at (5.4 and 6.4 mg/kg every 3 weeks) in patients with HER2+ mCRC IHC 3+ or IHC 2+/in situ hybridization (ISH+). Most patients had an IHC 3+ in the 5.4 mg/kg and the 6.4 mg/kg arms (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and an average

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

of 3-4 prior lines of therapy, respectively.$^{164}$ Confirmed objective response rate (cORR) was 37.8% (95% CI, 27.3–49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6–43.9%) in the 6.4 mg/kg arm.$^{164}$

Based on these data the NCCN Panel recommends fam-trastuzumab deruxtecan-nxki as a treatment option for locally advanced or metastatic small bowel adenocarcinoma for HER2 IHC (3+) solid tumors in previously treated patients and/or those with no available alternative treatment options.

Taxane-Based Chemotherapy

While almost all of the phase II trials of systemic therapy for SBA have focused on first-line therapy, a phase II trial including 13 patients with SBA studied the efficacy of nab-paclitaxel in the refractory disease setting.$^{165}$ Patients with SBA in this trial had received a median of 2 prior lines of therapy including a fluoropyrimidine and oxaliplatin. Of the 10 patients with SBA who were evaluable for efficacy, 2 showed a partial response to nab-paclitaxel and an additional 3 had stable disease per RECIST criteria, yielding a disease control rate of 50%. Common grade 3 or 4 toxicities across the entire study population included fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%).$^{165}$

A single-center, retrospective review reported on 20 patients with advanced SBA who were treated with taxane-based therapy (either as single therapy or in combination).$^{166}$ Of these cases, 30% showed disease response, 35% showed stable disease, and 35% showed progression. Median time to progression was 3.8 months (95% CI, 2.9–4.6) and median OS was 10.7 months (95% CI, 3.1–18.3). Based on these data, taxane-based chemotherapy is a recommended option for second- or subsequent-line therapy, although only nab-paclitaxel has prospective, published data to support its use for treatment of SBA.

FOLFIRI

A retrospective, multicenter study evaluated the efficacy of FOLFIRI as second-line therapy for patients with advanced SBA who had received platinum-based chemotherapy in the first-line setting.$^{167}$ Of the 28 patients who fit this treatment paradigm, the ORR was 20% and disease control rate was 52%. The median PFS and OS were 3.2 and 10.5 months. Grade 3-4 toxicity was reported in 48% of patients. Based on these data, FOLFIRI is recommended as a treatment option for second- or subsequent-line treatment of advanced SBA. While FOLFIRI has not been studied as first-line treatment for advanced SBA, it may be a reasonable first-line option for some patients based on extrapolation of studies in CRC and the regimen's differing toxicity profile compared to oxaliplatin-containing regimens.

Larotrectinib, Entrectinib, or Repotrectinib (for NTRK gene fusion-positive tumors)

A pooled analysis of 3 studies (a phase 1 including adults, a phase 1/2 involving children, and a phase 2 involving adolescents and adults) studied the safety and efficacy of larrotectinib in patients with NTRK gene fusion-positive tumors, including 4 patients with colon cancer and 1 with cancer of the appendix.$^{168}$ For the whole population, the ORR was 75% (95% CI, 61%–85%) by independent review and 80% (95% CI, 67%–90%) by investigator assessment. Larrotectinib was found to be well-tolerated as the majority (93%) of AEs were grades 1 or 2 and no treatment-related AEs of grades 3 or 4 occurred in >5% of patients.$^{168}$

An integrated analysis of three global phase I/II studies (ALKA-372-001, STARTRK-1, and STARTRK-2) tested the efficacy and safety of entrectinib in 54 adult patients with advanced or metastatic NTRK gene fusion-positive solid tumors.$^{169}$ For the whole population, ORR was 57% (95% CI, 43.2%–70.8%), median PFS was 11 months (95% CI, 8.0–14.9), and median OS was 21 months (95% CI, 14.9–not estimable) by independent review. Median duration of response was 10 months (95%

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

CI, 7.1-not estimable). Of the four patients with CRC on this study, one was recorded as having a response. Notably, a similar ORR (50% vs. 60%) was observed among those with central nervous system metastasis, indicating that entrectinib has activity in this population. Entrectinib was found to be well-tolerated as most treatment-related AEs were grade 1 or 2 and managed with dose reduction, leading few (4%) patients to discontinue therapy due to treatment-related AEs.

The phase I/II TRIDENT-1 trial tested repotrectinib in two cohorts of patients with NTRK gene fusion-positive advanced solid tumors; 40 patients in the NTRK TKI-naïve cohort, who received repotrectinib as their first NTRK TKI treatment, and 48 patients in the NTRK TKI-pretreated cohort, who had already received larotrectinib or entretinib.$^{170}$ One patient on the NTRK TKI-naïve cohort had CRC and two had CRC in the NTRK TKI-pretreated cohort. An abstract presented at ESMO Congress 2023 reported a confirmed ORR of 58%, 12-month DOR of 86%, and 12-month PFS of 56% for the TKI-naïve group and a confirmed ORR of 50%, 12-month DOR of 39%, and 12-month PFS of 22% for the TKI-pretreated population. Grade ≥3 treatment-emergent AEs occurred in 51% of patients (29% were treatment-related), with dizziness being most common. Treatment discontinuation due to AEs occurred in 7% of patients. Although there were no SBA patients in the TRIDENT trial, treatment implications are based on the data extrapolated from the patients with CRC. Based on these data, the FDA has approved larotrectinib, entrectinib, and repotrectinib for metastatic solid tumors with NTRK gene fusion and no satisfactory alternative treatment,$^{105}$ and the NCCN Panel recommends these therapies as options for subsequent-line treatment of metastatic SBA that is NTRK gene fusion positive.

