NCCN临床实践指南：结肠癌（2025.V1）

指南肿瘤内科· 消化道肿瘤 · 2025

Lynch Syndrome

Lynch syndrome is the most common form of genetically determined colon cancer predisposition, accounting for 2% to 4% of all CRC cases.15,16,20,21 This hereditary syndrome results from germline mutations in DNA

mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2).

Although identifying a germline mutation in an MMR gene through

sequencing is definitive for Lynch syndrome, patients usually undergo selection by considering family history and performing an initial test on tumor tissue before sequencing. One of two different initial tests can be performed on CRC specimens to identify individuals who might have

Lynch syndrome: 1) immunohistochemical (IHC) analysis for MMR protein expression, which is often diminished because of mutation; or 2) analysis for MSI, which results from MMR deficiency (dMMR) and is detected as changes in the length of repetitive DNA elements in tumor tissue caused by the insertion or deletion of repeated units.22 Testing the BRAF gene for mutation is indicated when IHC shows that MLH1 expression is absent in the tumor. The presence of a BRAF mutation indicates that MLH1

expression is down-regulated through somatic methylation of the promoter

region of the gene and not through a germline mutation.22 Testing for

MLH1 promoter methylation may also be used to determine this.

Many NCCN Member Institutions and other comprehensive cancer centers now perform IHC and sometimes MSI testing on all newly diagnosed

colorectal and endometrial cancers regardless of family history to

determine which patients should have genetic testing for Lynch

syndrome.23-26 The cost effectiveness of this approach, referred to as

universal or reflex testing, has been confirmed for CRC, and this approach has been endorsed by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group at the Centers for Disease

Control and Prevention (CDC)27-29 and by the American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and American Society of Clinical Oncology

The Role of Vitamin D in CRC

(ASCO) in a guideline on molecular biomarkers for CRC.30 The U.S. Multi-

Society Task Force on Colorectal Cancer also recommends universal

genetic testing of tumors of all patients with newly diagnosed CRC, as

does the American Gastroenterological Association.31,32 The Cleveland Clinic recently reported on its experiences implementing such a screening approach.33

The NCCN Colon/Rectal Cancer Panel endorses universal MMR or MSI testing of all patients with a personal history of colon or rectal cancer to identify individuals with Lynch syndrome. This testing is also relevant for adjuvant therapy planning for stage II disease and treatment selection in stage IV disease (see Microsatellite Instability and Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive

Disease in the First-Line and Non–First-Line Settings, below). An

infrastructure needs to be in place to handle the screening results in either case. A more detailed discussion is available in the NCCN Guidelines for Colorectal Cancer Screening.

The Role of Vitamin D in CRC

Prospective studies have suggested that vitamin D deficiency may

contribute to CRC incidence and/or that vitamin D supplementation may decrease CRC risk.34-40 Furthermore, several prospective studies have shown that low vitamin D levels are associated with increased mortality of patients with CRC.41-44 In fact, a systematic review and meta-analysis of f ive studies totaling 2330 patients with CRC compared the outcomes of patients in the highest and lowest categories of vitamin D levels and found better overall survival (OS) (hazard ratio [HR], 0.71; 95% CI, 0.55–0.91) and disease-specific mortality (HR, 0.65; 95% CI, 0.49–0.86) in those with higher vitamin D levels.45 Another meta-analysis determined that the

relationship between vitamin D levels and mortality is linear.46

Results of a recent randomized, double-blind, placebo-controlled trial,

however, showed that supplementation with vitamin D and/or calcium had no effect on the recurrence of colorectal adenomas within 3 to 5 years after removal of adenomas in 2259 participants.47 A later analysis of the same study reported that the effect of vitamin D supplementation on

recurrence of advanced adenomas varied significantly based on the

genotype of the vitamin D receptor, indicating that only individuals with specific vitamin D receptor alleles may benefit from vitamin D

supplementation for prevention of advanced adenomas.48

Furthermore, no study has yet definitively shown that vitamin D

supplementation improves outcomes in patients with CRC. Several studies have reported that supplementation did not improve survival.49-51 In

addition, while the randomized, double-blind, phase II SUNSHINE trial

reported a longer progression-free survival (PFS) for patients with

previously untreated mCRC randomized to standard treatment plus highdose vitamin D supplementation compared to those randomized to

standard treatment plus low-dose vitamin D supplementation (13.0 vs.

11.0 months), this difference was not significant (HR, 0.64; 95% CI, 0–

0.90; P = .02).52 There was also no significant difference between highand standard-dose vitamin D supplementation for overall response rate (ORR) or OS. In a 2010 report, the Institute of Medicine (now known as the National Academy of Medicine) concluded that data supporting a role for vitamin D were only conclusive in bone health, and not in cancer and other diseases.53 Citing this report and the lack of level 1 evidence, the Panel does not currently recommend routine screening for vitamin D

deficiency or supplementation of vitamin D in patients with CRC.

Other Risk Factors for CRC

It is well-recognized that individuals with inflammatory bowel disease (ie, ulcerative colitis, Crohn’s disease) are at an increased risk for CRC.54-56 Other possible risk factors for the development of CRC include smoking,

Other Risk Factors for CRC

the consumption of red and processed meats, alcohol consumption,

diabetes mellitus, low levels of physical activity, metabolic syndrome, and obesity/high body mass index (BMI).55,57-73 In fact, in the EPIC cohort of almost 350,000 individuals, those who adhered to five healthy lifestyle

factors (healthy weight, physical activity, non-smoking, limited alcohol

consumption, and healthy diet) had an HR for the development of CRC of

0.63 (95% CI, 0.54–0.74) compared with those who adhered to one or fewer of the factors.74 Other large studies support the conclusion that

adherence to healthy lifestyle factors can reduce the risk of CRC.75,76

||adjacent organ or structure |N2a |Four to six regional lymph nodes |are positive |

||perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum) |M |Distant Metastasis ||

|T4b |Tumor directly invades* or adheres** to adjacent organs or structures |M0 |No distant metastasis by imaging, in distant sites or organs. (This pathologists) |etc.; no evidence of tumor category is not assigned by |

|||M1 |Metastasis to one or more metastasis is identified |distant sites or organs or peritoneal |

|||M1a |Metastasis to one site or organ metastasis |is identified without peritoneal |

|||M1b M1c |Metastasis to two or more sites peritoneal metastasis Metastasis to the peritoneal other site or organ metastases |or organs is identified without surface is identified alone or with |

|* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct |* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct |* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct |* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct |* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct |

Used with 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.

invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon

invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).

** Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification

should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or

lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.

ST-1

|American Joint Committee on Cancer (AJCC) TNM Staging System for Colon Cancer 8th ed., 2017 Table 2. Prognostic Groups |American Joint Committee on Cancer (AJCC) TNM Staging System for Colon Cancer 8th ed., 2017 Table 2. Prognostic Groups |American Joint Committee on Cancer (AJCC) TNM Staging System for Colon Cancer 8th ed., 2017 Table 2. Prognostic Groups |American Joint Committee on Cancer (AJCC) TNM Staging System for Colon Cancer 8th ed., 2017 Table 2. Prognostic Groups | |---|---|---|---|

||T |N |M|

|Stage 0 |Tis |N0 |M0 |

|Stage I |T1, T2 |N0 |M0 |

|Stage IIA |T3 |N0 |M0 |

|Stage IIB |T4a |N0 |M0 |

|Stage IIC |T4b |N0 |M0 |

|Stage IIIA |T1-T2 |N1/N1c |M0 |

||T1 |N2a |M0 |

|Stage IIIB |T3-T4a |N1/N1c |M0 |

||T2-T3 |N2a |M0 |

||T1-T2 |N2b |M0 |

|Stage IIIC |T4a |N2a |M0 |

||T3-T4a |N2b |M0 |

||T4b |N1-N2 |M0 |

ST-2

|||ABBREVIATIONS |ABBREVIATIONS |ABBREVIATIONS |ABBREVIATIONS ||| |---|---|---|---|---|---|---|---|

|AA appendiceal |adenocarcinoma ||H&E |hematoxylin and eosin ||NET |neuroendocrine tumor |

|ASCO American Society of ||Clinical |HAI |hepatic arterial infusion ||NGS |next-generation sequencing |

|Oncology |||HAMN |high-grade appendiceal mucinous neoplasms ||||

||||HIPEC|hyperthermic intraperitoneal||PCI |peritoneal cancer index |

|C/A/P |chest/abdomen/pelvis ||HIPEC |hyperthermic intraperitoneal chemotherapy ||PCR |polymerase chain reaction |

|CBC complete blood |count ||HR |hazard ratio ||PMCA |peritoneal mucinous carcinoma |

|CC completeness of ||cytoreduction ||||pMMR |proficient mismatch repair |

|CEA carcinoembryonic |antigen ||IGRT |image-guided radiation therapy ||PNI |perineural invasion |

|CLIA-88 clinical laboratory amendments of |1988 |improvement |IHC |immunohistochemistry ||PPAP |polymerase proofreading- associated polyposis |

|CRC colorectal cancer |||IMRT |intensity-modulated radiation therapy ||PV |pathogenic variant |

|ctDNA circulating tumor |DNA ||IORT |intraoperative radiation therapy ||SBRT |stereotactic body radiation therapy |

|DFS disease-free |survival ||LAMN |low-grade appendiceal mucinous |||therapy|

|dMMR mismatch repair |deficient ||LAMN|neoplasms ||SNV |single nucleotide variant |

|DPAM diffuse peritoneal ||adenomatosis |LS |Lynch syndrome ||||

|DVH dose-volume |histogram |||||TMB |tumor mutational burden |

||||MANEC|mixed adenocarcinoma-||TMB-H |tumor mutational burden-high |

||||MANEC |mixed adenocarcinoma- |||tumor mutational burden-high|

|EBRT external beam |radiation |therapy ||neuroendocrine ||||

|ED exonuclease |domain ||MCP-H |high-grade mucinous carcinoma peritonei ||3D-CRT |three-dimensional conformal |

|FAP familial adenomatous ||polyposis |MCP-H-S |high-grade mucinous carcinoma peritonei with signet ring cells ||||

|FISH fluorescence in situ ||hybridization |MCP-L |low-grade mucinous carcinoma peritonei ||||

|GBCA gadolinium-based |contrast |agent |MEN2 |multiple endocrine neoplasia type 2 ||||

|GFR glomerular |filtration rate ||MMR |mismatch repair ||||

||||MSI microsatellite instability|MSI microsatellite instability|MSI microsatellite instability|||

|||MSI microsatellite instability |MSI microsatellite instability |MSI microsatellite instability |MSI microsatellite instability |||

|||MSI-H microsatellite instability-high |MSI-H microsatellite instability-high |MSI-H microsatellite instability-high |MSI-H microsatellite instability-high |||

|||MSS microsatellite stable |MSS microsatellite stable |MSS microsatellite stable |MSS microsatellite stable |||

|Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |Version 1.2025, 02/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. |

radiation therapy

CAT-1

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference |NCCN Categories of Preference | |---|---|

|Preferred intervention |Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability. |

|Other recommended |Other interventions that may be somewhat less efficacious, more toxic, or based on less mature dat |

|intervention |or significantly less affordable for similar outcomes. |

|Useful in certain |Other interventions that may be used for selected patient populations (defined with recommendation |

|circumstances ||

All recommendations are considered appropriate.

|Discussion This discussion for Colon |corresponds to the NCCN Guidelines Cancer. Last updated January 17, 2025. |Workup and Management of Invasive Nonmetastatic Colon |Cancer ................................................................................................... MS-14 | |---|---|---|---|

|Table of Contents ||Adjuvant Chemotherapy for Resectable Colon Cancer ............... |MS-17 |

|Overview |......................................................................................... MS-2 |Perioperative Chemoradiation .................................................... |MS-28 |

|Guidelines Update Methodology |................................................... MS-2 |Management of Metastatic Disease ............................................ |MS-28 |

|Literature Search Criteria .............................................................. |MS-2 |Surgical Management of Colorectal Metastases ......................... |MS-29 |

|Sensitive/Inclusive Language |Usage ............................................ MS-3 |Local Therapies for Metastases.................................................. |MS-30 |

|Risk Assessment |........................................................................... MS-3 |Peritoneal Carcinomatosis.......................................................... |MS-36 |

|Lynch |Syndrome........................................................................... MS-4 |Determining Resectability |........................................................... MS-37 |

|The Role of Vitamin D in CRC |...................................................... MS-4 |Neoadjuvant Therapy and Conversion to Resectability ............... |MS-38 |

|Other Risk Factors for CRC .......................................................... |MS-5 |Perioperative Therapy for Resectable Metachronous Metastatic ||

|||Disease |...................................................................................... MS-41 |

|Staging............................................................................................ |Staging............................................................................................ |MS-6 |MS-6 |

|Pathology ....................................................................................... |Pathology ....................................................................................... |MS-6 |MS-6 |

|||||

|Margins ........................................................................................ |Margins ........................................................................................ |MS-7 |MS-7 |

|Workup and Management of Metachronous Metastatic Disease |Workup and Management of Metachronous Metastatic Disease |Workup and Management of Metachronous Metastatic Disease |. MS-81 |

|Lymph Nodes ............................................................................... |Lymph Nodes ............................................................................... |MS-7 ||

|Tumor Deposits ............................................................................ |Tumor Deposits ............................................................................ |MS-8 |Endpoints for Advanced CRC Clinical Trials |

|Perineural Invasion ....................................................................... |Perineural Invasion ....................................................................... |MS-8 |Post-Treatment Surveillance |

|Tumor Budding |Tumor Budding |............................................................................. MS-9 |Survivorship................................................................................. |

|Appendiceal Neoplasms ................................................................ |Appendiceal Neoplasms ................................................................ |MS-9 |Summary |

|Clinical Presentation and Treatment of Nonmetastatic |Clinical Presentation and Treatment of Nonmetastatic |Disease |References ................................................................................... |

|...................................................................................................... MS-13 |...................................................................................................... MS-13 |...................................................................................................... MS-13 |...................................................................................................... MS-13 |

Workup and Management of the Malignant Polyp ....................... MS-13

Overview

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In

2024, an estimated 106,590 new cases of colon cancer and 46,220 cases of rectal cancer will occur. During the same year, an estimated 53,010

people will die of colon and rectal cancer combined.1 Despite these high numbers, the incidence of colon and rectal cancers per 100,000 people decreased from 60.5 in 1976 to 46.4 in 2005 and, more recently, 38.7 in

2016.2,3 In addition, mortality from CRC has been decreasing for decades (since 1947 in females and since 1980 in males) and is currently down by >50% from peak mortality rates.1,3 These improvements in incidence of

and mortality from CRC are thought to be a result of cancer prevention

and earlier diagnosis through screening and better treatment modalities.

Recent data show continued rapid declines in incidence among those

aged ≥65 years, with a decrease of 3.3% annually between 2011 and

2016.3 CRC incidence and mortality rates vary by race and ethnicity with the highest rates in non-Hispanic Black individuals and lowest in Asian

Americans/Pacific Islanders.3 The magnitude of inequity in mortality rates is double that of incidence rates. Reasons for these racial inequities

include differences in risk factor prevalence, access to health care and

other social determinants of health, comorbidities, and tumor

characteristics.

Conversely, incidence has increased among those <65 years, with a 1%

annual increase in those aged 50 to 64 years and 2% annual increase in those <50 years. CRC death rates also showed age-dependent trends, declining by 3% annually for those ≥65 years, compared to a 0.6% annual decline for individuals aged 50 to 64 years and a 1.3% annual increase for

individuals <50 years.3 A retrospective cohort study of the SEER CRC

registry also found that the incidence of CRC in patients <50 years has been increasing.4 The authors estimate that the incidence rates for colon

Literature Search Criteria

and rectal cancers will increase by 90.0% and 124.2%, respectively, for

patients 20 to 34 years of age by 2030. The cause of this trend is currently unknown. One review suggests that CRC that occurs in patients <45 years may be clinicopathologically and genetically different from CRC in adults ≥45 years, although this has not been confirmed broadly. If cancer in this population is different, there would be a need to develop specific treatment strategies for this population.5 In a cohort study of 1959 patients with

metastatic CRC (mCRC), patients who developed mCRC at a younger

age (<50 years) showed worse survival outcomes and unique adverse

event (AE) profiles, which the authors partially attribute to distinct genetic profiles.6

This Discussion summarizes the NCCN Clinical Practice Guidelines in

Oncology (NCCN Guidelines®) for Colon Cancer. These guidelines begin with the clinical presentation of the patient to the primary care physician or gastroenterologist, and address diagnosis, pathologic staging, surgical

management, perioperative treatment, 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, metastasis) staging system (see Table 1 in the algorithm).7 Although the guidelines are believed to represent the optimal treatment strategy, the Panel believes that, when appropriate, patients should preferentially be included in a clinical trial over standard or accepted therapy.

Guidelines Update Methodology

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

Literature Search Criteria

Prior to the update of the NCCN Guidelines® for Colon Cancer, an

electronic search of the PubMed database was performed to obtain key

literature in the field of CRC published since the previous Guidelines

update, using the following search terms: colon cancer, colorectal cancer, and rectal cancer. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peerreviewed biomedical literature.8

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;

Guideline; Practice Guideline; Randomized Controlled Trial; MetaAnalysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as

relevant to these Guidelines as discussed by the Panel during the

Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of

equity, inclusion, and representation.9 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, 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

Sensitive/Inclusive Language Usage

Risk Assessment

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.