Selpercatinib (for RET gene fusion-positive tumors)

In the ongoing phase 1/2 LIBRETTO-001 trial, the efficacy and safety of the highly selective RET kinase inhibitor selpercatinib is being investigated

in a diverse group of patients with RET gene fusion-positive tumors, including 10 patients with colon cancer and 1 patient with small bowel cancer.$^{171}$ Patients in this trial had received a median of 2 prior lines of systemic therapy and 31% of patients received 3 or more prior lines of treatment. Of a total of 41 efficacy-evaluable patients, the ORR by independent review was 43.9% (95% CI, 28.5%–60.3%). There were 2 complete responses (5%), including the one patient with small bowel cancer involved in the study. By independent review, the median duration of response for the patient with small bowel cancer was 24.5 months. For the entire cohort, median PFS was 13.2 months (95% CI, 7.4–26.2) by independent review, median OS was 18 months (95% CI, 10.7–not evaluable), and median duration of response was 24.5 months (95% CI, 9.2–not evaluable). The most common grade 3 or higher treatment emergent AEs were hypertension and transaminitis. The most common treatment-related serious AEs were drug-induced livery injury, fatigue, and hypersensitivity. One patient had to permanently discontinue selpercatinib due to drug-induced liver injury.

Based on these data, the FDA has approved selpercatinib for locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.$^{172}$

Posttreatment Surveillance

After curative-intent surgery and adjuvant chemotherapy, if administered, post-treatment surveillance of patients with SBA is performed to evaluate for possible therapeutic complications, identify disease recurrence, and discover new metachronous neoplasms at a preinvasive stage. A retrospective study of 146 patients with SBA who underwent cancer-directed surgery found that 39% subsequently developed disease recurrence, with a median time to recurrence of 25 months. Of the patients with disease recurrence, 57% developed distant metastases, 19%

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

developed carcinomatosis, 7% recurred in the abdominal wall, and 17% developed local recurrences.$^{36}$ Due to the lack of data regarding optimal surveillance following curative-intent treatment of SBA, a similar approach to CRC surveillance is recommended—including history and physical examination; CEA and/or CA 19-9 measurement; and CT of the chest, abdomen, and pelvis. For data supporting the recommended surveillance approach for CRC, see the Posttreatment Surveillance section in the NCCN Guidelines for Colon Cancer.

Patients with SBA who were determined to have Crohn's disease or familial syndromes (ie, Lynch syndrome, FAP, PJS) may require more intensive surveillance due to their elevated risk of developing further SBAs.$^{12,13}$ Endoscopy may be a feasible method for SBA surveillance in patients with Crohn's disease,$^{13,173}$ although one prospective study found a low (33%) sensitivity rate for SBA endoscopic screening.$^{174}$ A number of studies have supported the use of endoscopy/enteroscopy for small bowel surveillance in patients with Lynch syndrome, FAP, or PJS.$^{175-182}$ For further details on endoscopic small bowel evaluation, see the section on Imaging and Endoscopy under Clinical Presentation and Workup, above.

Survivorship

Based on the rarity and poor prognosis of SBA, there is a dearth of data regarding survivorship for this disease. The Panel recommendations for survivorship are largely extrapolated from the NCCN Guidelines for Colon Cancer, with some specific recommendations included for patients with celiac or Crohn's disease who are at elevated risk of developing additional SBAs.$^{12,13,183}$ This section will provide an overview of the Panel recommendations for survivorship; for more detailed information, see the Survivorship section in the NCCN Guidelines for Colon Cancer.

The Panel recommends that a prescription for survivorship and transfer of care to the primary care physician be written.$^{184}$ The oncologist and

primary care provider should have defined roles in the surveillance period, with roles communicated to the patient. Other recommendations include monitoring for late or long-term sequelae of treatment, such as oxaliplatin-induced peripheral neuropathy, fatigue, pain, sexual dysfunction, and emotional or social distress.$^{185-189}$ Specific management interventions to address these and other side effects are described in a review.$^{190}$ Disease preventive measures, such as immunizations; early disease detection through periodic screening for second primary cancers (eg, breast, cervical, or prostate cancers); and routine good medical care and monitoring are recommended. The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common consequences of cancer and cancer treatment to aid health care professionals who work with survivors of adult-onset cancer in the post-treatment period, including those in specialty cancer survivor clinics and primary care practices.

Summary

SBA is a rare malignancy, with a rising incidence in recent decades. Compared to CRC, SBA is more often diagnosed at advanced stages, suggesting the difficulty of detecting these cancers and highlighting the lack of screening programs, even for high-risk individuals. The majority of SBAs arise in the duodenum and are associated with poorer prognosis, with up to a third of resectable patients experiencing early relapse. To date, the only curative therapy for SBA is surgery.

For local disease, segmental resection of the small bowel is the mainstay of treatment, though duodenal tumors may require either pancreaticoduodenectomy or segmental duodenal resection. Database analyses have reported significantly improved outcomes when 8 or more lymph nodes are resected. In addition, the use of radiation therapy for retroperitoneal-based duodenal adenocarcinomas is a complex decision-making process. Fluoropyrimidine-based adjuvant therapy may be

considered for some patients with SBA, though no studies have yet shown a definitive benefit of this approach. Results from the international, phase III adjuvant clinical study (BALLAD) investigating observation versus 5-FU versus FOLFOX for patients with resected stage I–III SBA should shed light on this approach in the coming years.

Metastatic SBA may rarely be treated with curative intent via primary

tumor resection and metastasectomy; however, most patients with

metastatic SBA are treated with systemic therapy. Systemic therapy

options include fluoropyrimidine-based chemotherapy, taxane-based

chemotherapy, or checkpoint inhibitors. Recently, SBA’s unique genetic profile has been a topic of research, which may lead to new targeted or immunotherapeutic treatment options for SBA.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. Available at:

2. Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015, based on November 2017 SEER data submission, posted to the SEER web site, April 2018. Bethesda, MD: National Cancer Institute; 2018. Available at: https://seer.cancer.gov/csr/1975_2015/.

3. Li J, Saif MW. Small Bowel Adenocarcinoma. In: Saif MW, ed. Gastrointestinal Malignancies. New York, NY: Demos Medical Publishing, LLC; 2010:171-176.

4. Bilimoria KY, Bentrem DJ, Wayne JD, et al. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 2009;249:63-71. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19106677.

5. Locher C, Batumona B, Afchain P, et al. Small bowel adenocarcinoma: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO). Dig Liver Dis 2018;50:15-19. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29174568.

6. Amin MB, Edge SB, Greene F, et al., eds. AJCC Cancer Staging Manual, 8th ed. New York: Springer International Publishing; 2017.

7. PubMed Overview. Available at: https://pubmed.ncbi.nlm.nih.gov/about/. Accessed February 4, 2022.

8. Freedman-Cass DA, Fischer T, Alpert AB, et al. The Value and Process of Inclusion: Using Sensitive, Respectful, and Inclusive Language and Images in NCCN Content. J Natl Compr Canc Netw 2023;21:434-441. Available at:

9. Bennett CM, Coleman HG, Veal PG, et al. Lifestyle factors and small intestine adenocarcinoma risk: A systematic review and meta-analysis. Cancer Epidemiol 2015;39:265-273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25736860.

10. Boffetta P, Hazelton WD, Chen Y, et al. Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine--a pooled analysis of over 500,000 subjects in the Asia Cohort Consortium. Ann Oncol 2012;23:1894-1898. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22147734.

11. Algaba A, Guerra I, Marin-Jimenez I, et al. Incidence, management, and course of cancer in patients with inflammatory bowel disease. J Crohns Colitis 2015;9:326-333. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25687203.

12. Cahill C, Gordon PH, Petrucci A, Boutros M. Small bowel adenocarcinoma and Crohn's disease: any further ahead than 50 years ago? World J Gastroenterol 2014;20:11486-11495. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25206256.

13. Grolleau C, Pote NM, Guedj NS, et al. Small bowel adenocarcinoma complicating Crohn's disease: a single-centre experience emphasizing the importance of screening for dysplasia. Virchows Arch 2017;471:611-617. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28421339.

14. Laukoetter MG, Mennigen R, Hannig CM, et al. Intestinal cancer risk in Crohn's disease: a meta-analysis. J Gastrointest Surg 2011;15:576-583. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21152994.

15. Aparicio T, Henriques J, Manfredi S, et al. Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients. Int J Cancer 2020;147:967-977. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31912484.

16. Uchino M, Ikeuchi H, Hata K, et al. Intestinal cancer in patients with Crohn's disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2021;36:329-336. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32865278.

17. Emilsson L, Semrad C, Lebwohl B, et al. Risk of Small Bowel Adenocarcinoma, Adenomas, and Carcinoids in a Nationwide Cohort of Individuals With Celiac Disease. Gastroenterology 2020;159:1686-1694.e1682. Available at: https://doi.org/10.1053/j.gastro.2020.07.007.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

18. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol 2006;101:385-398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16454848.

19. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis 2009;4:22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19822006.

20. Shenoy S. Genetic risks and familial associations of small bowel carcinoma. World J Gastrointest Oncol 2016;8:509-519. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27326320.

21. Tomlinson IP, Houlston RS. Peutz-Jeghers syndrome. J Med Genet 1997;34:1007-1011. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9429144.

22. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998;391:184-187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9428765.

23. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998;18:38-43. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9425897.

24. Lim W, Hearle N, Shah B, et al. Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 2003;89:308-313. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12865922.

25. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:1447-1453. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11113065.

26. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 2006;12:3209-3215. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16707622.

27. Koornstra JJ, Kleibeuker JH, Vasen HF. Small-bowel cancer in Lynch syndrome: is it time for surveillance? Lancet Oncol 2008;9:901-905. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18760246.

28. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020-1027. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8612988.

29. Hendriks YM, de Jong AE, Morreau H, et al. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin 2006;56:213-225. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16870997.

30. Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 2012;30:1058-1063. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22355048.

31. Burt RW. Who should have genetic testing for the Lynch syndrome? Ann Intern Med 2011;155:127-128. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21768586.

32. Matloff J, Lucas A, Polydorides AD, Itzkowitz SH. Molecular tumor testing for Lynch syndrome in patients with colorectal cancer. J Natl Compr Canc Netw 2013;11:1380-1385. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24225971.

33. Ward RL, Hicks S, Hawkins NJ. Population-based molecular screening for Lynch syndrome: implications for personalized medicine. J Clin Oncol 2013;31:2554-2562. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23733757.

34. Aparicio T, Svrcek M, Zaanan A, et al. Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study. Br J Cancer 2013;109:3057-3066. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24196786.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

35. Schrock AB, Devoe CE, McWilliams R, et al. Genomic Profiling of Small-Bowel Adenocarcinoma. JAMA Oncol 2017;3:1546-1553. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28617917.

36. Dabaja BS, Suki D, Pro B, et al. Adenocarcinoma of the small bowel: presentation, prognostic factors, and outcome of 217 patients. Cancer 2004:nt01:518-526. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15274064.

37. Halfdanarson TR, McWilliams RR, Donohue JH, Quevedo JF. A single-institution experience with 491 cases of small bowel adenocarcinoma. Am J Surg 2010;199:797-803. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20609724.

38. Howe JR, Karnell LH, Menck HR, Scott-Conner C. The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel review of the National Cancer Data Base, 1985-1995. Cancer 1999;86:2693-2706. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10594865.

39. Akce M, Jiang R, Zakka K, et al. Clinical Outcomes of Small Bowel Adenocarcinoma. Clin Colorectal Cancer 2019;18:257-268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606297.

40. Overman MJ, Hu CY, Kopetz S, et al. A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease. Ann Surg Oncol 2012;19:1439-1445. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22187121.

41. Negoi I, Paun S, Hostiuc S, et al. Most small bowel cancers are revealed by a complication. Einstein (Sao Paulo) 2015;13:500-505. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26676271.