Some data suggest that consumption of dairy may lower risk for the

development of CRC.72,77,78 However, a systematic review and metaanalysis of 15 cohort studies (>900,000 patients; >5200 cases of CRC) only found an association between risk for colon cancer in males and the consumption of nonfermented milk.79 No association was seen for rectal cancer in males or for colon or rectal cancer in females, and no

association was seen for either cancer in either sex with consumption of solid cheese or fermented milk. Large cohort studies and meta-analyses suggest that other dietary factors may also lower the risk for CRC,

including the consumption of f ish and legumes.80-82 Furthermore, the use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) may also

decrease the risk for CRC,83-88 although evidence supporting this

association is limited and variable.89 While the U.S. Preventive Services Task Force (USPSTF) guidance previously recommended daily low-dose aspirin for CRC prevention,90 the 2022 update concluded that there was insufficient evidence that aspirin use reduces CRC incidence.91

In addition, some data suggest that smoking, metabolic syndrome,

obesity, and red/processed meat consumption are associated with a poor prognosis.59,92-96 Conversely, post-diagnosis fish consumption may be

associated with a better prognosis.97 A family history of CRC increases

risk while improving prognosis.98 Data on the effect of dairy consumption on prognosis after diagnosis of CRC are conflicting.99,100

The relationship between diabetes and CRC is complex. Whereas

diabetes and insulin use may increase the risk of developing CRC,

treatment with metformin appears to decrease risk, at least in women.101-110 Results of a small randomized study suggest that 1 year of low-dose metformin in patients without diabetes with previously resected colorectal adenomas or polyps may reduce the likelihood of subsequent adenomas or polyps.111 In addition, although patients with CRC and diabetes appear to have a worse prognosis than those without diabetes,112,113 patients with CRC and diabetes treated with metformin seem to have a survival benefit over those not treated with metformin.109,114,115 The data regarding the

effects of metformin on CRC incidence and mortality, however, are not completely consistent, with some studies seeing no effect.116,117

Staging

Staging in colon cancer is based on the TNM system. The TNM categories reflect very similar survival outcomes for rectal and colon cancer; these diseases therefore share the same staging system.7

In the 8th edition of the AJCC Staging Manual, T1 tumors involve the

submucosa; T2 tumors penetrate through the submucosa into the

muscularis propria; T3 tumors penetrate through the muscularis propria; T4a tumors directly penetrate to the surface of the visceral peritoneum; and T4b tumors directly invade or are adherent to other organs or

structures.7 The T component of colon cancer staging is very important in prognostication, because analyses have shown that patients with T4,N0 tumors have a lower survival than those with T1–2,N1–2 tumors.118-120

Furthermore, in an analysis of 109,953 patients with invasive colon cancer included in the SEER colon cancer database from 1992 to 2004, the

relative 5-year survival rate (ie, 5-year survival corrected by age-related

Pathology

morbidity) was considerably higher (79.6%) for patients with nodenegative T4a tumors compared with patients with node-negative T4b

tumors (58.4%).121

Regional lymph node classification includes N1a (1 positive lymph node); N1b (2–3 positive lymph nodes); N2a (4–6 positive nodes); and N2b (7 or more positive nodes). In addition, tumor deposit(s) in the subserosa,

mesentery, or non-peritonealized pericolic or perirectal tissues without regional nodal metastasis (ie, satellite tumor nodules) have been classified as N1c. Within each T stage, survival is inversely correlated with N stage (N0, N1a, N1b, N2a, and N2b).7

Metastatic disease is classified as M1a when metastases that are limited to only one site/solid organ (including to lymph nodes outside the primary tumor regional drainage area) are positive. M1b is used for metastases to multiple distant sites or solid organs, exclusive of peritoneal

carcinomatosis. The 8th edition of the AJCC Cancer Staging Manual

includes the M1c category for peritoneal carcinomatosis with or without blood-borne metastasis to visceral organs.7 Patients with peritoneal

metastases have a shorter PFS and OS than those without peritoneal involvement.122

Pathology

CRCs are usually staged after surgical exploration of the abdomen and pathologic examination of the surgical specimen. Some of the criteria that should be included in the report of the pathologic evaluation include the following: grade of the cancer; depth of penetration and extension to

adjacent structures (T); number of regional lymph nodes evaluated;

number of positive regional lymph nodes (N); an assessment of the

presence of distant metastases to other organs, to the peritoneum or an abdominal structure, or in non-regional lymph nodes (M); the status of

proximal, distal, radial, and mesenteric margins; lymphovascular invasion;

perineural invasion (PNI); and tumor deposits.7,123-131 The prefixes “p” and “yp” used in TNM staging denote “pathologic staging” and “pathologic

staging after neoadjuvant therapy and surgery,” respectively.7

Margins

In colon cancer, the radial margin (or circumferential resection margin,

CRM) represents the adventitial soft tissue closest to the deepest

penetration of the tumor. It is created surgically by blunt or sharp

dissection of the retroperitoneal aspect, and it corresponds to any aspect of the colon that is not covered by a serosal layer of mesothelial cells.7 It must be dissected from the retroperitoneum to remove the viscus. The serosal (peritoneal) surface does not constitute a surgical margin. The

radial margins should be assessed in all colonic segments with nonperitonealized surfaces. In segments of the colon that are completely

encased by peritoneum, such as the transverse colon, the mesenteric

resection margin is the only relevant radial margin.7 On pathologic

examination, it is diff icult to appreciate the demarcation between the

peritonealized surface and the non-peritonealized surface. The surgeon is therefore encouraged to mark the area of non-peritonealized surface with a clip or suture.7 In a study of 608 patients with rectal cancer, a positive radial margin was shown to be a negative prognostic factor for both local recurrence and OS.132 Patients who have had CRM-positive resections had a 38.2% local recurrence rate, whereas those with CRM-negative

resections had a 10.0% local recurrence rate.132

Lymph Nodes

The number of lymph nodes evaluated is important to note on the

pathology report. A secondary analysis of patients from the Intergroup Trial INT-0089 showed that an increase in the number of lymph nodes examined was associated with increased survival for patients with both node-negative and node-positive disease.133 In addition, results from population-based studies show an association between improvement in

Lymph Nodes

survival and examination of ≥12 lymph nodes.134,135 The mechanism for this correlation is poorly understood. It has been hypothesized that the analysis of more lymph nodes would result in more accurate staging and thus better tailored treatments, but more recent results suggest that this

idea is not correct.136-138 Instead it is likely that other factors associated with lymph node harvest are important for the survival advantage. For

instance, the extent and quality of surgical resection can have an impact on the node harvest.139 The number of regional lymph nodes retrieved from a surgical specimen also varies with age of the patient, sex, and

tumor grade or site.133,134,140,141 In addition, it has been suggested that

lymph nodes in patients who have a strong anti-cancer immune response are easier to find, and that such patients have an improved prognosis.142 Another possibility is that the underlying tumor biology affects lymph node yield and prognosis in parallel. For instance, MSI and wild-type

KRAS/BRAF have been associated with improved prognosis and

increased lymph node retrieval.143,144

Regardless of the mechanism for the observed correlation, the Panel

recommends examination of ≥12 lymph nodes. This recommendation is supported by CAP145 and the 8th edition of the AJCC Cancer Staging

Manual,7 which also specify pathologic examination of ≥12 lymph nodes. Notably, emerging evidence suggests that a greater number of nodes may need to be examined in some situations, particularly for T4 lesions, to

provide an adequate assessment of disease stage.146 For stage II (pN0) colon cancer, it is recommended that the pathologist go back to the

specimen and submit more tissue of potential lymph nodes if <12 nodes were initially identif ied. Patients considered to have N0 disease but for whom <12 nodes have been examined are suboptimally staged and

should be considered to be at higher risk.

The ratio of positive lymph nodes to the total number of lymph nodes

examined is also being evaluated for possible prognostic impact. Case

series have suggested cutoffs of 0.1, 0.2, or 0.25 as lymph node ratios that are prognostic for OS or PFS.147-150 A systematic review and metaanalysis of 33 studies that included >75,000 patients with node-positive CRC concluded that a higher lymph node ratio was significantly

associated with shorter OS and disease-free survival (DFS).151 Analysis of the SEER database, however, suggests that the lymph node ratio does not adequately represent the different effects of both the number of

positive lymph nodes and the number of lymph nodes examined.152

The potential benefit of sentinel lymph node evaluation for colon cancer has mostly been associated with providing more accurate staging of nodal pathology through detection of micrometastatic disease in the sentinel

node(s).153 Results of studies evaluating the sentinel node for

micrometastatic disease through use of hematoxylin and eosin (H&E)

staining to identify small foci of tumor cells and the identif ication of

particular tumor antigens through IHC have been reported.153-158

There is also a potential benefit of assessing regional lymph nodes for micrometastases and isolated tumor cells.156,159-162 The 8th edition of the AJCC Cancer Staging Manual considers clusters of 10 to 20 tumor cells, or clumps of tumor that measure ≥0.2 mm in diameter, but <2 mm in

diameter, to be micrometastases.7 Such micrometastases have been

shown to be a poor prognostic factor. One study of 312 consecutive

patients with pN0 disease found that positive cytokeratin staining was

associated with a higher risk of recurrence.163 Relapse occurred in 14% of patients with positive nodes compared to 4.7% of those with negative

nodes (HR, 3.00; 95% CI, 1.23–7.32; P = .013). A 2012 systematic review and meta-analysis came to a similar conclusion, finding decreased

survival in patients with pN0 tumors with IHC or reverse transcriptase

polymerase chain reaction (RT-PCR) evidence of tumor cells in regional nodes.164 A 2014 meta-analysis also found that the presence of

micrometastases increases the likelihood of disease recurrence.165

Tumor Deposits

Tumor deposits, also called extranodal tumor deposits, peritumoral

deposits, or satellite nodules, are irregular discrete tumor deposits in the pericolic or perirectal fat that show no evidence of residual lymph node tissue but are within the lymphatic drainage of the primary tumor. They are not counted as lymph nodes replaced by tumor. Most of these tumor

deposits are thought to arise from lymphovascular invasion or,

occasionally, PNI.166,167 The number of tumor deposits should be recorded in the pathology report, because they have been shown to be associated with reductions in DFS and OS.130,131,168,169 Multivariate survival analysis in one study showed that patients with pN0 tumors without satellite nodules had a 91.5% 5-year survival rate compared with a 37.0% 5-year survival rate for patients with pN0 tumors and the presence of satellite nodules (P < .0001).131

Perineural Invasion

Several studies have shown that the presence of PNI is associated with a significantly worse prognosis.127-129,168,170-173 For example, one

retrospective analysis of 269 consecutive patients who had colorectal

tumors resected at one institution found a four-fold greater 5-year survival in patients with tumors without PNI versus patients whose tumors invaded nearby neural structures.128 Multivariate analysis of patients with stage II rectal cancer showed that patients with tumors with PNI have a

significantly worse 5-year DFS compared with those without PNI (29% vs. 82%; P = .0005).129 Similar results were seen for patients with stage III disease.127 A meta-analysis that included 58 studies and 22,900 patients also found that PNI is associated with a worse 5-year OS (relative risk

[RR], 2.09; 95% CI, 1.68–2.61) and 5-year DFS (RR, 2.35; 95% CI, 1.66–

3.31).171 PNI is therefore included as a high-risk factor for systemic

recurrence.

Tumor Budding

Pathologic and Molecular Classification

Tumor budding is defined as the presence of a single cell or a cluster of four or fewer neoplastic cells as detected by H&E staining at the

advancing edge of an invasive carcinoma. As specified by the 2016

International Tumor Budding Consensus Conference (ITBCC), the total number of buds should be reported from a selected hot spot measuring

0.785 mm2.174 Budding is separated into three tiers: low (0–4 buds),

intermediate (5–9 buds), and high (≥10 buds).

Several studies have shown that high-grade tumor budding in pT1 CRC or malignant polyps is associated with an increased risk of lymph node

metastasis, although the methodologies for assessing tumor budding were not uniform.175-179 Studies have also supported tumor budding as an

independent prognostic factor for stage II colon cancer. A retrospective study that assessed tumor budding in 135 stage II colon cancer

specimens according to ITBCC criteria found that tumor budding

correlated with survival outcomes.180 Disease-specific survival (DSS) was 89% for low-tier tumor budding, 73% for intermediate-tier, and 52% for high-tier (P = .001). Another retrospective study evaluated 174 stage II colon cancer specimens for tumor budding.181 This study also used the ITBCC criteria and found tumor budding to be independently associated

with DSS (P = .01); specifically, 5-year DSS was 96% for low-tier tumor budding compared to 92% for high-tier for all patients. The difference was even more dramatic for those patients who received no adjuvant

chemotherapy. For these patients, 5-year DSS was 98% for low-tier tumor budding versus 80% for high-tier (P = .008). A post-hoc analysis of the PRODIGE-GERCOR study also reported that tumor budding is an

independent prognostic factor for both DFS and OS in stage III colon

cancer.182 Tumor budding is therefore included as a high-risk factor for recurrence and may inform decisions related to adjuvant therapy.

Tumor Budding

Appendiceal Neoplasms

Primary appendiceal neoplasms are rare and most often found incidentally during an appendectomy following clinical presentation of acute

appendicitis. Management and treatment of primary appendiceal cancers are dependent on classification, grading, and staging of these

neoplasms.183 Appendiceal neoplasms can be histopathologically

classified as neuroendocrine neoplasms (NENs), mucinous neoplasms, goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (nonmucinous), and signet ring cell carcinomas (epithelial origin).184,185

Mucinous neoplasms can be further subclassified into low-grade

appendiceal mucinous neoplasms (LAMNs), high-grade appendiceal

mucinous neoplasms (HAMNs), and mucinous adenocarcinomas with or without signet ring cells. Both colonic-type adenocarcinoma and colorectal adenocarcinoma develop from precancerous adenomas and are managed and treated similarly.186,187 In contrast, GCAs are primarily composed of epithelial and neuroendocrine elements and characteristically contain

goblet cells. Neuroendocrine cells are composed of enterochromaffin-like cells (ECLs) and often produce serotonin.185

Appendiceal Adenocarcinomas

Histopathologic features of LAMN present as circumferential proliferation of low-grade mucinous epithelium with a pushing pattern into the lamina propria, submucosa, muscularis propria, and into the subserosa.188 LAMN can also present with fibrosis of the submucosa, pushing patterns

resembling diverticulum, and mucin and/or cells from the neoplasm

outside of the appendix.7,189 HAMNs have similar features to LAMN but have more extensive and complex atypical cytologic features.

Comparably, both LAMN- and HAMN-classified tumors lack infiltrative

invasion and are both maintained within the appendix.183

Data suggest that appendiceal mucinous neoplasms (AMNs) develop from the same mutational sequence as colorectal carcinomas beginning with a point mutation in KRAS. In addition, genetic mutations in GNAS and

RNF43 are found in both LAMN and HAMN, which further supports the theory that HAMN tumors progress from LAMN tumors.190-192 In contrast, HAMN tumors have been shown to harbor additional mutations in TP53, ATM, and APC, which may be linked to their more aggressive

phenotype.191-193 In addition, mucinous adenocarcinomas resemble

LAMNs and HAMNs but with the presence of infiltrative invasion (instead of the signature pushing pattern seen in the mucinous neoplasms).

Mucinous adenocarcinomas can be further subclassified based on the

presence of signet ring cells. If a tumor is composed of ≤50% signet ring cells, then it is classified as a mucinous adenocarcinoma with signet ring cells. If there is a presence of >50% signet ring cells, then the tumor is

classified as a signet ring cell carcinoma.183

The cells that compose the mucinous adenocarcinomas produce an

excess of extra- and intracellular mucin; the intracellular mucin displaces the cell’s nuclei resulting in its characteristic ring-like appearance.194 It has been well-established that the presence of signet ring cells leads to a

poorer prognosis; 10% to 40% of patients with G3 (poorly differentiated) mucinous adenocarcinoma with signet ring cells have a 5-year OS.195-197 The 8th edition of the AJCC Staging Manual now uses the following

terminology to further characterize appendiceal neoplasms: well,

moderately, and poorly differentiated with corresponding alphanumeric classification of G1, G2, and G3, respectively.183

stage II colonic-type AA should be considered for adjuvant systemic

chemotherapy.185 A univariate and multivariate analysis was performed on patients diagnosed with stage II and stage III GCC who received surgical resection and adjuvant chemotherapy to evaluate the impact of adjuvant chemotherapy on OS. Out of 619 patients, adjuvant chemotherapy was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III individuals.214 For patients with stage II disease, 5-year OS was 96.9%

with adjuvant chemotherapy and 89.1% without adjuvant chemotherapy (P = .236). Patients with stage III disease had a 5-year OS of 77.1% with

adjuvant chemotherapy and 42.8% without adjuvant chemotherapy (P = .003). This study concluded that administration of adjuvant chemotherapy was associated with better OS in patients with stage III GCC.214

In certain patients who are candidates for disease monitoring, surveillance imaging should occur at least annually and may occur more frequently in patients with acellular mucinous spread noted during surgery. If evidence of appendiceal rupture and dissemination of tumor cells were found

outside of the appendix, imaging may not be a reliable source for accurate disease monitoring. If there is clinical suspicion of active disease (eg,

symptoms, elevated tumor markers) despite unremarkable imaging,

laparoscopy should be considered.