42. Gustafsson BI, Siddique L, Chan A, et al. Uncommon cancers of the small intestine, appendix and colon: an analysis of SEER 1973-2004, and current diagnosis and therapy. Int J Oncol 2008;33:1121-1131. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19020744.

43. Hara AK, Leighton JA, Sharma VK, et al. Imaging of small bowel disease: comparison of capsule endoscopy, standard endoscopy, barium examination, and CT. Radiographics 2005;25:697-711; discussion 711-698. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15888619.

44. Nylund K, Odegaard S, Hausken T, et al. Sonography of the small intestine. World J Gastroenterol 2009;15:1319-1330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19294761.

45. Chen WG, Shan GD, Zhang H, et al. Double-balloon enteroscopy in small bowel diseases: Eight years single-center experience in China. Medicine (Baltimore) 2016;95:e5104. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27759639.

46. Cazzato IA, Cammarota G, Nista EC, et al. Diagnostic and therapeutic impact of double-balloon enteroscopy (DBE) in a series of 100 patients with suspected small bowel diseases. Dig Liver Dis 2007;39:483-487. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17379586.

47. Mitsui K, Tanaka S, Yamamoto H, et al. Role of double-balloon endoscopy in the diagnosis of small-bowel tumors: the first Japanese multicenter study. Gastrointest Endosc 2009;70:498-504. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19555947.

48. Sunada K, Yamamoto H, Kita H, et al. Clinical outcomes of enteroscopy using the double-balloon method for strictures of the small intestine. World J Gastroenterol 2005;11:1087-1089. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15742422.

49. Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield of small bowel tumors with capsule endoscopy. Cancer 2006;107:22-27. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16736516.

50. Bailey AA, Debinski HS, Appleyard MN, et al. Diagnosis and outcome of small bowel tumors found by capsule endoscopy: a three-center Australian experience. Am J Gastroenterol 2006;101:2237-2243. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17032187.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

51. Cheung DY, Lee IS, Chang DK, et al. Capsule endoscopy in small bowel tumors: a multicenter Korean study. J Gastroenterol Hepatol 2010;25:1079-1086. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20594222.

52. Boudiaf M, Jaff A, Soyer P, et al. Small-bowel diseases: prospective evaluation of multi-detector row helical CT enteroclysis in 107 consecutive patients. Radiology 2004;233:338-344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15459329.

53. Soyer P, Aout M, Hoeffel C, et al. Helical CT-enteroclysis in the detection of small-bowel tumours: a meta-analysis. Eur Radiol 2013:23:388-399. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22865269.

54. Cronin CG, Lohan DG, Browne AM, et al. Magnetic resonance enterography in the evaluation of the small bowel. Semin Roentgenol 2009;44:237-243. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19715789.

55. Masselli G, Casciani E, Polettini E, et al. Magnetic resonance imaging of small bowel neoplasms. Cancer Imaging 2013;13:92-99. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23524074.

56. Masselli G, Di Tola M, Casciani E, et al. Diagnosis of Small-Bowel Diseases: Prospective Comparison of Multi-Detector Row CT Enterography with MR Enterography. Radiology 2016;279:420-431. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26599801.

57. Cronin CG, Scott J, Kambadakone A, et al. Utility of positron emission tomography/CT in the evaluation of small bowel pathology. Br J Radiol 2012;85:1211-1221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22919004.

58. Sakae H, Kanzaki H, Nasu J, et al. The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study. Br J Cancer 2017;117:1607-1613. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28982111.

59. Young JI, Mongoue-Tchokote S, Wieghard N, et al. Treatment and Survival of Small-bowel Adenocarcinoma in the United States: A Comparison With Colon Cancer. Dis Colon Rectum 2016;59:306-315. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26953989.

60. Overman MJ, Hu CY, Wolff RA, Chang GJ. Prognostic value of lymph node evaluation in small bowel adenocarcinoma: analysis of the surveillance, epidemiology, and end results database. Cancer 2010;116:5374-5382. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20715162.

61. Tran TB, Qadan M, Dua MM, et al. Prognostic relevance of lymph node ratio and total lymph node count for small bowel adenocarcinoma. Surgery 2015;158:486-493. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26013988.

62. Wilhelm A, Muller SA, Steffen T, et al. Patients with Adenocarcinoma of the Small Intestine with 9 or More Regional Lymph Nodes Retrieved Have a Higher Rate of Positive Lymph Nodes and Improved Survival. J Gastrointest Surg 2016;20:401-410. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26487334.

63. Wu S, Chen JN, Zhang QW, et al. A New Metastatic Lymph Node Classification-based Survival Predicting Model in Patients With Small Bowel Adenocarcinoma: A Derivation and Validation Study. EBioMedicine 2018;32:134-141. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29908920.

64. Zhang S, Yuan W, Zhang J, et al. Clinicopathological features, surgical treatments, and survival outcomes of patients with small bowel adenocarcinoma. Medicine (Baltimore) 2017;96:e7713. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28767610.

65. Hashimoto D, Arima K, Chikamoto A, et al. Limited Resection of the Duodenum for Nonampullary Duodenal Tumors, with Review of the Literature. Am Surg 2016;82:1126-1132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28206943.

NCCN

National Comprehensive Cancer Small Bowel Adenocarcinoma NCCN

66. Onkendi EO, Boostrom SY, Sarr MG, et al. 15-year experience with surgical treatment of duodenal carcinoma: a comparison of periampullary and extra-ampillary duodenal carcinomas. J Gastrointest Surg 2012;16:682-691. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22350721.

67. Meijer LL, Alberga AJ, de Bakker JK, et al. Outcomes and Treatment Options for Duodenal Adenocarcinoma: A Systematic Review and Meta-Analysis. Ann Surg Oncol 2018;25:2681-2692. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29946997.

68. Cloyd JM, Norton JA, Visser BC, Poultsides GA. Does the extent of resection impact survival for duodenal adenocarcinoma? Analysis of 1,611 cases. Ann Surg Oncol 2015;22:573-580. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25160736.

69. Burasakarn P, Higuchi R, Nunobe S, et al. Limited resection vs. pancreaticoduodenectomy for primary duodenal adenocarcinoma: a systematic review and meta-analysis. Int J Clin Oncol 2021;26:450-460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33386555.

70. Raghav K, Overman MJ. Small bowel adenocarcinomas--existing evidence and evolving paradigms. Nat Rev Clin Oncol 2013;10:534-544. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23897080.

71. U.S. National Library of Medicine. Phase III Trial Investigating the Potential Benefit of Adjvant Chemotherapy for Small Bowel Adenocarcinoma (BALLAD). ClinicalTrials.gov: 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT02502370. Accessed February 14, 2022.

72. Evans TRJ, Aparicio T, Le Malicot K, et al. GLOBAL BALLAD: An International Rare Cancers Initiative trial to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma (IRCI 002) [abstract]. Journal of Clinical Oncology 2016;34:TPS4154-TPS4154. Available at: http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.TPS4154.

73. Ecker BL, McMillan MT, Datta J, et al. Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: A propensity score-matched analysis. Cancer 2016;122:693-701. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26717303.

74. Swartz MJ, Hughes MA, Frassica DA, et al. Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum. Arch Surg 2007;142:285-288. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17372054.

75. Kelsey CR, Nelson JW, Willett CG, et al. Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;69:1436-1441. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17689032.

76. Aydin D, Sendur MA, Kefeli U, et al. Evaluation of Prognostic Factors and Adjuvant Chemotherapy in Patients With Small Bowel Adenocarcinoma Who Underwent Curative Resection. Clin Colorectal Cancer 2017;16:220-227. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27670893.

77. Ye X, Zhang G, Chen H, Li Y. Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma. PLoS One 2018;13:e0200204. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30096150.

78. Kim K, Chie EK, Jang JY, et al. Role of adjuvant chemoradiotherapy for duodenal cancer: a single center experience. Am J Clin Oncol 2012;35:533-536. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21659832.

79. Overman MJ, Kopetz S, Lin E, et al. Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine. Acta Oncol 2010;49:474-479. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20397775.

80. Andre T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

3 trials. Lancet Oncol 2020;21:1620-1629. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33271092.

81. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 2018;378:1177-1188. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29590544.

82. Iveson TJ, Sobrero AF, Yoshino T, et al. Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer. J Clin Oncol 2021;39:631-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33439695.

83. Ecker BL, McMillan MT, Datta J, et al. Adjuvant chemotherapy versus chemoradiotherapy in the management of patients with surgically resected duodenal adenocarcinoma: A propensity score-matched analysis of a nationwide clinical oncology database. Cancer 2017;123:967-976. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28263387.

84. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009;361:2449-2460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20018966.

85. Kim GP, Colangelo LH, Wieand HS, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 2007;25:767-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17228023.

86. Klingbiel D, Saridaki Z, Roth AD, et al. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol 2015;26:126-132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25361982.

87. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-257. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12867608.

88. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010;28:3219-3226. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20498393.

89. Kim JE, Hong YS, Kim HJ, et al. Defective Mismatch Repair Status was not Associated with DFS and OS in Stage II Colon Cancer Treated with Adjuvant Chemotherapy. Ann Surg Oncol 2015;22 Suppl 3:S630-637. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26271397.

90. Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011;29:1261-1270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21383284.

91. Bertagnolli MM, Redston M, Compton CC, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer—a study of CALGB 9581 and 89803. J Clin Oncol 2011;29:3153-3162. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21747089.

92. Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:979-994. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10888773.

93. Fujita S, Shimoda T, Yoshimura K, et al. Prospective evaluation of prognostic factors in patients with colorectal cancer undergoing curative resection. J Surg Oncol 2003;84:127-131. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14598355.

94. Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 2009;27:5131-5137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19738119.

95. Onkendi EO, Boostrom SY, Sarr MG, et al. Neoadjuvant treatment of duodenal adenocarcinoma: a rescue strategy. J Gastrointest Surg 2012;16:320-324. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21956430.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

96. Yeung RS, Weese JL, Hoffman JP, et al. Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A Phase II Study. Cancer 1993;72:2124-2133. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8374871.

97. Coia L, Hoffman J, Scher R, et al. Preoperative chemoradiation for adenocarcinoma of the pancreas and duodenum. Int J Radiat Oncol Biol Phys 1994;30:161-167. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8083109.

98. Minardi AJ, Jr., Zibari GB, Aultman DF, et al. Small-bowel tumors. J Am Coll Surg 1998;186:664-668. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9632155.

99. Ciresi DL, Scholten DJ. The continuing clinical dilemma of primary tumors of the small intestine. Am Surg 1995;61:698-702; discussion 702-693. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7618809.

100. Ojha A, Zacherl J, Scheuba C, et al. Primary small bowel malignancies: single-center results of three decades. J Clin Gastroenterol 2000;30:289-293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10777190.

101. Oh SY, Edwards A, Mandelson M, et al. Survival and clinical outcome after endoscopic duodenal stent placement for malignant gastric outlet obstruction: comparison of pancreatic cancer and nonpancreatic cancer. Gastrointest Endosc 2015;82:460-468 e462. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25851162.

102. van den Berg MW, Haijtink S, Fockens P, et al. First data on the Evolution duodenal stent for palliation of malignant gastric outlet obstruction (DUOLUTION study): a prospective multicenter study. Endoscopy 2013;45:174-181. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23348890.

103. Upchurch E, Ragusa M, Cirocchi R. Stent placement versus surgical palliation for adults with malignant gastric outlet obstruction. Cochrane Database Syst Rev 2018;5:CD012506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29845610.

104. National Audit of Small Bowel Obstruction Steering G, National Audit of Small Bowel Obstruction C. Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction. Eur J Surg Oncol 2019;45:2319-2324. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31378418.