Workup and Management of Metastatic Appendiceal Adenocarcinoma

The heterogeneity of the appendiceal neoplasms causes a varying risk of metastasis across histologic tumor types. Distant metastasis in colonictype adenocarcinomas has been reported in 23% to 37% of cases with the most common site being dissemination to the peritoneum, with metastasis to the liver and lung being less common.186,215 The pathologic M stage

distinguishes between intraperitoneal acellular mucin only (M1a),

intraperitoneal mucinous epithelium (M1b), and non-intraperitoneal

metastasis (M1c). If metastasis spreads beyond the peritoneum, then

treatment should follow the NCCN Guidelines for Colon Cancer

recommendations for metastatic disease.

Appendiceal neoplasms (mucinous and non-mucinous) tend to

metastasize within the peritoneal cavity through various ways of

dissemination. Metastasis of a mucinous adenocarcinoma can arise from the excess secretion of mucin from neoplastic epithelial cells. This results in appendiceal rupture and spread of mucin and tumor cells within the

peritoneal cavity leading to neoplastic epithelial cells adhering to the

peritoneal surface and causing varying sized lesions.185,216 The clinical

syndrome of mucinous ascites was once referred to as pseudomyxoma peritonei (PMP), but has since been further subclassified into multiple

histologic grading systems by the World Health Organization (WHO). PMP

Workup and Management of Metastatic Appendiceal Adenocarcinoma

is now used as an outdated umbrella term for the following classifications: low-grade mucinous carcinoma peritonei (MCP-L), which is also

synonymous with the previous classification of DPAM (disseminated

peritoneal adenomucinosis). MCP-L presents as mucin pools with <10% cellularity and non-stratif ied cuboidal epithelium that lack infiltrative

growth.217 High-grade mucinous carcinoma peritonei (MCP-H) is

synonymous with the previous classification, peritoneal mucinous

carcinomatosis (PMCA), presenting with mucin pools of high atypical

cellularity, high mitotic index, cribriform growth pattern, and infiltrative

invasion of underlying organs. An MCP-H classification with the presence of signet ring cells is denoted MCP-H-S and was previously classified as PMCA-S. 217

Cytotoxic chemotherapy with efficacy against CRC is used to treat AA. It is reasonable to use other targeted therapy options for MSI-high (MSI-H), BRAF mutation, or HER2 status, which is consistent with

recommendations within the NCCN Guidelines for Colon Cancer and

NCCN Guidelines for Rectal Cancer. There is no clear evidence for antiepidermal growth factor receptor (EGFR) therapy even if the patient’s

tumor is RAS/RAF wild-type. A retrospective medical record review of

patients with AA was conducted to test for differentials in OS when

adjuvant chemotherapy followed complete cytoreduction.218 In total, 103 patients with AA were enrolled in the study, and 68 patients (66%)

achieved a cytoreductive score of 0–1. Out of these 68 patients, 26

received adjuvant chemotherapy. The median OS was 9.03 years

compared to 2.88 years in those who did not receive adjuvant

chemotherapy (P = .02). This increase in OS was only observed in

patients who did not have low-grade AA.218 This study suggests that

adjuvant chemotherapy does not have a benefit in patients with LAMN but does show an increase of OS in patients with other histologic tumor types. In addition, a study was conducted to identify the association of systemic chemotherapy and survival in patients with grade 1, stage IV appendiceal

mucinous neoplasm (low-grade appendiceal neoplasm). Out of 639

patients identif ied, 5-year OS for patients not undergoing chemotherapy was 52.9% and for patients undergoing chemotherapy was 61.3%. No

association between receiving chemotherapy and OS was observed in this cohort.219

In select patients diagnosed with metastatic spread to the peritoneum,

CRS and HIPEC have the potential to be curative.220,221 CRS and HIPEC are associated with morbidity and mortality, and it is imperative that a

capable multidisciplinary medical team perform extensive preoperative

tests to deem a patient f it for this combination therapy. The intent of CRS is to achieve maximum cytoreduction before the initiation of HIPEC.

Because of this, presurgical evaluation of peritoneal involvement is

recommended and can be achieved through laparoscopy and the

peritoneal carcinomatosis index (PCI) scoring system.222 The PCI

quantif ies the distribution of tumors throughout 13 regions of the abdomen

and pelvis along with a lesion size score. Cases with higher PCI scores are associated with worse prognosis and lack of benefit from CRS.223 The completeness of cytoreduction (CC) score is also used to determine

patient prognosis after surgery. Complete cytoreduction is denoted with a CC-0 or CC-1, while incomplete cytoreduction is denoted with a CC-2 or a CC-3.223 Complete cytoreduction is defined by the removal of all

macroscopic disease found on the peritoneum or surrounding viscera. For unresected tumors, the size of each tumor cannot be >2.5 mm in size.

This is because intraperitoneal chemotherapy is not effective against

tumors >2.5 mm.224 In addition, for appendiceal tumors and PMP, the

grade of the tumor and its histologic features also have an impact on the outcome of complete cytoreduction.224

Once an individual is deemed a candidate for CRS/HIPEC they should

continue chemotherapy for up to 6 months, preferably in the neoadjuvant setting. Additional chemotherapy may be considered for patients whose

Workup and Management of the Malignant Polyp

disease is not resectable at initial diagnosis but has the potential to

convert to resectable disease.221 In successful cases, data suggest that the combined therapeutic approach of CRS and HIPEC offered patients a 15-year survival rate of 59% and a PFS of 8.2 years.225 Patients are

discouraged from CRS if they have been diagnosed with biliary

obstruction, extensive disease at the gastrohepatic ligament/porta hepatis,extensive retroperitoneal disease, intraparenchymal liver lesions (requiring major resection), diffuse small bowel serosa/mesenteric involvement,

and/or multiple sites of small bowel obstruction. If a patient is not a

candidate for surgery, treatment should follow metastatic colon cancer

guidelines, as found in the NCCN Guidelines for Colon Cancer. Prognosis is best for patients when disease is localized only.

Clinical Presentation and Treatment of Nonmetastatic Disease

Workup and Management of the Malignant Polyp

A malignant polyp is defined as one with cancer invading the submucosa (pT1). Conversely, polyps classified as carcinoma in situ (pTis) have not penetrated the submucosa and are therefore not considered capable of regional nodal metastasis.124 The Panel recommends marking the polyp site during colonoscopy or within 2 weeks of the polypectomy, if

appropriate. Testing for MMR/MSI should be done during the initial workup to help with diagnosis of Lynch syndrome and inform treatment decisionmaking.

Before making a decision about surgical resection for an endoscopically resected adenomatous polyp or adenoma, physicians should review the pathology and consult with the patient.226 In patients with invasive cancer in a pedunculated or sessile polyp (adenoma), no additional surgery is

required if the polyp has been completely resected and has favorable

histologic features.227,228 Favorable histologic features include lesions of grade 1 or 2, no angiolymphatic invasion, and a negative resection margin.

However, in addition to the option of observation, the Panel includes the option of colectomy in patients with a completely removed, singlespecimen, sessile polyp with favorable histologic features and clear

margins. This option is included because the literature seems to indicate

that patients with sessile polyps may have a significantly greater incidence of adverse outcomes, including disease recurrence, mortality, and

hematogenous metastasis compared with those with pedunculated polyps. This increased incidence likely occurs because of the high probability of a positive margin after endoscopic removal.229-231

If the polyp specimen is fragmented, the margins cannot be assessed; if the specimen shows unfavorable histopathology, additional workup

including complete blood count (CBC), chemistry profile, carcinoembryonic antigen (CEA) determination, chest/abdomen/pelvis CT, and consideration of pelvic MRI should be performed to better assess for local staging and extent of disease (see Workup and Management of Invasive

Nonmetastatic Colon Cancer for more details on this workup). If

appropriate following workup, colectomy with en bloc removal of lymph nodes is recommended.226,232-234 Laparoscopic surgery is an option.235

Unfavorable histopathologic features for malignant polyps include grade 3 or 4, angiolymphatic invasion, or a positive margin of resection.177,236

Notably, no consensus currently exists as to the definition of what

constitutes a positive margin of resection. A positive margin has been

defined as the presence of tumor within 1 to 2 mm of the transected

margin or the presence of tumor cells within the diathermy of the

transected margin.226,237-239 In addition, several studies have shown that tumor budding is an adverse histologic feature associated with adverse outcome and may preclude polypectomy as an adequate treatment of

endoscopically removed malignant polyps.240-243

All patients who have malignant polyps removed by transanal excision or transabdominal resection should undergo total colonoscopy to rule out

Workup and Management of Invasive Nonmetastatic Colon Cancer

other synchronous polyps and should subsequently undergo appropriate follow-up surveillance endoscopy. Adjuvant chemotherapy is not

recommended for patients with stage I lesions.

Workup and Management of Invasive Nonmetastatic Colon Cancer

Patients who present with invasive colon cancer appropriate for resection require a complete staging workup, including biopsy, pathologic tissue

review, total colonoscopy, CBC, chemistry profile, CEA determination, and baseline CT scans of the chest, abdomen, and pelvis.244 Testing for

MMR/MSI should be done at diagnosis to help with detection of Lynch syndrome and to inform treatment decision-making. CT should be with intravenous (IV) and oral contrast. If the CT of the abdomen and pelvis is inadequate or if CT with IV contrast is contraindicated, an abdomen/pelvis MRI with contrast plus a non-contrast chest CT should be considered. The chest CT can identify lung metastases, which occur in approximately 4% to 9% of patients with colon and rectal cancer.245-247 One series of 378 patients found that resection of pulmonary metastases resulted in 3-year relapse-free survival (RFS) of 28% and 3-year OS of 78%.248 Fertility risks should be discussed with appropriate patients prior to treatment and

referral for and/or counseling on fertility preservation options should be done if indicated (see the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology for more information on this topic).

The consensus of the Panel is that a PET/CT scan is not indicated at

baseline for preoperative workup. In fact, PET/CT scans are usually done without contrast and multiple slicing and do not obviate the need for a

contrast-enhanced diagnostic CT scan. If, however, abnormalities are

seen on CT or MRI scan that are considered suspicious but inconclusive for metastases, then a PET/CT scan may be considered to further

delineate that abnormality, if this information will change management. A PET/CT scan is not indicated for assessing subcentimeter lesions,

because these are routinely below the level of PET/CT detection.

For resectable colon cancer that is causing overt obstruction, one-stage colectomy with en bloc removal of regional lymph nodes, resection with diversion, or diversion or stent (in selected cases) followed by colectomy are options. Stents are generally reserved for cases of distal lesions in which a stent can allow decompression of the proximal colon with later

elective colostomy with primary anastomosis.249 A meta-analysis found

that oncologic outcomes were similar for surgery and for stenting followed by elective surgery.250 This result was supported by the ESCO trial, an RCT from Europe that reported similar outcomes between colonic stenting as a bridge to surgery compared to emergency surgery for malignant

colon obstruction.251,252 Another meta-analysis of comparative studies

compared colectomy to diversion followed by colectomy.253 Although 30-day mortality and morbidity were the same between the groups, the

diversion group was less likely to have a permanent colostomy (OR [odds ratio], 0.22; 95% CI, 0.11–0.46). Preoperative stoma education and

marking of the site by an enterostomal therapist have been shown to

improve outcomes and are therefore recommended for patients who are expected to receive a stoma following surgery.254-256

Bulky nodal disease or clinical T4b may benefit from neoadjuvant therapy prior to resection, oxaliplatin-based chemotherapy for MMR-proficient

(pMMR)/microsatellite-stable (MSS) disease, and either chemotherapy or a checkpoint inhibitor for cT4b dMMR/MSI-H disease. If the cancer is

locally unresectable or the patient is medically inoperable, systemic

therapy, radiation, and/or chemoradiation is recommended, possibly with the goal of converting the lesion to a resectable state.

Neoadjuvant Therapy for Resectable Colon Cancer

For bulky nodal disease or clinical T4b, neoadjuvant treatment with

FOLFOX or CAPEOX may be considered prior to surgery. The

randomized phase III FOxTROT trial is assessing whether this approach improves DFS. Results from the feasibility phase of the trial were reported

Neoadjuvant Therapy for Resectable Colon Cancer

in 2012.257 One hundred fifty patients with T3 (with ≥5 mm invasion

beyond the muscularis propria) or T4 tumors were randomly assigned to three cycles of preoperative therapy (fluorouracil [5-FU]/leucovorin

[LV]/oxaliplatin), surgery, and nine additional cycles of the same therapy or to surgery with 12 cycles of the same therapy given postoperatively.

Preoperative therapy resulted in significant downstaging compared with postoperative therapy (P = .04), with acceptable toxicity. Mature results from the FOxTROT trial reported on 1053 total randomized patients,

including 699 randomized to neoadjuvant chemotherapy and 354 to the control group.258 The primary outcome of 2-year residual or recurrent

disease was 16.9% with neoadjuvant chemotherapy compared to 21.5% in the control group, representing a 28% lower recurrence rate with

neoadjuvant chemotherapy. The neoadjuvant chemotherapy group

showed marked T and N downstaging and histologic tumor regression. Resection was more often histopathologically complete with neoadjuvant chemotherapy compared to control (94% vs. 89%; P < .001). These

results support the feasibility of neoadjuvant therapy as a treatment option for colon cancer.

For the dMMR/MSI-H population, the NICHE and NICHE-2 studies have shown high rates of pathologic response with neoadjuvant immunotherapy in early-stage colon cancers prior to resection.259,260 The NICHE-2 study reported results from 115 enrolled patients with nonmetastatic dMMR

colon cancer treated with ipilimumab plus nivolumab.260 In the efficacy

population, 109 of 111 (98%; 95% CI, 94–100) were observed to have pathologic disease response, including 95% major pathologic responses and 68% pathologic complete responses. At a median follow-up of 26

months, no cases of disease recurrence were reported. Grade 3–4

immune-related AEs were reported in 4% of patients. While neoadjuvant chemotherapy with FOLFOX or CAPEOX is considered an option by the NCCN Panel for cT4b dMMR/MSI-H disease, it is important to note that the FOxTROT trial results reported little benefit from neoadjuvant

chemotherapy for patients with dMMR tumors, leading checkpoint inhibitor therapy to be the preferred approach in this setting.258

Surgical Management

For resectable nonmetastatic colon cancer, the preferred surgical

procedure is colectomy with en bloc removal of the regional lymph

nodes.261,262 The extent of colectomy should be based on the tumor

location, resecting the portion of the bowel and arterial arcade containing the regional lymph nodes. Other nodes, such as those at the origin of the vessel feeding the tumor (ie, apical lymph node), and suspicious lymph nodes outside the field of resection, should also be biopsied or removed if possible. Resection must be complete to be considered curative, and

positive lymph nodes left behind indicate an incomplete (R2) resection.263 There has been some attention focused on the quality of colectomy.264 The phase III ESCME trial compared the outcomes of patients who had undergone complete mesocolic excision (CME) to those who had a nonCME.265 Five-year local RFS was similar between the groups; however, the absolute risk reduction of 5-year cumulative death and disease

progression after CME was 9.1% for Union for International Cancer

Control (UICC) stage I–III and 16.1% for UICC stage III, specifically.