105. NIH NCI SEER Program. Cancer Stat Facts: Small Intestine Cancer. 2021. Available at: https://seer.cancer.gov/statfacts/html/smint.html. Accessed February 14, 2022.

106. Adam R, Chiche L, Aloia T, et al. Hepatic resection for noncolorectal nonendocrine liver metastases: analysis of 1,452 patients and development of a prognostic model. Ann Surg 2006;244:524-535. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16998361.

107. Rompteaux P, Gagniere J, Gornet JM, et al. Resection of small bowel adenocarcinoma metastases: Results of the ARCAD-NADEGE cohort study. Eur J Surg Oncol 2019;45:331-335. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30501999.

108. Rovers KP, de Bree E, Yonemura Y, de Hingh IH. Treatment of peritoneal metastases from small bowel adenocarcinoma. Int J Hyperthermia 2017;33:571-578. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27919181.

109. Legue LM, Simkens GA, Creemers GM, et al. Synchronous peritoneal metastases of small bowel adenocarcinoma: Insights into an underexposed clinical phenomenon. Eur J Cancer 2017;87:84-91. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29132061.

110. Elias D, Glehen O, Pocard M, et al. A comparative study of complete cytoreductive surgery plus intraperitoneal chemotherapy to treat peritoneal dissemination from colon, rectum, small bowel, and nonpseudomyxoma appendix. Ann Surg 2010;251:896-901. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20395843.

111. Liu Y, Ishibashi H, Takeshita K, et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Dissemination from Small Bowel Malignancy: Results from a Single Specialized Center.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Ann Surg Oncol 2016;23:1625-1631. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26717938.

112. Liu Y, Yonemura Y, Levine EA, et al. Cytoreductive Surgery Plus Hyperthermic Intraiperitoneal Chemotherapy for Peritoneal Metastases From a Small Bowel Adenocarcinoma: Multi-Institutional Experience. Ann Surg Oncol 2018;25:1184-1192. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29484565.

113. Saxena A, Valle SJ, Liauw W, Morris DL. Recurrence and Survival Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Small Bowel Adenocarcinoma. Anticancer Res 2017;37:5737-5742. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28982894.

114. van Oudheusden TR, Lemmens VE, Braam HJ, et al. Peritoneal metastases from small bowel cancer: Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in The Netherlands. Surgery 2015;157:1023-1027. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25818658.

115. Quenet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256-266. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33476595.

116. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol) 2007;19:143-149. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17355111.

117. Jigyasu D, Bedikian AY, Stroehlein JR. Chemotherapy for primary adenocarcinoma of the small bowel. Cancer 1984;53:23-25. Available at: https://www.ncbi.nlm.nih.gov/pubmed/6690001.

118. Zhang L, Wang LY, Deng YM, et al. Efficacy of the FOLFOX/CAPOX regimen for advanced small bowel adenocarcinoma: a three-center study

from China. J BUON 2011;16:689-696. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22331723.

119. Aydin D, Sendur MA, Kefeli U, et al. Evaluation of prognostic factors and treatment in advanced small bowel adenocarcinoma: report of a multi-institutional experience of Anatolian Society of Medical Oncology (ASMO). J BUON 2016;21:1242-1249. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27837629.

120. Pedersen K, Smyrk TC, Harrington S, McWilliams RR. Programmed death-ligand 1 (PD-L1) expression in small bowel adenocarcinomas (SBA) [abstract]. Journal of Clinical Oncology 2015;33:3619-3619. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.3619.

121. Thota R, Gonzalez RS, Berlin J, et al. Could the PD-1 Pathway Be a Potential Target for Treating Small Intestinal Adenocarcinoma? Am J Clin Pathol 2017;148:208-214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28821192.

122. Laforest A, Aparicio T, Zaanan A, et al. ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Eur J Cancer 2014;50:1740-1746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24797764.

123. Giuffrida P, Arpa G, Grillo F, et al. PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability. Mod Pathol 2020;33:1398-1409. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32066859.

124. Takayoshi K, Kusaba H, Uenomachi M, et al. Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer. Cancer Chemother Pharmacol 2017;80:333-342. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28653251.

125. Gulhati P, Raghav K, Shroff R, et al. Phase II Study of Panitumumab in RAS Wild-Type Metastatic Adenocarcinoma of Small Bowel or Ampulla of Vater. Oncologist 2018;23:277-e226. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29259073.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

126. Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009;27:2598-2603. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19164203.

127. Xiang XJ, Liu YW, Zhang L, et al. A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma. Anticancer Drugs 2012;23:561-566. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22481063.

128. Horimatsu T, Nakayama N, Moriwaki T, et al. A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. Int J Clin Oncol 2017;22:905-912. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28536826.

129. Gibson MK, Holcroft CA, Kvols LK, Haller D. Phase II study of 5-fluorouracil, doxorubicin, and mitomycin C for metastatic small bowel adenocarcinoma. Oncologist 2005;10:132-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15709215.

130. Tsushima T, Taguri M, Honma Y, et al. Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated with chemotherapy. Oncologist 2012;17:1163-1170. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22622149.

131. Zaanan A, Costes L, Gauthier M, et al. Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study. Ann Oncol 2010;21:1786-1793. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20223786.

132. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol 2006;24:394-400. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16421419.

133. Berry SR, Cosby R, Asmis T, et al. Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic

review and meta-analysis. Ann Oncol 2015;26:477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25057174.

134. Seymour M. Conceptual approaches to metastatic disease. Ann Oncol 2012;23 Suppl 10:x77-80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22987997.

135. McWilliams RR, Foster NR, Mahoney MR, et al. North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic-based dosing of irinotecan, oxaliplatin, and capecitabine as first-line therapy for patients with advanced small bowel adenocarcinoma. Cancer 2017;123:3494-3501. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28493308.

136. Gulhati P, Raghav K, Shroff RT, et al. Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater: A single-center, open-label, phase 2 study. Cancer 2017;123:1011-1017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27859010.