In addition, a retrospective observational study found a possible OS

advantage for surgery in the mesocolic plane over surgery in the

muscularis propria plane.266 A comparison of resection techniques by

expert surgeons in Japan and Germany showed that CME with central

vascular ligation resulted in greater mesentery and lymph node yields than the Japanese D3 high tie surgery.267 Differences in outcomes were not reported. A retrospective, population-based study in Denmark also

supports the benefit of a CME approach in patients with stage I–III colon cancer, with a significant difference in 4-year DFS (P = .001) between

those undergoing CME resection (85.8%; 95% CI, 81.4–90.1) and those undergoing conventional resection (75.9%; 95% CI, 72.2–79.7).268 A

Minimally Invasive Approaches to Colectomy

systematic review found that four of nine prospective studies reported improved lymph node harvest and survival with CME compared with nonCME colectomy; the other studies reported improved specimen quality.269

Minimally Invasive Approaches to Colectomy

Laparoscopic colectomy is an option in the surgical management of colon cancer.270-273 In a small European randomized trial (Barcelona), the

laparoscopic approach seemed to be associated with some modest

survival advantage, significantly faster recovery, and shorter hospital

stays.274 More recently, a similar but larger trial (COLOR trial) of 1248

patients with colon cancer randomly assigned to curative surgery with

either a conventional open approach or laparoscopic-assisted surgery

showed a nonsignificant absolute difference of 2.0% in 3-year DFS

favoring open colectomy.275 Noninferiority of the laparoscopic approach could not be established because of study limitations. Ten-year outcomes of the COLOR trial also showed similar rates of DFS, OS, and recurrence between open and laparoscopic surgery.276 In the CLASICC study of 794 patients with CRC, no statistically significant differences in 3-year rates of OS, DFS, and local recurrence were observed between these surgical approaches.277 Long-term follow-up of participants in the CLASICC trial showed that the lack of differences in outcomes between arms continued over a median of 62.9 months.278

Due to the rarity of appendiceal adenocarcinomas (AAs), treatment

typically follows CRC despite AAs having distinct histologic, biological, and clinical manifestations. A recent molecular analysis was performed on

Goblet Cell and Neuroendocrine Carcinomas of the Appendix

patients diagnosed with mucinous AAs (MAAs) in order to guide clinical decision-making. Out of 164 MAAs tested, 24 were predominantly RASmutated with GNAS and TP53 wild-type.198 This tumor type has

significantly fewer mutations and chromosomal alterations when compared to GNAS or TP53 mutation predominance, and OS in this subgroup was improved when compared to GNAS-mutant (P = .05) and TP53-mutant (P = .04) tumors. In addition, RAS-mutant predominant tumors had reduced tumor bulk (P = .04) and stromal invasion (P < .01) and responded more to first-line chemotherapy (50%) compared to GNAS-mutant predominant (6%, P = .03) tumors.198 The following molecular subtypes were identif ied in this study: RAS-mutant/GNAS-wild-type/TP53-wild-type, which was

typically clinically indolent; GNAS-mutant predominance, which showed chemotherapy resistance; and TP53-mutant predominance, which was

highly aneuploid and aggressive. This clinical behavior was observed

regardless of histopathology.198

Goblet Cell and Neuroendocrine Carcinomas of the Appendix

Appendiceal goblet cell carcinomas (GCCs) account for approximately

14% to 19% of primary appendiceal neoplasms and consist of both

glandular epithelial cells and neuroendocrine components.186,199,200 GCCs are considered mixed adenoneuroendocrine carcinomas (MANECs) and display the IHC staining consistent with neuroendocrine markers but

behave more aggressively like an adenocarcinoma. For this reason, it is recommended to clinically treat GCCs as an adenocarcinoma.201,202

Appendiceal neuroendocrine carcinomas (ANCs) can develop in the

jejunum/ileum, appendix, or cecum. They are composed of ECLs in the bowel wall and can often produce serotonin.185 They are usually indolent tumors when found in the appendix or the rectum but progress more

aggressively when found in the colon.203 ANCs are usually asymptomatic and found incidentally if tumor development occurs at the tip of the

appendix, but can cause symptomatic obstruction and appendicitis if found in the mid or proximal portions.203 Progression and OS of the patient is dependent on the histologic subtype of the appendiceal neoplasm.202

Clinical Presentation

Patients typically present with symptoms resembling appendicitis, which include but are not limited to: abdominal pain in the right lower quadrant, vomiting, change in bowel habits, intestinal obstruction, compression of the ureters, and nausea.204-207 There should be increased suspicion of an appendiceal neoplasm if the patient is >50 years of age with a family

history of inflammatory bowel disease, colon cancer, and/or unexplained anemia.208 Additionally, if appendicitis is treated nonoperatively (typically with antibiotics), repeat interval imaging is crucial to ensure that the

imaging findings resolve. Lack of resolution may suggest an appendiceal malignancy.

Diagnosing neoplasms of the appendix is challenging and symptoms may overlap with colon cancer, gynecologic cancers, or varying abdominal

pathologies. Diagnostic tests to be considered at initial presentation

include imaging studies such as CT/MRI, endoscopy, tumor biopsy, and in some cases surgery, in addition to a thorough medical history and physical examination.209 An appendix >15 mm on a CT or MRI with an irregular or thickened wall is suggestive of appendiceal carcinoma.210 Non-specific abdominal bloating/distention and/or postprandial discomfort may also be observed with mucinous peritoneal involvement. Colonoscopy is

recommended if the patient has been diagnosed with mucinous

adenocarcinoma of the appendix as there is an increased risk of colonic polyps and neoplasia.210,211

Tumor biomarkers CEA and CA 19-9 can be evaluated and used as

prognostic indicators for patients receiving cytoreductive surgery and

hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).212 In a recent study, a multivariate analysis was performed to establish predictors of

disease progression using tumor biomarkers. This analysis concluded that when CA 19-9 was elevated preoperatively, PFS was unfavorable.

Additionally, when CEA was elevated preoperatively, OS was also

Workup and Management of Localized Appendiceal Adenocarcinoma

unfavorable.212 CA-125 level was inconclusive in this study; however,

other studies suggest normal serum levels of CA-125 and CA 19-9

correspond to an increase in survival and a decrease in recurrence.213 Tumor differentiation and classification were the strongest predictors of both PFS and OS.

Workup and Management of Localized Appendiceal Adenocarcinoma

A screening colonoscopy is recommended in all patients diagnosed with AA to rule out synchronous large polyps or cancer. CT of the chest,

abdomen, and pelvis is also recommended for evaluation of the primary tumor and any possibility of metastatic disease.213 Tis- and T1-staged

tumors may be managed with appendectomy alone if negative margins

are obtained during resection and there is no evidence of angiolymphatic invasion.185 T1 and T2 tumors with unfavorable characteristics such as

angiolymphatic invasion or positive margins should be considered for a right hemicolectomy and removal of ≥12 lymph nodes for accurate

resection and staging.185

Extrapolating from CRC, patients with stage III (nodal involvement) or

Another pooled analysis aimed to determine if patients aged ≥70 years derive a benefit with oxaliplatin-based adjuvant chemotherapy for

treatment of high-risk stage II–III colon or rectal cancer.371 This analysis included OS data from 1985 patients and showed that while oxaliplatinbased adjuvant chemotherapy reduced the mortality risk by 26% in

patients <70 years, it did not yield an improvement for patients ≥70 years. Similar results were seen for DFS.

However, a pooled analysis of individual patient data from the NSABP C08, XELOXA, X-ACT, and AVANT trials found that DFS (HR, 0.77; 95% CI, 0.62–0.95; P = .014) and OS (HR, 0.78; 95% CI, 0.61–0.99; P = .045) were improved with adjuvant CAPEOX or FOLFOX over 5-FU/LV in

patients ≥70 years.372 Likewise, a subgroup analysis of the phase III

TOSCA trial (part of the IDEA collaboration) found that once the

multivariable analysis was corrected for sex, performance status, tumor site, grade, treatment, treatment duration, and dose reduction, there was no significant difference in time to tumor recurrence between patients ≥70 years compared to those <70 years when treated with oxaliplatin-based adjuvant therapy (HR, 1.19; 95% CI, 0.98–1.44; P = .082), although worse prognostic factors and a higher rate of treatment discontinuation had a

negative impact on efficacy measures of DFS and OS in the population ≥70 years of age.373

As for the risks of adjuvant therapy in older patients, a pooled analysis of 37,568 patients from adjuvant trials in the ACCENT database found that the likelihood of early mortality after adjuvant treatment increased with age in a nonlinear fashion (P < .001).374 For instance, the ORs for 30-day

mortality for patients aged 70 and 80 years compared to patients aged 60 years were 2.58 (95% CI, 1.88–3.54) and 8.61 (95% CI, 5.34–13.9),

respectively. Patients aged 50 years, on the other hand, had a

corresponding OR of 0.72 (95% CI, 0.47–1.10). However, the absolute risk

of early mortality was very small, even for older patients (30-day mortality for 80-year-olds was 1.8%).

Overall, the benefit and toxicities of 5-FU/LV as adjuvant therapy seem to be similar in older and younger patients. However, the Panel cautions that a benefit for the addition of oxaliplatin to 5-FU/LV in patients ≥70 years has not been proven in stage II or stage III colon cancer.

Timing of Adjuvant Therapy

A systematic review and meta-analysis of 10 studies involving >15,000 patients examined the effect of timing of adjuvant therapy after

resection.375 Results of this analysis showed that each 4-week delay in chemotherapy results in a 14% decrease in OS, indicating that adjuvant therapy should be administered as soon as the patient is medically able. These results are consistent with other similar analyses. In addition, a

retrospective study of 7794 patients with stage II or III colon cancer from the National Cancer Database found that a delay of >6 weeks between surgery and adjuvant therapy reduced survival after adjustment for

clinical-, tumor-, and treatment-related factors.376 Another retrospective study of 6620 patients with stage III colon cancer from the Netherlands Cancer Registry also found that starting adjuvant therapy after 8 weeks beyond resection was associated with worse survival.377 However, some

Timing of Adjuvant Therapy

Leucovorin Shortage

critics have pointed out that this type of analysis is biased by confounding factors such as comorbidities, which are likely to be higher in patients with a longer delay before initiation of chemotherapy.378 In fact, the registry study found that patients who started therapy after 8 weeks were more likely to be >65 years, have had an emergency resection, and/or have a prolonged postoperative admission.377 Additionally, a phase III intergroup trial of the ECOG-ACRIN Cancer Research Group (E1291) reported no significant difference in OS or DFS for perioperative therapy versus no perioperative therapy with 5-FU, although this trial was terminated early due to slow accrual.379

Leucovorin Shortage

A shortage of LV has existed in the United States. No specific data are available to guide management under these circumstances, and all

proposed strategies are empiric. The Panel recommends several possible options to help alleviate the problems associated with this shortage. One is the use of levoleucovorin, which is commonly used in Europe. A dose of 200 mg/m2 of levoleucovorin is equivalent to 400 mg/m2 of standard

LV. Use of levoleucovorin should only be considered during times of LV shortage since levoleucovorin is substantially more expensive than LV.

Another option is for practices or institutions to use lower doses of LV for all doses in all patients, because the Panel feels that lower doses are

likely to be as efficacious as higher doses, based on several studies. The QUASAR study found that 175 mg of LV was associated with similar

survival and 3-year recurrence rates as 25 mg of LV when given with

bolus 5-FU as adjuvant therapy to patients after R0 resections for CRC.380 Another study showed no difference in response rate or survival in

patients with mCRC receiving bolus 5-FU with either high-dose (500

mg/m2) or low-dose (20 mg/m2) LV.381 Furthermore, the Mayo Clinic and North Central Cancer Treatment Group (NCCTG) determined that no

therapeutic difference was seen between the use of high-dose (200

mg/m2) or low-dose (20 mg/m2) LV with bolus 5-FU in the treatment of

advanced CRC, although the 5-FU doses were different in the treatment arms.382 Finally, if none of the above options are available, treatment

without LV would be reasonable. For patients who tolerate this without grade II or higher toxicity, a modest increase in 5-FU dose (in the range of 10%) may be considered.

Adjuvant FOLFOX and Infusional 5-FU/LV

Adjuvant Capecitabine and CAPEOX

The European MOSAIC trial compared the efficacy of FOLFOX and 5-

FU/LV in the adjuvant setting in 2246 patients with completely resected stage II and III colon cancer. Although this initial trial was performed with FOLFOX4, mFOLFOX6 has been the control arm for all recent and current National Cancer Institute (NCI) adjuvant studies for CRC, and the Panel believes that mFOLFOX6 is the preferred FOLFOX regimen for adjuvant and metastatic treatments. Results of this study have been reported with median follow-ups of up to 9.5 years.303-305 For patients with stage III

disease, DFS at 5 years was 58.9% in the 5-FU/LV arm and 66.4% in the FOLFOX arm (P = .005), and 10-year OS of patients with stage III disease receiving FOLFOX was statistically significantly increased compared with those receiving 5-FU/LV (67.1% vs. 59.0%; HR, 0.80; P = .016).305

Although the incidence of grade 3 peripheral sensory neuropathy was

12.4% for patients receiving FOLFOX and only 0.2% for patients receiving 5-FU/LV, long-term safety results showed a gradual recovery for most of these patients. However, neuropathy was present in 15.4% of examined patients at 4 years (mostly grade 1), suggesting that oxaliplatin-induced neuropathy may not be completely reversible in some patients.304

An analysis of f ive observational data sources, including the SEERMedicare and NCCN Outcomes Databases, showed that the addition of oxaliplatin to 5-FU/LV gave a survival advantage to the general stage III

colon cancer population treated in the community.383 Another populationbased analysis found that the harms of oxaliplatin in the Medicare

Duration of Adjuvant Therapy

population with stage III colon cancer were reasonable, even in patients ≥75 years.384 In addition, a pooled analysis of individual patient data from four RCTs revealed that the addition of oxaliplatin to capecitabine or 5-

FU/LV improved outcomes in patients with stage III colon cancer.385

Furthermore, analysis of data from 12,233 patients in the ACCENT

database of adjuvant colon cancer trials supports the benefit of oxaliplatin in patients with stage III disease.386

Adjuvant Capecitabine and CAPEOX

Single-agent oral capecitabine as adjuvant therapy for patients with stage III colon cancer was shown to be at least equivalent to bolus 5-FU/LV

(Mayo Clinic regimen) with respect to DFS and OS, with respective HRs of

0.87 (95% CI, 0.75–1.00; P < .001) and 0.84 (95% CI, 0.69–1.01; P = .07) in the X-ACT trial.310 Final results of this trial were subsequently

reported.387 After a median follow-up of 6.9 years, the equivalencies in DFS and OS were maintained in all subgroups, including those ≥70 years. Capecitabine was also assessed as adjuvant therapy for stage III colon cancer in combination with oxaliplatin (CAPEOX) in the NO16968 trial and showed an improved 3-year DFS rate compared with bolus 5-FU/LV

(66.5% vs. 70.9%).307,308 Final results of this trial showed that OS at 7

years was improved in the CAPEOX arm compared with the 5-FU/LV arm (73% vs. 67%; HR, 0.83; 95% CI, 0.70–0.99; P = .04).388 Another phase III trial compared CAPEOX to mFOLFOX6 in 408 patients with stage III or high-risk stage II colon cancer.389 No significant differences were seen in 3-year DFS and 3-year OS. In addition, a pooled analysis of individual

patient data from four RCTs revealed that the addition of oxaliplatin to

capecitabine or 5-FU/LV improved outcomes in patients with stage III

colon cancer.385

Duration of Adjuvant Therapy

The IDEA collaboration investigated whether limiting adjuvant treatment to 3 months of FOLFOX or CAPEOX—which would markedly decrease the

incidence of neuropathy—would compromise oncologic outcomes. IDEA included 12,834 patients in an international effort that pooled data from six concurrently conducted, randomized phase III trials to assess the

noninferiority of 3 months compared with 6 months of adjuvant FOLFOX or CAPEOX in patients with stage III colon cancer.309 The median follow-up was 39 months. Importantly, grade 3+ neurotoxicity rates were lower in the 3-month versus 6-month treatment arms (3% vs. 16% for FOLFOX; 3% vs.

9% for CAPEOX; P < .0001), as were grade 2 neurotoxicity rates (14% vs.

32% for FOLFOX; 12% vs. 36% for CAPEOX; P < .0001). Grade 2 and grade 3/4 diarrhea rates were also lower with the shorter duration of

therapy (P < .0001 for FOLFOX; P = .01 for CAPEOX).

The primary endpoint of 3-year DFS did not meet the prespecified cutoff for noninferiority in the overall population, despite the small absolute

difference of 0.9% (74.6% for 3 months vs. 75.5% for 6 months; HR, 1.07; 95% CI, 1.00–1.15), which is of questionable clinical significance.

However, noninferiority was observed within certain subgroups.

Specifically, in the low-risk (T1–3, N1) subgroup, the DFS for 3 months of CAPEOX was noninferior to 6 months of CAPEOX (HR, 0.85; 95% CI,

0.71–1.01), whereas noninferiority could not be proven for 3 months

versus 6 months of FOLFOX (HR, 1.10; 95% CI, 0.96–1.26). In the highrisk (T4 and/or N2) subgroup, DFS for 3 months of FOLFOX was inferior to 6 months of FOLFOX (HR, 1.20; 95% CI, 1.07–1.35), whereas

noninferiority could not be proven for the 3- to 6-month comparison with CAPEOX (HR, 1.02; 95% CI, 0.89–1.17).

Results of the final analysis of IDEA were reported after an overall median survival follow-up of 72.3 months.390 In the final analysis, 5-year OS was

82.4% for 3 months of therapy compared to 82.8% for 6 months (HR, 1.02; 95% CI, 0.95–1.11; P = .058). The HR for 5-year OS was 0.96 for

CAPEOX (3 vs. 6 months) and 1.07 for FOLFOX (3 vs. 6 months).

Likewise, long-term DFS HRs were 0.98 for CAPEOX (3 vs. 6 months)

and 1.16 for FOLFOX (3 vs. 6 months). The authors of this study

concluded that, while the differences in OS did not meet the statistical

assumptions for noninferiority, the overall 0.4% difference in 5-year OS should be placed in clinical context, especially considering the marked

reduction in toxicity associated with the shorter duration of therapy.

A pooled analysis of patients with high-risk stage II colon cancer in the IDEA collaboration did not show noninferiority of 3 months compared to 6 months of adjuvant treatment based on 5-year DFS (80.7% for 3 months vs. 83.9% for 6 months; HR, 1.17; 80% CI, 1.05–1.31). Similar to stage III, the duration of therapy was associated with a small, not statistically

significant difference in 5-year DFS between 3 and 6 months of CAPEOX (HR, 1.02; 80% CI, 0.88–1.17).391 Two of the published trials within the IDEA collaboration reported similar results for high-risk stage II disease. For the TOSCA trial, 5-year RFS was found to be similar between 3 and 6 months of CAPEOX, while the difference was more pronounced between 3 and 6 months of FOLFOX (8.56% difference favoring 6 months of

FOLFOX).392 The OS analysis of TOSCA at a median follow-up of 7 years reported an HR of 1.09 for OS in the 3- versus 6-month arms (95% CI,

0.93–1.26; P for superiority = .288).393 In the Hellenic Oncology Research Group (HORG)-IDEA trial, 3-year DFS was 76.7% for 3 months versus

79.3% for 6 months of FOLFOX (HR, 1.21; 95% CI, 0.54–2.70) and 85.4% for 3 months versus 83.8% for 6 months of CAPEOX (HR, 0.99; 95% CI,

0.59–1.67).394

ACHIEVE was another phase III trial that investigated similar questions

regarding duration of adjuvant therapy for 1313 patients of Asian descent with stage III colon cancer.395 The results of ACHIEVE were consistent with IDEA, finding that the incidence of long-lasting peripheral neuropathy was significantly lower with 3 months of adjuvant therapy compared to 6 months (9.7% vs. 24.3% after 3 years; P < .001). DFS rates were similar between the 3- and 6-month arms (HR, 0.95; 95% CI, 0.76–1.20). Final

results from the ACHIEVE trial showed comparable 5-year OS results

between the two arms (87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group).396 Long-term peripheral neuropathy was more common following 6 months of treatment (16% vs. 8%). ACHIEVE-2 was a randomized phase III trial comparing adjuvant chemotherapy

duration of 3 versus 6 months for 525 patients with high-risk stage II colon cancer.397 Similar to the other studies, the 3-year DFS rate with CAPEOX was 88.2% in the 3-month arm and 88.4% in the 6-month arm, with a

lower discontinuation rate (15% vs. 35%; P < .0001) and lower rate of

grade 2 or higher peripheral sensory neuropathy (16% vs. 43%; P <

.0001) for 3 months of CAPEOX compared to 6 months. Other trials,

including the phase III KCSG CO09-07 trial,398 have reported similar

results when comparing 3 to 6 months of adjuvant therapy in patients with stage II–III colon cancer.

Based on these data, 3 months of CAPEOX or 3 to 6 months of FOLFOX are listed in the guidelines as preferred adjuvant therapy options for

patients with low-risk stage III colon cancer. Three to 6 months of

CAPEOX or 6 months of FOLFOX are listed as preferred adjuvant therapy options for patients with high-risk stage III colon cancer. Six months of infusional 5-FU/LV or single-agent capecitabine are included as other

adjuvant therapy options for low- or high-risk stage III colon cancer. For stage II colon cancer at high risk for systemic recurrence, the

recommended options for adjuvant treatment are 6 months of

capecitabine, 5-FU/LV, or FOLFOX or 3 months of CAPEOX. Observation may also be an appropriate option for high-risk stage II disease. In this population, no adjuvant treatment option is preferred over the others.

Adjuvant Regimens Not Recommended

Other adjuvant regimens studied for the treatment of early-stage colon cancer include 5-FU–based therapies incorporating irinotecan. The

CALGB 89803 trial evaluated the IFL regimen versus 5-FU/LV alone in

Adjuvant Regimens Not Recommended

stage III colon cancer.399 No improvement in either OS (P = .74) or DFS (P = .84) was observed for patients receiving IFL compared with those

receiving 5-FU/LV. However, IFL was associated with a greater degree of neutropenia, neutropenic fever, and death.399,400 Similar results were

observed in a randomized phase III trial comparing bolus 5-FU/LV with the IFL regimen in stage II/III colon cancer.401 In addition, FOLFIRI (infusional 5-FU/LV/irinotecan) has not been shown to be superior to 5-FU/LV in the adjuvant setting.402,403 Thus, data do not support the use of irinotecancontaining regimens in the treatment of stage II or III colon cancer.

In the NSABP C-08 trial comparing 6 months of mFOLFOX6 with 6

months of mFOLFOX6 with bevacizumab plus an additional 6 months of bevacizumab alone in patients with stage II or III colon cancer, no

statistically significant benefit in 3-year DFS was seen with the addition of bevacizumab (HR, 0.89; 95% CI, 0.76–1.04; P = .15).404 Similar results were seen after a median follow-up of 5 years.405 The results of the phase III AVANT trial evaluating bevacizumab in the adjuvant setting in a similar protocol also did not show a benefit associated with bevacizumab in the adjuvant treatment of stage II or III CRC, and in fact showed a trend

toward a detrimental effect to the addition of bevacizumab.406,407

Furthermore, results of the open-label, randomized, phase III QUASAR 2 trial showed that bevacizumab had no benefit in the adjuvant colorectal setting when added to capecitabine.408 Therefore, bevacizumab has no role in the adjuvant treatment of stage II or III colon cancer.

The NCCTG Intergroup phase III trial N0147 assessed the addition of

cetuximab to FOLFOX in the adjuvant treatment of stage III colon cancer. In patients with wild-type or mutant KRAS tumors, cetuximab provided no added benefit and was associated with increases in grade 3/4 AEs.409 In addition, all subsets of patients treated with cetuximab experienced

increases in grade 3/4 AEs. The open-label, randomized, phase III

PETACC-8 trial also compared FOLFOX with and without cetuximab.410

Analysis of the wild-type KRAS exon 2 subset found that DFS was similar in both arms (HR, 0.99; 95% CI, 0.76–1.28), while AEs (ie, rash, diarrhea, mucositis, infusion-related reactions) were more common in the cetuximab group. However, a more recent analysis of PETACC-8 that looked at

mutations in KRAS, NRAS, and BRAF found that patients with RAS wildtype/BRAF wild-type tumors had a non-significant trend towards improved DFS (HR, 0.76) for the addition of cetuximab to FOLFOX.411 Therefore, cetuximab also has no role in the adjuvant treatment of colon cancer at this time, but further trials may define a subset of patients who might

benefit from cetuximab in the adjuvant setting.

A randomized phase III trial (NSABP C-07) compared the efficacy of FLOX with that of bolus 5-FU/LV in 2407 patients with stage II or III colon cancer. While FLOX showed significantly higher rates of 4- and 7-year DFS, 326,412 no statistically significant differences in OS or colon-cancer–specific

mortality were observed when the arms were compared. Furthermore,

survival after disease recurrence was significantly shorter in the group receiving oxaliplatin (HR, 1.20; 95% CI, 1.00–1.43; P = .0497).326 Grade 3 neurotoxicity, diarrhea, and dehydration were higher with FLOX than with 5-FU/LV,326 and, when cross-study comparisons were made, the incidence of grade 3/4 diarrhea seemed to be considerably higher with FLOX than

with FOLFOX. For example, rates of grade 3/4 diarrhea were 10.8% and

6.6% for patients receiving FOLFOX and infusional 5-FU/LV in the

MOSAIC trial,303 whereas 38% and 32% of patients were reported to have grade 3/4 diarrhea in the NSABP C-07 trial when receiving FLOX and

bolus 5-FU/LV.412 For these reasons, FLOX is no longer recommended as adjuvant treatment for colon cancer.

Perioperative Chemoradiation

Neoadjuvant or adjuvant radiation therapy (RT) delivered concurrently with fluoropyrimidine–based chemotherapy may be considered for very select patients with disease characterized as T4 tumors penetrating to a fixed

Perioperative Chemoradiation

Management of Metastatic Disease

structure or for patients with recurrent disease.413 RT fields should include the tumor bed as defined by preoperative radiologic imaging and/or

surgical clips. Intraoperative RT (IORT), if available, should be considered for these patients as an additional boost.414,415 If IORT is not available, an additional 10 to 20 Gy of external beam RT (EBRT) and/or brachytherapy could be considered to a limited volume.

Chemoradiation can also be given to patients with locally unresectable

disease or who are medically inoperable. In such cases, surgery with or without IORT can then be considered or additional lines of systemic

therapy can be given.

Intensity-modulated RT (IMRT), which uses computer-assisted inverse treatment planning to focus radiation to the tumor site and potentially

decrease toxicity to normal tissue,416 or stereotactic body RT (SBRT; also called stereotactic ablative radiotherapy [SABR]) are preferred for unique clinical situations, such as reirradiation of previously treated patients with recurrent disease or anatomical situations where IMRT facilitates the

delivery of recommended target volume doses while respecting accepted normal issue dose-volume constraints.417

Management of Metastatic Disease

Approximately 50% to 60% of patients diagnosed with CRC develop

colorectal metastases,418-420 and 80% to 90% of these patients have

unresectable metastatic liver disease.419,421-424 Metastatic disease most

frequently develops metachronously after treatment for locoregional CRC, with the liver being the most common site of involvement.425 However,

20% to 34% of patients with CRC present with synchronous liver

metastases.424,426 Some evidence indicates that synchronous metastatic colorectal liver disease is associated with a more disseminated disease state and a worse prognosis than metastatic colorectal liver disease that develops metachronously. In a retrospective study of 155 patients who

underwent hepatic resection for colorectal liver metastases, patients with synchronous liver metastases had more sites of liver involvement (P =

.008) and more bilobar metastases (P = .016) than patients diagnosed

with metachronous liver metastases.427

It has been estimated that more than half of patients who die of CRC have liver metastases at autopsy, with metastatic liver disease being the cause of death in most patients.428 Reviews of autopsy reports of patients who died from CRC showed that the liver was the only site of metastatic

disease in one-third of patients.423 Furthermore, several studies have

shown rates of 5-year survival to be low in patients with metastatic liver disease not undergoing surgery.419,429 Certain clinicopathologic factors, such as the presence of extrahepatic metastases, the presence of more than three tumors, and a disease-free interval of <12 months, have been associated with a poor prognosis in patients with CRC.426,430-434

Contrast-enhanced ultrasound (CEUS) can be used for detection and

characterization of liver lesions as a screening tool in distinct patient

populations. This population includes those who cannot safely receive

contrast-enhanced CT/MRI and those who have indeterminate liver lesion on CT/MRI. Ultrasound contrast agents (UCAs) have a high sensitivity for detecting small liver metastases because of their high spacial resolution and their ability to be maintained in circulation and not in the interstitial

f luid.435 Because of the UCAs’ short half-life (about 5 minutes), contrast injection for lesion detection needs to be done repeatedly; if a patient has many liver metastases the ultrasound could be a lengthy test. In addition, many institutions do not have this technology or personnel with the

expertise to perform the CEUS and/or analyze the results. At this time

CEUS can be considered in certain patient populations as a screening tool at capable institutions.

Surgical Management of Colorectal Metastases

Studies of selected patients undergoing surgery to remove colorectal liver metastases have shown that cure is possible in this population and should be the goal for a substantial number of these patients.419,436 Reports have shown 5-year DFS rates of approximately 20% in patients who have

undergone resection of liver metastases,431,434 and a meta-analysis

reported a median 5-year survival of 38%.437 In addition, retrospective

analyses and meta-analyses have shown that patients with solitary liver metastases have a 5-year OS rate as high as 71% following resection.438-440 Therefore, decisions relating to patient suitability, or potential suitability, and subsequent selection for metastatic colorectal surgery are critical

In another trial (COST study) of 872 patients with colon cancer randomly assigned to undergo either open or laparoscopic-assisted colectomy for curable colon cancer, similar 5-year recurrence and 5-year OS rates were seen after a median of 7-year follow-up.279,280 A similar RCT in Australia and New Zealand also found no differences in disease outcomes.281 In addition, results of several meta-analyses have supported the conclusion that the two surgical approaches provide similar long-term outcomes with respect to local recurrence and survival in patients with colon cancer.282-287 Factors have been described that may confound conclusions drawn from

randomized studies comparing open colectomy with laparoscopic-assisted surgery for colon cancer.288,289

A subanalysis of results from the COLOR trial evaluating short-term

outcomes (eg, conversion rate to open colectomy, number of lymph nodes

collected, number of complications) based on hospital case volume

indicated that these outcomes were statistically significantly more

favorable when laparoscopic surgery was performed at hospitals with high case volumes.290 A meta-analysis of 18 studies (6153 patients) found a lower rate of cardiac complications with laparoscopic colectomy compared with open resection.291 Analyses of large national databases also support the benefits of the laparoscopic approach.292,293

In recent years, perioperative care has improved, with reductions in the average length of hospital stay and complication rates after surgery.294,295 The multicenter, randomized, controlled EnROL trial therefore compared conventional and laparoscopic colectomy with an enhanced recovery

program in place.296 Outcomes were the same in both arms, with the

exception of median length of hospital stay, which was significantly shorter in the laparoscopic group (5 vs. 7 days; P = .033).

Robotic colectomy has been compared to the laparoscopic approach,

mostly with observational cohort studies.297-300 In general, the robotic

approach results in longer operating times and is more expensive but may be associated with less blood loss, shorter time to recovery of bowel

function, shorter hospital stays, and lower rates of complications and

infections.

The Panel recommends that minimally invasive colectomy be considered only by surgeons experienced in the techniques. A thorough abdominal exploration is required as part of the procedure. Routine use of minimally invasive colon resection is generally not recommended for tumors that are acutely obstructed or perforated or tumors that are clearly locally invasive

Adjuvant Chemotherapy for Resectable Colon Cancer

into surrounding structures (ie, T4). Patients at high risk for prohibitive abdominal adhesions should not have minimally invasive colectomy, and those who are found to have prohibitive adhesions during exploration should be converted to an open procedure.235,301,302

Adjuvant Chemotherapy for Resectable Colon Cancer

Choices for adjuvant therapy for patients with resected, nonmetastatic colon cancer depend on the stage of disease:

• Patients with stage I disease and patients with MSI-H, stage II disease do not require any adjuvant therapy.

• Patients with low-risk stage II disease that is MSS or pMMR can be observed without adjuvant therapy or considered for capecitabine or 5-FU/LV. Based on results of the MOSAIC trial,303-305 and the possible long-term sequelae of oxaliplatin-based chemotherapy,the Panel does not consider FOLFOX (infusional 5-FU, LV,

oxaliplatin) to be an appropriate adjuvant therapy option for

patients with stage II disease without high-risk features.

• Patients with stage II disease that is MSS/pMMR and at high risk for systemic recurrence, defined as those with poor prognostic features, including T4 tumors (stage IIB/IIC); poorly

differentiated/undifferentiated histology; lymphovascular invasion;PNI; tumor budding; bowel obstruction; lesions with localized

perforation or close, indeterminate, or positive margins; or

inadequately sampled nodes (<12 lymph nodes), can be

considered for 6 months of adjuvant chemotherapy with 5-FU/LV,capecitabine, or FOLFOX, or 3 months of adjuvant chemotherapy with CAPEOX (capecitabine and oxaliplatin).125,306 Observation

without adjuvant therapy is also an option in this population. The factors in decision-making for stage II adjuvant therapy are

discussed in more detail below.