137. Aydin D, Sendur MA, Kefeli U, et al. Evaluation of Bevacizumab in Advanced Small Bowel Adenocarcinoma. Clin Colorectal Cancer 2017;16:78-83. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27247089.

138. U. S. Food & Drug Administration. Package Insert. Bevacizumab-awwb injection, for intravenous use. 2021. Available at: https://www.accessdata.fda.gov/drugsatfdadocs/label/2021/761028s008bl.pdf. Accessed February 13, 2023.

139. U. S. Food & Drug Administration. Package Insert. Bevacizumab-bvzr injection, for intravenous use. 2021. Available at: [https://www.accessdata.fda.gov/drugsatfdocs/label/2021/761099s006bl.pdf](https://www.accessdata.fda.gov/drugsatfdocs/label/2021/761099s006bl.pdf) Accessed February 13, 2023.

140. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-2520. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26028255.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

141. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. 2017. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. Accessed February 14, 2022.

142. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 2020;38:1-10. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31682550.

143. Pedersen KS, Foster NR, Overman MJ, et al. ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma. Clin Cancer Res 2021;27:3641-3648. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33883178.

144. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:1182-1191. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28734759.

145. Overman MJ, Lonardi S, Wong KYM, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol 2018;36:773-779. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29355075.

146. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of dual anti-ctla-4 and anti-pd-1 blockade in rare tumors (DART) swog s1609: High-grade neuroendocrine neoplasm cohort. Cancer 2021;127:3194-3201. Available at:

147. Kim JW, Lee HJ, Lee JY, et al. Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06). J Immunother Cancer 2024;12. Available at: https://www.ncbi.nlm.nih.gov/pubmed/38485184.

148. U.S. Food & Drug Administration. Package Insert. Dostarlimab-gxly injection, for intravenous use. 2021. Available at: https://www.accessdata.fda.gov/drugsatfdocs/label/2020/761223s000bl.pdf. Accessed February 13, 2023.

149. Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study. Journal of Clinical Oncology 2021;39:9-9. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.9.

150. André T, Berton D, Curigliano G, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient solid tumors: A nonrandomized controlled trial JAMA Netw Open 2023;6:e2341165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10623195.

151. Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 2020;383:2207-2218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33264544.

152. Mosalem O, Boston TW, Imperial R, et al. A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer. The Oncologist 2024;29:e1224-e1227. Available at: https://doi.org/10.1093/oncolo/oyae098.

153. Garmezy B, Gheeya J, Lin HY, et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. JCO Precision Oncology 2022;6:e2100267. Available at: https://ascopubs.org/doi/abs/10.1200/PO.21.00267.

154. Lutfi A, Afghan MK, Kasi PM. Circulating Tumor DNA Response and Minimal Residual Disease Assessment in DNA Polymerase Epsilon-Mutated Colorectal Cancer Undergoing Immunotherapy. Cureus 2023;15:e43391. Available at: http://dx.doi.org/10.7759/cureus.43391.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

155. Pandya K, Xiu J, Farrell A, et al. Comprehensive genomic and transcriptomic characterization of small bowel adenocarcinoma. Journal of Clinical Oncology 2022;40:4018-4018. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.4018.

156. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembroilizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353-1365. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32919526.

157. Alva AS, Mangat PK, Garrett-Mayer E, et al. Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. J Clin Oncol 2021;39:2443-2451. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844595.

158. Chida K, Kawazoe A, Kawazu M, et al. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin Cancer Res 2021;27:3714-3724. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33926917.

159. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nature Medicine 2023;29:1103-1112. Available at: https://doi.org/10.1038/s41591-023-02321-8.

160. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF v600-mutant colorectal cancer. J Clin Oncol 2015;33:4023-4031. Available at:

161. U.S. Food & Drug Administration. Package Insert. Dabrafenib in combination with trametinib, for oral use. . 2023. Available at: https://www.accessdata.fda.gov/drugsatfdadocs/label/2023/202806s0271bl.pdf. Accessed January 04, 2024.

162. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37870356.

163. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in her2-mutant non-small-cell lung cancer. N Engl J Med 2022;386:241-251. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34534430.

164. Raghav KPS, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. Journal of Clinical Oncology 2023;41:3501-3501. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.3501.

165. Overman MJ, Adam L, Raghav K, et al. Phase II study of nab-pacilitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer. Ann Oncol 2018;29:139-144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29069279.

166. Aldrich JD, Raghav KPS, Varadhachary GR, et al. Retrospective Analysis of Taxane-Based Therapy in small Bowel Adenocarcinoma. Oncologist 2019;24:e384-e386. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30598498.

167. Zaanan A, Gauthier M, Malka D, et al. Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study. Cancer 2011;117:1422-1428. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21425142.

168. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29466156.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

169. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31838007.

170. Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial. Annals of Oncology 2023;34:S787-S788. Available at: https://doi.org/10.1016/j.annonc.2023.09.2405.

171. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36108661.

172. U.S. Food & Drug Administration. Package Insert. Selpercatinib capsules, for oral use 2022. Available at: https://www.accessdata.fda.gov/drugsatfddocs/label/2022/21324650081bl.pdf. Accessed February 13, 2023.

173. Kim M, Jang HJ. The role of small bowel endoscopy in small bowel Crohn's disease: when and how? Intest Res 2016;14:211-217. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27433142.

174. Simon M, Cosnes J, Gornet JM, et al. Endoscopic Detection of Small Bowel Dysplasia and Adenocarcinoma in Crohn's Disease: A Prospective Cohort-Study in High-Risk Patients. J Crohns Colitis 2017;11:47-52. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27405958.

175. Goverde A, Korsse SE, Wagner A, et al. Small-bowel Surveillance in Patients With Peutz-Jeghers Syndrome: Comparing Magnetic Resonance Enteroclysis and Double Balloon Enteroscopy. J Clin Gastroenterol 2017;51:e27-e33. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27404294.