• For patients with low-risk (T1–3, N1) stage III disease, the

preferred adjuvant treatment options are 3 months of CAPEOX307-309 or 3 to 6 months of FOLFOX.303-305,309 Other treatment options include 6 months of single-agent capecitabine310 or 5-FU/LV in

patients for whom oxaliplatin therapy is believed to be

inappropriate.311-314

• For patients with high-risk (T4, N1–2 or any T, N2) stage III

disease, the preferred adjuvant treatment options are 6 months of FOLFOX303-305 or 3 to 6 months of CAPEOX.307-309 Other treatment options include 6 months of single-agent capecitabine310 or 5-

FU/LV in patients for whom oxaliplatin therapy is believed to be

Population and institutional studies have shown that patients with resected colon cancer treated with adjuvant therapy have a survival advantage over those not treated with adjuvant therapy.315-317 For example, patients from the National Cancer Database with stage III or high-risk stage II disease treated according to these NCCN Guidelines for Colon Cancer had a

survival advantage over patients whose treatment did not adhere to these guidelines.315 A retrospective cohort study of 852 patients with any stage of colon or rectal cancer treated at Memorial University Medical Center in Savannah, Georgia similarly found that concordance with the

recommendations in these NCCN Guidelines for Colon Cancer resulted in a lower risk of death.317

Endpoints for Adjuvant Chemotherapy Clinical Trials

The Adjuvant Colon Cancer End Points (ACCENT) collaborative group evaluated the appropriateness of various endpoints for adjuvant

chemotherapy trials in colon cancer. Results of an analysis of individual patient data from 20,898 patients in 18 randomized colon adjuvant clinical trials by the ACCENT group suggested that DFS after 2 and 3 years of follow-up are appropriate endpoints for clinical trials involving treatment of

Endpoints for Adjuvant Chemotherapy Clinical Trials

Adjuvant Chemotherapy in Stage II Disease

colon cancer with 5-FU–based chemotherapy in the adjuvant setting.318 An update of this analysis showed that most relapses occur within 2 years after surgery, and that recurrence rates were <1.5% per year and <0.5% per year after 5 and 8 years, respectively.319 More recently, however, a further update of the data suggested that the association between 2- or 3-year DFS and 5-year OS was reduced when patient survival after

recurrence was hypothetically prolonged to match the current time to

survival from recurrence seen with modern combination therapies (2

years), and that >5 years may now be required to evaluate the effect of adjuvant therapies on OS.320 Further confirmation of this result comes from a new analysis by the ACCENT group of data from 12,676 patients

undergoing combination therapies from six trials.321 This study determined that 2- and 3-year DFS correlated with 5- and 6-year OS in patients with stage III disease but not in those with stage II disease. In all patients, the correlation of DFS to OS was strongest at 6-year follow-up, suggesting that at least 6 years are required for adequate assessment of OS in

modern adjuvant colon cancer trials.321

Adjuvant Chemotherapy in Stage II Disease

The impact of adjuvant chemotherapy for patients with stage II colon

cancer has been addressed in several clinical trials and practice-based studies.125,303-306 Results from a 2015 meta-analysis of 25 high-quality

studies showed that 5-year DFS in patients with stage II colon cancer who did not receive adjuvant therapy was 81.4% (95% CI, 75.4–87.4), whereas it was 79.3% (95% CI, 75.6–83.1) for patients with stage II colon cancer treated with adjuvant chemotherapy.322 On the other hand, for patients with stage III colon cancer, the 5-year DFS was 49.0% (95% CI, 23.2–

74.8) and 63.6% (95% CI, 59.3–67.9) in those treated without and with adjuvant chemotherapy, respectively. These results suggest that the

benefit of adjuvant therapy is greater in patients at higher risk because of nodal status. In contrast to results from most other trials, the QUASAR trial indicated a small but statistically significant survival benefit for patients

with stage II disease treated with 5-FU/LV compared to patients not

receiving adjuvant therapy (RR of recurrence at 2 years, 0.71; 95% CI,

0.54–0.92; P = .01).323 In this trial, however, approximately 64% of patients had <12 lymph nodes sampled, and thus actually may have been patients with higher risk disease who were more likely to benefit from adjuvant

therapy.324

The benefit of oxaliplatin in adjuvant therapy for patients with stage II

colon cancer has also been addressed. Results from a post-hoc

exploratory analysis of the MOSAIC trial did not show a significant DFS benefit of FOLFOX over 5-FU/LV for patients with stage II disease at a follow-up of 6 years (HR, 0.84; 95% CI, 0.62–1.14; P = .258).325 After

longer follow-up, no difference in 10-year OS was observed in the stage II subpopulation (79.5% vs. 78.4%; HR, 1.00; P = .98).305 In addition,

patients with high-risk stage II disease (ie, disease characterized by at

least one of the following: T4 tumor; tumor perforation; bowel obstruction; poorly differentiated tumor; venous invasion; <10 lymph nodes examined) receiving FOLFOX did not have improved DFS compared with those

receiving infusional 5-FU/LV (HR, 0.72; 95% CI, 0.50–1.02; P = .063). Furthermore, no OS benefit was seen in the stage II population overall or in the stage II population with high-risk features. Similar results were seen in the C-07 trial, which compared FLOX to 5-FU/LV in patients with stage II and III disease.326 Results of a large population-based study also

support the lack of benefit of the addition of oxaliplatin to adjuvant

regimens for patients with stage II colon cancer.327

Clinical trial results are supported by data from the community setting.

Using the SEER databases, a 2002 analysis of outcomes of patients with stage II disease based on whether or not they had received adjuvant

chemotherapy showed no statistically significant difference in 5-year OS between the groups (78% vs. 75%, respectively), with an HR for survival of 0.91 (95% CI, 0.77–1.09) when patients receiving adjuvant treatment

were compared with patients who had not received adjuvant treatment.328 In contrast, a 2016 analysis of 153,110 patients with stage II colon cancer from the National Cancer Database found that adjuvant treatment was

associated with improved survival (HR, 0.76; P < .001) even after

adjustment for comorbidity and unplanned hospital readmissions.327

Results of another population-level analysis from the Netherlands

published in 2016 suggest that the benefit of adjuvant therapy in patients with stage II colon cancer may be limited to those with pT4 tumors.329

Decision-making regarding the use of adjuvant therapy for patients with stage II disease should incorporate patient/physician discussions

individualized for the patient, and should include explanations of the

specific characteristics of the disease and its prognosis and the evidence related to the efficacy and possible toxicities associated with treatment, centering on patient choice.306,330,331 Observation and participation in a

clinical trial are options that should be considered. Patients with averagerisk stage II colon cancer have a very good prognosis, so the possible

benefit of adjuvant therapy is small. Patients with disease with high-risk features, on the other hand, traditionally have been considered more likely to benefit from adjuvant chemotherapy. However, the current definition of high-risk stage II colon cancer is clearly inadequate, because many

patients with disease with high-risk features do not have a recurrence

while some patients with disease deemed to be average-risk do.332

Furthermore, no data point to features that are predictive of benefit from adjuvant chemotherapy, and no data correlate risk features and selection of chemotherapy in patients with high-risk stage II disease.

Overall, the NCCN Panel supports the conclusion of a 2022 ASCO Panel and believes that it is reasonable to accept the relative benefit of adjuvant therapy in stage III disease as indirect evidence of benefit for stage II

disease, especially for those with high-risk features.306 Additional

information that may influence adjuvant therapy decisions for stage II

and/or stage III disease (MSI, multigene assays, and the influence of patient age) is discussed below. Research into additional possible

predictive markers may allow for more informed decision-making in the future.333,334

Microsatellite Instability

MSI is an important piece of information to consider when deciding

whether to use adjuvant chemotherapy in patients with stage II disease. Mutation of MMR genes or modifications of these genes (eg, methylation) can result in MMR protein deficiency and MSI (see Risk Assessment,

above).335 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 MSS.336 Patients with tumors determined to have dMMR status are

biologically the same population as those with MSI-H status.

Germline mutations in the MMR genes MLH1, MSH2, MSH6, and/or

PMS2 or EpCAM are found in individuals with Lynch syndrome, which is responsible for 2% to 4% of colon cancer cases.15,16,20,21 Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors,337 whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors.338

Data from the PETACC-3 trial showed that tumor specimens characterized as MSI-H are more common in stage II disease than in stage III disease (22% vs. 12%, respectively; P < .0001).339 In another large study, the

percentage of stage IV tumors characterized as MSI-H was only 3.5%.340 These results suggest that MSI-H (ie, dMMR) tumors have a decreased likelihood to metastasize. In fact, substantial evidence shows that in

patients with stage II disease, a deficiency in MMR protein expression or MSI-H tumor status is a prognostic marker of a more favorable

outcome.341-343 In contrast, the favorable impact of dMMR on outcomes

Microsatellite Instability

seems to be more limited in stage III colon cancer and may vary with

primary tumor location.341,344

Some of these same studies also show that a deficiency in MMR protein expression or MSI-H tumor status may be a predictive marker of

decreased benefit and possibly a detrimental impact from adjuvant therapy with a fluoropyrimidine alone in patients with stage II disease.342,343,345 A retrospective study involving long-term follow-up of patients with stage II and III disease evaluated according to MSI tumor status showed that

those characterized as MSI-L or MSS had improved outcomes with 5-FU adjuvant therapy. However, patients with tumors characterized as MSI-H did not show a statistically significant benefit from 5-FU after surgery,

instead exhibiting a lower 5-year survival rate than those undergoing

surgery alone.342 Similarly, results from another retrospective study of

pooled data from adjuvant trials by Sargent et al343 showed that in tumors characterized as dMMR, adjuvant 5-FU chemotherapy seemed to be

detrimental in patients with stage II disease, but not in those with stage III disease.

In contrast to the findings of Sargent et al,343 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 (the

recurrence rate of dMMR tumors was 11% vs. 26% for pMMR tumors), it did not predict benefit or detrimental impact of chemotherapy.324 A study of patients in the CALGB 9581 and 89803 trials came to a similar

conclusion.346 MMR status was prognostic but not predictive of benefit or detrimental impact of adjuvant therapy (irinotecan plus bolus 5-FU/LV [IFL regimen]) in patients with stage II colon cancer.

The Panel recommends universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer to identify individuals with

Lynch syndrome (see Lynch Syndrome, above), to inform use of

immunotherapy in patients with metastatic disease (see Biomarkers for

Systemic Therapy, below), and to inform decisions for patients with stage II disease. Patients with stage II MSI-H tumors may have a good

prognosis and do not benefit from 5-FU adjuvant therapy, and adjuvant therapy should not be given to patients with low-risk stage II MSI-H

tumors. An exception is with T4b (stage IIC) dMMR/MSI-H tumors, which may carry a higher risk compared to other dMMR/MSI-H stage II tumors. For these patients, f luoropyrimidine-based adjuvant therapy, with or

without oxaliplatin, may be considered. It should be noted that poorly

differentiated histology is not considered a high-risk feature for patients with stage II disease whose tumors are MSI-H.

Multigene Assays, Immunoscore, and Circulating Tumor DNA

Several assays have been developed in hopes of providing prognostic and predictive information to aid in decisions regarding adjuvant therapy in

patients with stage II or III colon cancer.

Oncotype DX colon cancer assay quantif ies the expression of seven

recurrence-risk genes and five reference genes as a prognostic classifier of low, intermediate, or high likelihood of recurrence.347 Clinical validation in patients with stage II and III colon cancer from QUASAR348 and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07349 trials

showed that recurrence scores are prognostic for recurrence, DFS, and OS in stage II and III colon cancer, but are not predictive of benefit to

adjuvant therapy. For the low, intermediate, and high recurrence risk

groups, recurrence at 3 years was 12%, 18%, and 22%, respectively.348 Multivariate analysis showed that recurrence scores were related to

recurrence independently from TNM staging, MMR status, tumor grade, and number of nodes assessed in both stage II and III disease. Similar results were found in a prospectively designed study that tested the

correlation between recurrence score using the Oncotype DX colon cancer assay and the risk of recurrence in patients from the CALGB 9581 trial (stage II disease).350 An additional prospectively designed clinical

Multigene Assays, Immunoscore, and Circulating Tumor DNA

validation study in patients from the NSABP C-07 trial found that the assay results correlated with recurrence, DFS, and OS.349 This study also found some evidence that patients with higher recurrence scores may derive more absolute benefit from oxaliplatin, although the authors noted that the recurrence score is not predictive of oxaliplatin efficacy in that it does not identify patients who will or will not benefit from oxaliplatin treatment. An additional study validated the recurrence score in patients with stage II/III colon cancer treated with surgery alone.351

ColoPrint quantif ies the expression of 18 genes as a prognostic classifier of low versus high recurrence risk.352 In a set of 206 patients with stage I–III CRC, the 5-year RFS rates were 87.6% (95% CI, 81.5–93.7) and 67.2% (95% CI, 55.4–79.0) for those classified as low and high risk, respectively. In patients with stage II disease in particular, the HR for recurrence

between the high and low groups was 3.34 (P = .017).352 This assay was further validated in a pooled analysis of 416 patients with stage II disease, 301 of whom were assessed as a T3/MSS subset.353 In the T3/MSS

subset, patients classified as low risk and high risk had a 5-year risk of relapse (survival until f irst event of recurrence or death from cancer) of

22.4% and 9.9%, respectively (HR, 2.41; P = .005). As with the Oncotype DX colon cancer assay, recurrence risk determined by ColoPrint is

independent of other risk factors, including T stage, perforation, number of nodes assessed, and tumor grade. This assay is being further validated for its ability to predict 3-year relapse rates in patients with stage II colon cancer in a prospective trial (NCT00903565).

ColDx is a microarray-based multigene assay that uses 634 probes to

identify patients with stage II colon cancer at high risk of recurrence.354 In a 144-sample independent validation set, the HR for identif ication of

patients with high-risk disease was 2.53 (95% CI, 1.54–4.15; P < .001) for recurrence and 2.21 (95% CI, 1.22–3.97; P = .0084) for cancer-related death. A cohort study of patients in the C9581 trial found that patients with

stage II colon cancer identif ied as high risk by ColDx had a shorter

recurrence-free interval than those identif ied as low-risk (multivariable HR,

2.13; 95% CI, 1.3–3.5; P < .01).355 Similar to the other assays described here, the recurrence risk determined by ColDx is independent of other risk factors.

An international study led by the Society for Immunotherapy of Cancer aimed to validate Immunoscore, a scoring system reported as percentiles of CD3+ and CD8+ immune cell densities in prespecified regions of the tumor sample by dedicated software, for the assay’s prognostic value in patients with stage III colon cancer as well as its predictive value for

efficacy of adjuvant chemotherapy in these patients.356 This study reported that patients with the highest Immunoscore showed the lowest risk of

recurrence; 3-year RFS rates were 56.9%, 65.9%, and 76.4% for low,

medium, and high Immunoscore (HR [high vs. low], 0.48; 95% CI, 0.32–

0.71; P = .0003). A high Immunoscore also correlated with prolonged time to recurrence, OS, and DFS (all P < .001). The benefit of adjuvant

chemotherapy was also associated with a high Immunoscore for both

high-risk (P = .0015) and low-risk (P = .0011) tumors. The same was not true for tumors with a low Immunoscore (P > .12).

Post-surgical circulating tumor DNA (ctDNA) has also been studied as a marker for an elevated risk of recurrence in stage I–III colon cancer. A prospective, multicenter study of 130 patients with stage I–III colon cancer detected ctDNA by multiplex, PCR-based next-generation sequencing

(NGS).357 Thirty days after surgery, patients with positive ctDNA assays were seven times more likely to experience disease relapse than patients with negative ctDNA assays (HR, 7.2; 95% CI, 2.7–19.0; P < .001).

Likewise, after adjuvant chemotherapy, patients with ctDNA-positive

assays were 17 times more likely to have disease relapse (HR, 17.5; 95% CI, 5.4–56.5; P < .001). Another prospective study of 150 patients with localized colon cancer detected ctDNA with NGS following surgery.358 In

this study, detection of ctDNA was also associated with poorer DFS (HR,

17.56; log rank P = .0014 for ctDNA post-surgery and HR, 11.33; log rank P = .0001 for ctDNA in serial plasma samples during follow-up). Other

studies have reported similar results.359,360

In the DYNAMIC study, 455 patients with stage II colon cancer were

randomized to either ctDNA-guided management or standard

management.361 After a median follow-up of 37 months, a lower

percentage of patients in the ctDNA-guided management group received adjuvant chemotherapy compared to the standard management group

(15% vs. 28%; RR, 1.82; 95% CI, 1.25–2.65). Two-year RFS in the

ctDNA-guided management group was noninferior to the standard

management group (93.5% vs. 92.4%). An abstract reporting 5-year

results from the DYNAMIC study showed similar results, including mature OS data. Five-year RFS rates were 88% and 87% and 5-year OS rates were 93.8% and 93.3% for ctDNA-guided and standard management,

respectively.362

The GALAXY observational arm from the ongoing CIRCULATE-Japan

study has analyzed presurgical and postsurgical ctDNA in 1039 patients with stage II–IV resectable CRC.363 With a median follow-up of 16.74

months in this cohort, postsurgical ctDNA positivity at 4 weeks after

surgery was associated with a higher recurrence risk (HR, 10.0; P <

.0001) and identif ied patients with stage II or III CRC who derived a benefit from adjuvant chemotherapy (HR, 6.59; P < .0001). While these results support ctDNA as a prognostic marker, details such as the timing of the assay and the value of quantif ication of ctDNA are the subject of ongoing studies. Most importantly, the early detection of recurrent disease through ctDNA testing is not without drawbacks. A positive result in the absence of evident disease is only helpful if the patient has therapeutic options that have a reasonable chance to eradicate the disease. Early knowledge of

cancer recurrence in the absence of effective interventions could cause significant distress to a patient.

In summary, the information from these tests can further inform the risk of recurrence over other risk factors, but the Panel questions the value

added. Furthermore, evidence of predictive value in terms of the potential benefit of chemotherapy is lacking. Therefore, the Panel believes that

there are insufficient data to recommend the use of multigene assays,

Immunoscore, or post-surgical ctDNA to estimate risk of recurrence or determine adjuvant therapy. ESMO has released similar recommendations regarding these assays, stating that their role in predicting chemotherapy benefit is uncertain.364 The NCCN Panel encourages enrollment in clinical trials to help with the generation of additional data on these assays.

Adjuvant Chemotherapy in Older Patients

Adjuvant chemotherapy usage declines with the age of the patient.365

Questions regarding the safety and efficacy of chemotherapy in older

patients have been diff icult to answer, because older patients are

underrepresented in clinical trials. Some data speaking to these questions have been reviewed.366-368

Population studies have found that adjuvant therapy is beneficial in older patients. A retrospective analysis of 7263 patients from the linked SEERMedicare Databases found a survival benefit for the use of 5-FU/LV in patients ≥65 years with stage III disease (HR, 0.70; P < .001).369 Another analysis of 5489 patients aged ≥75 years diagnosed with stage III colon cancer between 2004 and 2007 from four datasets, including the SEERMedicare Databases and the NCCN Outcomes Database, showed a

survival benefit for adjuvant chemotherapy in this population (HR, 0.60; 95% CI, 0.53–0.68).365 This study also looked specifically at the benefit of the addition of oxaliplatin to adjuvant therapy in these patients ≥75 years with stage III disease, and found only a small, non-significant benefit.

Analysis of almost 12,000 patients from the ACCENT database also found

Adjuvant Chemotherapy in Older Patients

a reduced benefit to the addition of oxaliplatin to fluoropyrimidines in the adjuvant setting in patients ≥70 years.370

Subset analyses of major adjuvant therapy trials also show a lack of

benefit to the addition of oxaliplatin in older patients. Subset analysis of the NSABP C-07 trial showed that the addition of oxaliplatin to 5-FU/LV gave no survival benefit in patients ≥70 years with stage II or III colon

cancer (n = 396), with a trend towards decreased survival (HR, 1.18; 95% CI, 0.86–1.62).326 Similarly, in a subset analysis of the MOSAIC trial, 315 patients aged 70 to 75 years with stage II or III colon cancer derived no benefit from the addition of oxaliplatin (OS HR, 1.10; 95% CI, 0.73–

1.65).325

junctures in the management of metastatic colorectal liver disease

(discussed further in Determining Resectability).441

Colorectal metastatic disease sometimes occurs in the lung.418 Most of the treatment recommendations discussed for metastatic colorectal liver

disease also apply to the treatment of colorectal pulmonary

metastases.248,442,443 A series of 378 patients found that resection of

pulmonary metastases resulted in a 3-year RFS of 28% and a 3-year OS of 78%.248 Combined pulmonary and hepatic resections of resectable

metastatic disease have been performed in very highly selected cases,444-448 and an analysis of patients who underwent hepatic resection followed by subsequent pulmonary resection showed positive outcomes.449

Evidence supporting resection of extrahepatic metastases in patients with mCRC is limited. In a retrospective analysis of patients undergoing

concurrent complete resection of hepatic and extrahepatic disease, the 5-year survival rate was lower than in patients without extrahepatic disease, and virtually all patients who underwent resection of extrahepatic

metastases experienced disease recurrence.450,451 However, an

international analysis of 1629 patients with colorectal liver metastases

showed that 16% of the 171 patients (10.4%) who underwent concurrent

resection of extrahepatic and hepatic disease remained disease-free at a median follow-up of 26 months, suggesting that concurrent resection may be of significant benefit in well-selected patients (ie, those with a smaller total number of metastases).448 A systematic review concluded similarly that carefully selected patients might benefit from this approach.452

Data suggest that a surgical approach to the treatment of recurrent hepatic disease isolated to the liver can be safely undertaken.453-458 However, in a retrospective analysis, 5-year survival was shown to decrease with each subsequent curative-intent surgery, and the presence of extrahepatic

disease at the time of surgery was independently associated with a poor prognosis.454 In a more recent retrospective analysis of 43 patients who underwent repeat hepatectomy for recurrent disease, 5-year OS and PFS rates were reported to be 73% and 22%, respectively.453 A meta-analysis of 27 studies including <7200 patients found that those with longer

disease-free intervals; those whose recurrences were solitary, smaller, or unilobular; and those lacking extrahepatic disease derived more benefit from repeat hepatectomy.459 Panel consensus is that re-resection of liver or lung metastases can be considered in carefully selected

patients.443,457,460

Patients with a resectable primary colon tumor and resectable

synchronous metastases can be treated with a staged or simultaneous

resection, as discussed below in Recommendations for Resectable

Synchronous Liver or Lung Metastases. For patients presenting with

unresectable metastases and an intact primary that is not acutely

obstructed, palliative resection of the primary is rarely indicated, and

systemic therapy is the preferred initial maneuver (discussed further in Recommendations for Unresectable Synchronous Metastases).461

Local Therapies for Metastases

The standard of care for patients with resectable metastatic disease is

surgical resection. Image-guided thermal ablation has historically been

used for non-surgical patients462-464 but is also indicated in resectable

patients with small metastases where sufficient ablative margins can be achieved.465 Ablation is offered in combination with surgery or alone, as long as all visible disease is treated.466 The use of ablation instead of

resection is supported by recent evidence of high local tumor control rates (>93%) when thermal ablation with confirmation of tumor-free ablation

zone and margins can be achieved467-469 and within the concept of test of time.470 With this approach ablation can be offered ahead of resection for small tumors that can be treated with margins and with close follow-up for early detection of local progression or recurrence. This strategy allows for local tumor eradication while also allowing for biology of disease to be

declared over time. Most cases are controlled by ablation alone, whereas patients who develop multifocal progression in a short period of time are spared the more morbid resection. In cases where local progression or recurrence is seen, resection can be offered at a later time.470

SBRT is a reasonable option for patients whose disease cannot be

resected or ablated, as discussed in subsequent paragraphs.422,471,472

Many patients, however, are not surgical candidates and/or have disease that cannot be ablated with clear margins464 or safely treated by SBRT. In select patients with liver-only or liver-dominant metastatic disease that

cannot be resected or ablated, other local, arterially directed treatment

options may be offered.473-475

Recently, the administration of yttrium-90 microspheres in high radiation (ablative) doses (RADSEG) has been described as a local cure for limited liver metastases that cannot be technically resected or ablated. At least three small retrospective cohorts have shown very high response rates, favorable liver disease control, and patient survival in patients with liver

metastatic disease (including colorectal origin) after RADSEG.476-479 A

meta-analysis of 90 studies concluded that hepatic arterial infusion

chemotherapy (HAIC), yttrium-90 microsphere radioembolization, and

transcatheter arterial chemoembolization (TACE) have similar efficacy in patients with unresectable colorectal hepatic metastases.480 Local

therapies are described in more detail below. The exact role and timing of using non-extirpative local therapies in the treatment of colorectal

metastases remains controversial.

Hepatic Arterial Infusion

Placement of a hepatic arterial port or implantable pump during surgical intervention for liver resection with subsequent infusion of chemotherapy directed to the liver metastases through the hepatic artery (ie, HAIC) is an option (category 2B). In a randomized study of patients who had

undergone hepatic resection, administration of f loxuridine with

dexamethasone through HAIC and IV 5-FU with or without LV was shown to be superior to a similar systemic chemotherapy regimen alone with

respect to 2-year survival free of hepatic disease.423,481 The study was not

powered for long-term survival, but a trend (not significant) was seen

toward better long-term outcomes in the group receiving HAIC at later

follow-up periods.423,482

The phase II/III PRODIGE 43 PACHA-01 study included a phase II

portion, which was a non-comparative study that randomized patients who had undergone curative-intent hepatic resection of at least four colorectal liver metastases to adjuvant systemic FOLFOX or adjuvant HAIC with

oxaliplatin plus systemic 5-FU/LV.483 The intention-to-treat (ITT) analysis of the phase II portion of the trial showed a higher median 5-year hepatic RFS (h-RFS) in the HAIC arm compared to the control arm (25 vs. 12

months; HR, 0.598; 95% CI, 0.379–0.944; P = .027). Five-year OS was 60% in the HAIC arm compared to 46% in the control arm (P = .056). The rate of grade 3–4 AEs was 58% for HAIC compared to 31% for systemic

##### Transhepatic Arterial Chemoembolization

FOLFOX. The planned phase III portion of the trial was suspended for slow recruitment.484

Several other clinical trials have shown significant improvement in

response or time to hepatic disease progression when HAIC was

compared with systemic chemotherapy, although most have not shown a survival benefit of HAIC.423 Results of some studies also suggest that

HAIC may be useful in the conversion of disease from an unresectable to a resectable status.485,486

Some of the uncertainties regarding patient selection for preoperative

chemotherapy are also relevant to the application of HAIC.436 Limitations on the use of HAIC include the potential for biliary toxicity423 and the

requirement of specific technical expertise. Panel consensus is that HAIC should be considered selectively, and only at institutions with extensive experience in both the surgical and medical oncologic aspects of the

procedure.

Arterially Directed Embolic Therapy

Transhepatic Arterial Chemoembolization

TACE involves hepatic artery catheterization to locally deliver

chemotherapy followed by arterial occlusion.474 The most commonly

accepted variation for the treatment of mCRC involves the use of drugeluting bead TACE (DEB-TACE) using irinotecan as the chemotherapeutic agent (DEBIRI).487 A randomized trial reported an OS benefit (22 vs. 15 months; P = .031) of DEBIRI when compared to systemic FOLFIRI.488 A 2013 meta-analysis identif ied five observational studies and one

randomized trial and concluded that, although DEBIRI appears to be safe and effective for patients with unresectable colorectal liver metastases, additional trials are needed.489 A 2015 trial subsequently randomized 30 patients with colorectal liver metastases to FOLFOX/bevacizumab and 30 patients to FOLFOX/bevacizumab/DEBIRI.490 DEBIRI resulted in an

improvement in the primary outcome measure of response rate (78% vs. 54% at 2 months; P = .02).

Much of these data have been more recently validated in a single-arm

registry study of 152 patients with mCRC treated with DEBIRI across

Europe.491 The results of the CIREL study demonstrated DEBIRI to be feasible, safe, and performed with a high technical success rate leading its investigators to propose its use beyond subsequent-line indications alone. A 2023 single-arm study again demonstrated safety and efficacy of

DEBIRI, validating the results of the previously mentioned trials, with an OS of 15.3 months when used in the setting of patients who were able to tolerate more cycles of chemotherapy.492

Radioembolization

A prospective, randomized, phase III trial of 44 patients showed that

radioembolization combined with chemotherapy can lengthen time to

progression in patients with liver-limited mCRC following progression on initial therapy (2.1 vs. 4.5 months; P = .03).493 The effect on the primary endpoint of time to liver progression was more pronounced (2.1 vs. 5.5 months; P = .003). Treatment of liver metastases with yttrium-90 glass

radioembolization in a prospective, multicenter, phase II study resulted in a median PFS of 2.9 months for patients with colorectal primaries who

were refractory to standard treatment.494 In the refractory setting, a CEA level ≥90 and lymphovascular invasion at the time of primary resection

were negative prognostic factors for OS.495 Additional risk factors include tumor volume and liver replacement by disease as well as albumin and

bilirubin levels, performance status, and the presence of extrahepatic

disease for both glass496 and resin497 microspheres. Several large case series have been reported for yttrium-90 radioembolization in patients with refractory unresectable colorectal liver metastases, and the technique

appears to be safe with some clinical benefit.496,498,499 Median survival after radioembolization in the chemorefractory setting has been reported from 9

##### Radioembolization

to 15.1 months.494-499 Survival at 1 year from radioembolization of patients with heavily pretreated disease varies considerably based on the

accumulation of risk factors such as extrahepatic disease, large tumor

size, poor differentiation, higher CEA and alanine transaminase (ALT), and lower albumin levels.497

Results from the phase III randomized controlled SIRFLOX trial (yttrium-90 resin microspheres with FOLFOX ± bevacizumab vs. FOLFOX ±

bevacizumab) were reported.500 The trial assessed the safety and efficacy of yttrium-90 radioembolization as first-line therapy in 530 patients with colorectal liver metastases. Although the primary endpoint was not met, with PFS in the FOLFOX ± bevacizumab arm at 10.2 months versus 10.7 months in the FOLFOX/yttrium-90 arm (HR, 0.93; 95% CI, 0.77–1.12; P = .43), a prolonged liver PFS was demonstrated for the study arm (20.5

months for the FOLFOX/yttrium-90 arm vs. 12.6 months for the

chemotherapy only arm; HR, 0.69; 95% CI, 0.55–0.90; P = .002).

The FOXFIRE and FOXFIRE Global studies were performed in the same manner as the SIRFLOX trial with the intention to compile all data and

allow assessment of oncologic outcomes in a larger cohort.501 Pooled data from 1103 patients in these three prospective trials showed similar f indings as in the SIRFLOX trial with prolongation of the liver PFS in the group

treated by radioembolization but no difference in OS and PFS. Of interest was the finding of a median OS benefit with radioembolization plus

chemotherapy compared to chemotherapy alone in the subgroup of

patients with right-sided primary origin (22.0 vs. 17.1 months; HR, 0.641; P = .008).502 Based on these data, further investigation is needed to identify the role of radioembolization at earlier stages of disease in patients with right-sided primary origin.

Results from the EPOCH trial show the potential utility for

radioembolization in patients with liver-only mCRC who have progressed on first-line systemic therapy. EPOCH was a randomized phase III clinical

trial evaluating radioembolization in combination with second-line

chemotherapy in 428 patients with metastatic colorectal carcinoma of the liver who had progressed on oxaliplatin- or irinotecan-based first-line

chemotherapy.503 The results showed an improvement in PFS (8.0 vs. 7.2 months; HR, 0.69; P = .0013) and hepatic PFS (9.1 vs. 7.2 months; HR,

0.59; P < .0001) in favor of the radioembolization arm.

A retrospective study of yttrium-90 resin microsphere transarterial

radioembolization (TARE) indicated that patients with an overall response (OR) had an OS of 17.2 months versus 6.8 months for non-responders (P < .0001). In addition, a mean tumor dose of ≥100 Gy predicted a

significantly prolonged OS of 19 versus 11 months for those patients with tumors that received <100 Gy.504

In another study of glass microsphere yttrium-90 TARE, a median tumorabsorbed dose of 85 measurable metastases was 133 Gy. A significant dose-response relationship was found on a tumor level, with a significantly higher tumor-absorbed dose in metastases with complete response

(+94%) and partial response (+74%) compared to metastases with

progressive disease (P < .001). A tumor-absorbed dose of >139 Gy

predicted a 3-month metabolic response with the greatest accuracy. The median healthy liver-absorbed dose was 63 Gy. While a dose-toxicity

relationship was not established, treatment was generally well-tolerated. This significant relationship observed between dose and response in

patients treated with glass yttrium-90 radioembolization further

demonstrates the importance of tumor delivered dose and oncologic

outcomes.505

Whereas very little data show any impact on patient survival and the data supporting its efficacy are limited, toxicity with radioembolization is

relatively low.500,506-508 Consensus amongst Panel members is that

arterially directed catheter therapy and, in particular, yttrium-90

microsphere selective internal radiation is an option in highly selected

Tumor Ablation

patients with chemotherapy-resistant/-refractory disease and with predominant hepatic metastases.

Tumor Ablation

Resection is the standard approach for the local treatment of resectable metastatic disease. However, patients with liver or lung oligometastases can also be considered for tumor ablation therapy, particularly in cases that may not be optimal for resection,509,510 or for patients with resectable disease that can be ablated with sufficient margins and within the concept of the “test of time.”465 Ablative techniques include radiofrequency ablation (RFA),464,511 microwave ablation (MWA), cryoablation, and electrocoagulation (irreversible electroporation).512 There is extensive evidence on the use of RFA as a reasonable treatment option for non-surgical

candidates and for recurrent disease after hepatectomy with small liver metastases that can be treated with clear margins.464,511,513-515 More recent data describe outcomes of MWA that have been superior to RFA, mostly because of the ability of MWA to overcome the limitations of RFA and, in particular, those related to the heat sink phenomenon and the inability to completely ablate tumors when located near a blood vessel.516

A prospective cohort study investigated patient OS when treating

potentially resectable CRC liver metastasis with stereotactic MWA

(SMWA) as opposed to hepatic resection.517 Three-year OS rates were 78% for SMWA versus 76% for resection (P = .861). Estimated 5-year OS rates were 56% and 58%, respectively. Overall and major complications were lower after SMWA (P < .01), although hepatic retreatments were

more frequent (percentage increase 78%, P < .01). This supports the use of ablation in selected patients with small resectable CRC liver

metastases.

COLLISION is a randomized phase III trial comparing thermal ablation to resection of CRC liver metastases. According to an abstract presentation of data from the COLLISON trial, thermal ablation was shown to be

noninferior to liver resection in terms of local and distant PFS as well as OS.518 Thermal ablation showed lower rates of AEs, lower procedurerelated mortality, and a shorter median length of hospitalization. Based on these results, thermal ablation should be considered a valid and potentially less invasive alternative for treatment of small-size (≤3 cm) CRC liver

A 2012 phase II trial randomized 119 patients to receive systemic

treatment alone (FOLFOX with or without bevacizumab) or systemic

treatment plus RFA, with or without resection.519 No difference in OS was initially seen, but PFS was improved at 3 years in the RFA group (27.6% vs. 10.6%; HR, 0.63; 95% CI, 0.42–0.95; P = .025). A subsequent analysis following prolonged follow-up of the same population in this phase II RCT showed that OS was improved in the combined modality arm (HR, 0.58; 95% CI, 0.38–0.88; P = .01), with a 3-, 5-, and 8-year OS of 56.9%,

43.1%, and 35.9% for the combined modality arm compared to 55.2%,

30.3%, and 8.9% for the chemotherapy alone arm.466 This study

documented a long-term survival benefit for patients receiving RFA in

addition to chemotherapy compared to those treated by chemotherapy only. A 2018 meta-analysis compared RFA and MWA to systemic

chemotherapy and to partial hepatectomy in the treatment of CRC liver metastases and indicated that chemotherapy alone is no longer justif ied when metastases are amenable to thermal ablation.520 Furthermore, it

demonstrated that there was no difference in terms of local tumor control and OS between limited liver resection and MWA.

Data on ablative techniques other than RFA are growing.510,521-528

However, in a comparison of RFA with MWA, outcomes were similar with no local tumor progression for metastases ablated with margins >10 mm (A0) and a relatively better control of perivascular tumors with the use of MWA (P = .021).528 Similarly, two studies and a position paper by a panel of experts indicated that ablation may provide acceptable oncologic

outcomes for selected patients with small liver metastases that can be

ablated with sufficient margins.463,464,529 In fact, more recent data

demonstrated that with confirmation of ablative margins, local tumor

control after MWA can be >93%, which compares favorably with historic data for limited metastasectomy.468,530 Several publications have indicated that the significance of margin creation is particularly important for RASmutant metastases.531-533 Recent prospective467 and retrospective534 trials have also indicated the superiority of intraprocedural margin assessment in improving local tumor control of thermal ablation when treating CRC

liver metastases. The ongoing ACCLAIM trial (NCT05265169) is an

international multicenter single-arm phase II/III of microwave ablation

which mandates intraprocedural 3D margin assessments and immediate reablation when margins are <5 mm with the aim to provide local tumor control rates to over 90%.