176. Haanstra JF, AI-Toma A, Dekker E, et al. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Gut

2015;64:1578-1583. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25209657.

177. Katsinelos P, Kountouras J, Chatzimavroudis G, et al. Wireless capsule endoscopy in detecting small-intestinal polyps in familial adenomatous polyposis. World J Gastroenterol 2009;15:6075-6079. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20027680.

178. Koornstra JJ. Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. Best Pract Res Clin Gastroenterol 2012;26:359-368. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22704577.

179. Postgate A, Hyer W, Phillips R, et al. Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps. J Pediatr Gastroenterol Nutr 2009;49:417-423. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19543117.

180. Serrano M, Mao-de-Ferro S, Pinho R, et al. Double-balloon enteroscopy in the management of patients with Peutz-Jeghers syndrome: a retrospective cohort multicenter study. Rev Esp Enferm Dig 2013;105:594-599. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24641456. https://www.ncbi.nlm.nih.gov/pubmed/24641456.

181. van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 2010;105:1258-1264; author reply 1265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20051941.

182. Drini M, Speer A, Dow C, et al. Management of duodenal adenomatosis in FAP: single centre experience. Fam Cancer 2012;11:167-173. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22131053.

183. Rampertab SD, Forde KA, Green PH. Small bowel neoplasia in coeliac disease. Gut 2003;52:1211-1214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12865284.

NCCN NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

184. Hewitt M, Greenfield S, Stovall E, eds. From Cancer Patient to Cancer Survivor: Lost in Transition. Committee on Cancer Survivorship: Improving Care and Quality of Life, Institute of Medicine and National Research Council: National Academy of Sciences; 2006. Available at: http://www.nap.edu/catalog/11468.html.

185. Jansen L, Herrmann A, Stegmaier C, et al. Health-related quality of life during the 10 years after diagnosis of colorectal cancer: a population-based study. J Clin Oncol 2011;29:3263-3269. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21768465.

186. Lynch BM, Steginga SK, Hawkes AL, et al. Describing and predicting psychological distress after colorectal cancer. Cancer 2008;112:1363-1370. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18318044.

187. Mols F, Beijers T, Lemmens V, et al. Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry. J Clin Oncol 2013;31:2699-2707. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23775951.

188. Thong MS, Mols F, Wang XS, et al. Quantifying fatigue in (long-term) colorectal cancer survivors: a study from the population-based patient reported outcomes following initial treatment and long term evaluation of survivorship registry. Eur J Cancer 2013;49:1957-1966. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23453750.

189. Wright P, Downing A, Morris EJ, et al. Identifying Social Distress: A Cross-Sectional Survey of Social Outcomes 12 to 36 Months After Colorectal Cancer Diagnosis. J Clin Oncol 2015;33:3423-3430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26282636.

190. Denlinger CS, Barsevick AM. The challenges of colorectal cancer survivorship. J Natl Compr Canc Netw 2009;7:883-893; quiz 894. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19755048.

表 1
CHECKPOINT INHIBITOR THERAPY FOR ANY LINE OF THERAPY$^{i,j,*}$
PD-1	PD-L1	PD-1/CTLA-4
Cemiplimab-rwlcDostarlimab-gxlyNivolumabqPembrolizumabkPenpulimab-kcqxRetifanlimab-dlwrTislelizumabjsgrToripalimab-tpzi	AtezolizumabrAvelumabCosibelimab-ipdlDurvalumab	• Ipilimumab + Nivolumabq,s

表 2
	T	N	M
Stage 0	Tis	N0	M0
Stage I	T1-2	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T4	N0	M0
Stage IIIA	Any T	N1	M0
Stage IIIB	Any T	N2	M0
Stage IV	Any T	Any N	M1

表 3
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.

引用 / 出处

（2026.V1）NCCN临床实践指南：小肠腺癌. 2026.

（2026.V1）NCCN临床实践指南：小肠腺癌

NCCN Guidelines Version 1.2026

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

PRINCIPLES OF IMAGING AND ENDOSCOPY

Initial Workup/Staging

Monitoring

Surveillance

PRINCIPLES OF PATHOLOGIC REVIEW

Small Bowel Adenocarcinoma Appropriate for Resection

Discrimination of Duodenal Malignancy from Other Primary Sites

Pathologic Stage

Lymph Node Evaluation

Microsatellite Instability/Mismatch Repair Testing

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NEOADJUVANT OR ADJUVANT THERAPY REGIMENS<sup>a,c,t</sup>

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

ADVANCED OR METASTATIC THERAPY REGIMENSª, c

ADVANCED OR METASTATIC THERAPY REGIMENSª,c

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

American Joint Committee on Cancer (AJCC) TNM Staging Classification for Small Intestine Adenocarcinoma 8th ed., 2017

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Overview

Literature Search Criteria and Guidelines Update Methodology

Sensitive/Inclusive Language Usage

Risk Factors for Small Bowel Adenocarcinoma

Lifestyle Factors

Inflammatory Bowel Disease and Celiac Disease

Familial Syndromes

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Familial Adenomatous Polyposis

Peutz-Jeghers Syndrome

Lynch Syndrome

Clinical Presentation and Workup

Imaging and Endoscopy

Pathology and Staging

Lymph Node Evaluation

Treatment of Stage I-III Small Bowel Adenocarcinoma

Surgical Management of Localized Resectable Disease

Adjuvant Therapy

MSI/MMR Status for Adjuvant Therapy

NCCN Recommendations for Adjuvant Therapy

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Small Bowel Adenocarcinoma

Primary Treatment of Unresectable Disease

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Treatment of Distant Metastatic (Stage IV) Small Bowel Adenocarcinoma

Metastectomy

Peritoneal Carcinomatosis

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Systemic Therapy for Metastatic Disease

Genetic Alterations in SBA

NCCN Guidelines Version 1.2026

Small Bowel Adenocarcinoma

Regimens Not Recommended for SBA

FOLFOX or CAPEOX