Regarding pulmonary ablation, a large prospective database of two

French cancer centers that enrolled 566 consecutive patients with 1037 lung metastases (the majority colorectal in origin) received initial treatment with RFA and 136 patients (24%) underwent repeat RFA.535 PFS rates at years 1 through 4 were 40.2%, 23.3%, 16.4%, and 13.1%, respectively. Five-year OS after RFA in CRC pulmonary ablation ranged from 40.7% to

67.5% depending on risk factors. MWA has been used increasingly within the latest years with a report indicating no local progression for small

tumors ablated with margins of ≥5 mm.536 The major complication rate

within this database study was 13% with 75% of these including

pneumothoraces requiring prolonged hospitalization.

A multicenter, prospective phase II study (SOLSTICE) included 128

patients with 224 metastatic lung tumors that were targeted by pulmonary cryoablation.537 In this trial, investigators demonstrated a local response of the ablated tumor at 1 and 2 years of 85.1% and 77.2%, respectively. With the use of a second cryoablation for recurrent tumor, 1- and 2-year local

tumor control reached 91.1% and 84.4%, respectively. In this study, 1- and 2-year survival rates were 97.6% and 86.6%, respectively. The grade 3 and grade 4 complication rates were low, at 4.7% and 0.6%, although 26%of patients on this study had a pneumothorax requiring pleural catheter placement.

The ECLIPSE prospective, single-arm study aimed to evaluate the

feasibility and efficacy of cryoablation for local tumor control in patients

with pulmonary metastatic disease with 5 years of follow-up.538 The cohort included patients with 1 to 5 metastatic lung tumors, each with a diameter ≤3.5 cm. The primary endpoint was local tumor control, both per tumor and per patient; secondary endpoints included cancer-specific survival, OS, and quality of life. Overall local tumor control rates at 3 and 5 years were 87.9% and 79.2% per tumor and 83.3% and 75.0% per patient,

respectively. DSS was 74.8% at 3 years and 55.3% at 5 years, and OS was 63.2% at 3 years and 46.7% at 5 years. Patient quality-of-life scores did not reach statistical significance.

An emergent indication for ablation is the discontinuation of chemotherapy while controlling oligometastatic pulmonary disease.536,539 The median

chemotherapy-free survival (time interval between ablation and resuming chemotherapy or death without chemotherapy) was 12.2 months. Patients with no extrapulmonary metastases had a longer median chemotherapyfree survival compared to those without (20.9 vs. 9.2 months).539

Resection or ablation (either alone or in combination with resection)

should be reserved for patients with metastatic disease that is entirely

amenable to local therapy with adequate margins. Use of surgery,

ablation, or the combination of both modalities, with the goal of less-thancomplete eradication of all known sites of disease is not recommended other than in the scope of a clinical trial. Results from the ORCHESTRA trial were recently reported, which was a randomized phase III trial

investigating the addition of tumor debulking to first-line palliative systemic

Liver- or Lung-Directed External Beam Radiation

therapy in patients with multisite mCRC.540 The study included one third of patients with peritoneal disease, and tumor debulking was defined as

addressing ≥80% of metastatic disease with any combination of resection, radiation, and/or thermal ablation. No benefit in OS was observed with the addition of tumor debulking to systemic therapy alone (30.0 months with tumor debulking vs. 27.5 months with systemic therapy alone; HR, 0.88; 95% CI, 0.70–1.10; P = .225).

Liver- or Lung-Directed External Beam Radiation

EBRT to metastatic sites can be considered in selected cases in which the patient has a limited number of metastases, including the liver or lung or other select locations; or if the patient is symptomatic; or in the setting of a clinical trial. It should be delivered in a highly conformal manner and

should not be used in place of surgical resection. The possible techniques include three-dimensional conformal RT (CRT), SBRT,422,471,472,541 and

IMRT, which uses computer-assisted inverse treatment planning to focus radiation to the tumor site and potentially decrease toxicity to healthy

tissue.416,542-545

While CRC has been shown to be a relatively radioresistant

histology,546,547 multiple studies have demonstrated effective local control with minimal toxicity using SBRT in the treatment of liver542,548,549 and

lung550-555 metastases. In addition, data on the benefit of using SBRT to treat multiple metastatic lesions are emerging. SABR-COMET was a

randomized phase II trial with multiple cancer types, including a small

number of CRC origin, and ≤5 metastatic lesions in different organs that demonstrated an improvement in OS with the addition of SBRT to

standard-of-care treatment.556 An extended long-term analysis (5–10

years) of the SABR-COMET study showed durable improvements in OS and PFS with the addition of SBRT, with 21.3% of patients achieving >5 years without disease recurrence.557 In patients with liver- or lung-limited disease that is not amenable to complete resection or ablation, SBRT may

be considered as local therapy in centers with expertise. SBRT for the treatment of extrahepatic or extrapulmonary disease can be considered in select cases, or as part of a clinical trial.

Peritoneal Carcinomatosis

Approximately 17% of patients with mCRC have peritoneal

carcinomatosis, with 2% having the peritoneum as the only site of

metastasis. Patients with peritoneal metastases generally have a shorter PFS and OS than those without peritoneal involvement.122,558 The goal of treatment for most abdominal/peritoneal metastases is palliative, rather

than curative, and primarily consists of systemic therapy (see Systemic Therapy for Advanced or Metastatic Disease) with palliative surgery or stenting if needed for obstruction or impending obstruction.559-561 If an R0 resection can be achieved, however, surgical resection of isolated

peritoneal disease may be considered at experienced centers. The Panel cautions that the use of bevacizumab in patients with colon or rectal stents is associated with a possible increased risk of bowel perforation.562,563

Cytoreductive Debulking with Hyperthermic Intraperitoneal Chemotherapy

Several surgical series and retrospective analyses have addressed the role of CRS (ie, peritoneal stripping surgery) in combination with

perioperative HIPEC for the treatment of peritoneal carcinomatosis without extra-abdominal metastases.564-573 In an RCT of this approach, Verwaal et al randomized 105 patients to either standard therapy (5-FU/LV with or without palliative surgery) or to aggressive CRS and HIPEC with

mitomycin C; postoperative 5-FU/LV was given to 33 of 47 patients.574 OS was 12.6 months in the standard arm and 22.3 months in the HIPEC arm (P = .032). However, treatment-related morbidity was high, and the

mortality was 8% in the HIPEC group, mostly related to bowel leakage. In addition, long-term survival does not seem to be improved by this

treatment as seen by follow-up results.575 Importantly, this trial was

performed without oxaliplatin, irinotecan, or molecularly targeted agents.

Cytoreductive Debulking with Hyperthermic Intraperitoneal Chemotherapy

Some experts have argued that the OS difference seen might have been much smaller if these agents had been used (ie, the control group would have had better outcomes).576

Other criticisms of the Verwaal trial have been published.576 One important point is that the trial included patients with peritoneal carcinomatosis of appendiceal origin, a group that has seen greater benefit with the

CRS/HIPEC approach.565,569,577,578 A retrospective multicenter cohort study reported median OS times of 30 and 77 months for patients with peritoneal carcinomatosis of colorectal origin and appendiceal origin, respectively, treated with HIPEC or with CRS and early postoperative intraperitoneal chemotherapy.569 The median OS time for patients with PMP, which arises from mucinous appendiceal carcinomas, was not reached (NR) at the time of publication. A retrospective international registry study reported 10- and 15-year survival rates of 63% and 59%, respectively, in patients with PMP from mucinous appendiceal carcinomas treated with CRS and HIPEC.225 HIPEC was not shown to be associated with improvements in OS in this study, whereas completeness of cytoreduction was. Thus, for patients with PMP, optimal treatment is still unclear.579

More recently, the randomized, phase III, multicenter PRODIGE 7 trial

reported results from 265 patients with colorectal peritoneal

carcinomatosis who received standard treatment of systemic

chemotherapy before and/or after CRS and were randomized to standard treatment plus HIPEC with oxaliplatin or standard treatment alone.580 This study reported no significant difference in OS, with a median OS of 41.7 months in the HIPEC arm versus 41.2 months in the non-HIPEC arm.

While the morbidity rates did not differ significantly at 30 days, the 60-day grade 3–5 morbidity rate was significantly higher in the HIPEC arm

(26% vs. 16%; P = .035). Another randomized, phase III study,

PROPHYLOCHIP-PRODIGE 15, reported similar results to PRODIGE 7 in that the group randomized to second-look surgery plus HIPEC showed

worse 3-year DFS compared to surveillance (44% vs. 53%) for patients with mCRC and synchronous and localized peritoneal metastases

removed during tumor resection, resected ovarian metastases, or a

perforated tumor.581 Forty-one percent of patients in the second-look

surgery plus HIPEC group reported grade 3 or 4 complications.

The individual components of the HIPEC approach have not been well studied. In fact, studies in rats have suggested that the hyperthermia

component of the treatment is irrelevant.582 Results of a retrospective

cohort study also suggest that heat may not affect outcomes from the

procedure.566 In addition, a randomized trial compared systemic 5-

FU/oxaliplatin to CRS and intraperitoneal 5-FU without heat.583 Although terminated prematurely because of poor accrual, analysis suggested that the CRS plus HIPEC approach may have been superior to the systemic therapy approach (2-year OS, 54% vs. 38%; P = .04) for patients with

resectable colorectal peritoneal metastases.

In addition, significant morbidity and mortality are associated with this

procedure. A 2006 meta-analysis of two RCTs and 12 other studies

reported morbidity rates ranging from 23% to 44% and mortality rates

ranging from 0% to 12%.573 Furthermore, recurrences after the procedure are very common.584 Whereas the risks are reportedly decreasing with

time (ie, more recent studies report 1%–5% mortality rates at centers of excellence570,576), the benefits of the approach have not been definitively shown, and HIPEC remains very controversial.585-588

There are also limited data to inform the use of perioperative systemic

therapy before or after resection of peritoneal metastases. An

observational cohort study from the Netherlands Cancer Registry used data from 393 patients with isolated synchronous CRC peritoneal

metastases to investigate the potential benefit of adjuvant

chemotherapy.589 This study found that following complete CRS and

HIPEC, adjuvant systemic chemotherapy was associated with improved

A study of 6286 patients from nine trials that evaluated the benefits and risks associated with intensive first-line treatment in the setting of mCRC treatment showed similar therapeutic efficacy for patients with a

performance status of 2 or 1 or less as compared with control groups.

However, the risks of certain GI toxicities were significantly increased for patients with a performance status of 2.654

The phase III C-cubed study compared upfront combination therapy with a fluoropyrimidine and oxaliplatin with bevacizumab to sequential treatment

using a fluoropyrimidine with bevacizumab followed by the addition of

oxaliplatin at f irst progression.655 Sequential treatment showed superiority in terms of time to failure of strategy (15.2 vs. 7.8 months; P < .001);

however, median OS was similar between the sequential and combination arms (27.5 vs. 27.0 months; HR, 0.92; 95% CI, 0.66–1.28; P = .61) and ORR was improved in the combination arm compared to the sequential arm (51.7% vs. 33.1%; P = .002).

Overall, the Panel does not consider one regimen to be preferable over another as initial therapy for metastatic disease. The Panel also does not indicate a preference for biologic agents used as part of initial therapy (ie, bevacizumab, cetuximab, panitumumab, none). See First-Line Systemic Therapy, below, for more information on data supporting bevacizumab versus cetuximab or panitumumab as part of the initial therapy regimen.

Therapy Retreatment/Rechallenge

Due to few efficacious options in later lines of therapy, there has been considerable interest in the possibility of retreating with a systemic therapy used during an earlier line of treatment. Most studies that have reported on this approach have been retrospective, detailing institutional

experiences retreating with chemotherapeutics656-658 or targeted therapies (eg, EGFR inhibitors)656,659-663 and concluded that a retreatment approach was feasible, based on response and/or toxicity data. However, these

studies were mainly small and did not differentiate between patients who had therapy stopped due to progression compared to other reasons,

limiting the quality of these data. The randomized phase III FIRE-4 trial seeks to address this question by comparing first-line treatment efficacy of FOLFIRI in combination with cetuximab given using the standard dosing schedule compared to early switch maintenance.664 An abstract reporting preliminary results from this trial has shown that application of one initial cycle with chemotherapy alone did not influence the efficacy of f irst-line FOLFIRI plus cetuximab.

Therapy Retreatment/Rechallenge

Maintenance Therapy

Therefore, until stronger data become available, the Panel agrees that for patients who had therapy stopped for a reason other than progression (eg, use as adjuvant therapy, cumulative toxicity, treatment break, patient

preference), rechallenge with this therapy would be an option. However, based on the current lack of evidence, retreatment with a therapy following progression on that regimen is not recommended.

Maintenance Therapy

Interest in the use of a maintenance therapy approach after first-line

treatment of unresectable mCRC is growing. In general, this approach

involves intensive first-line therapy, followed by less intensive therapy until progression in patients whose disease had a good response to initial

treatment.

The CAIRO3 study was an open-label, phase III, multicenter RCT

assessing maintenance therapy with capecitabine/bevacizumab versus

observation in 558 patients with mCRC and with stable disease or better after f irst-line treatment with CAPEOX/bevacizumab.665 Following first

progression, both groups were to receive CAPEOX/bevacizumab again until second progression (PFS2). After a median follow-up of 48 months, the primary endpoint of PFS2 was significantly better in the maintenance arm (8.5 vs. 11.7 months; HR, 0.67; 95% CI, 0.56–0.81; P < .0001), with 54% of patients overall receiving CAPEOX/bevacizumab the second time. Quality of life was not affected by maintenance therapy, although 23% of patients in the maintenance group developed hand-foot syndrome during the maintenance period. A non-significant trend towards improved OS was seen in the maintenance arm (18.1 vs. 21.6 months; adjusted HR, 0.83; 95% CI, 0.68–1.01; P = .06). A molecular subgroup analysis of CAIRO3 showed that the capecitabine/bevacizumab maintenance strategy was

effective across all mutational subgroups (RAS/BRAF wild-type, RAS

mutant, and BRAF V600E), although the benefit of maintenance was most

pronounced for patients with RAS/BRAF wild-type or BRAF V600E

mutation-positive tumors.666

The AIO 0207 trial was an open-label, noninferiority, randomized phase III trial that randomized 472 patients whose disease did not progress on

induction FOLFOX/bevacizumab or CAPEOX/bevacizumab to no

maintenance therapy or to maintenance therapy with

fluoropyrimidine/bevacizumab or with bevacizumab alone.667 The planned protocol included re-introduction of primary therapy after first progression. The primary endpoint was time to failure of strategy, defined as time from randomization to second progression, death, and initiation of treatment with a new drug. After a medium follow-up of 17 months, the median time to failure of strategy was 6.4 months (95% CI, 4.8–7.6) for the no

treatment group, 6.9 months (95% CI, 6.1–8.5) for the

fluoropyrimidine/bevacizumab group, and 6.1 months (95% CI, 5.3–7.4) for the bevacizumab alone group. Compared with

fluoropyrimidine/bevacizumab, bevacizumab alone was noninferior,

whereas the absence of maintenance therapy was not. However, only

about one third of trial participants received the re-induction therapy, thus limiting the interpretation of results. OS was one of the secondary

endpoints of the trial, and no relevant difference was seen between the arms.

PRODIGE 9 was a randomized phase III trial that investigated the effect of bevacizumab maintenance compared to no treatment during

chemotherapy-free intervals following induction chemotherapy with 12 cycles of FOLFIRI plus bevacizumab. Median tumor control duration was 15 months in both groups. PFS was 9.2 and 8.9 months and OS was 21.7 and 22.0 months for bevacizumab maintenance and no treatment,

respectively. Therefore, this study concluded that bevacizumab

maintenance did not improve outcomes.668

The randomized phase III noninferiority SAKK 41/06 trial addressed the question of continuing bevacizumab alone as maintenance therapy after chemotherapy plus bevacizumab in first-line therapy.669 The primary

endpoint of time to progression was not met (4.1 months for bevacizumab continuation vs. 2.9 months for no continuation; HR, 0.74; 95% CI, 0.58–

0.96), and no difference in OS was observed (25.4 vs. 23.8 months; HR,

0.83; 95% CI, 0.63–1.1; P = .2). Therefore, noninferiority for treatment holidays versus bevacizumab maintenance therapy was not

demonstrated.

The GERCOR DREAM trial (OPTIMOX3) was an international, open-label, phase III study that randomized patients with mCRC without disease

progression on bevacizumab-based therapy to maintenance therapy with bevacizumab or bevacizumab plus erlotinib.670 ITT analysis revealed an advantage in PFS (5.4 vs. 4.9 months; stratif ied HR, 0.81; 95% CI, 0.66–

1.01; P = .06) and OS (24.9 vs. 22.1 months; stratif ied HR, 0.79; 95% CI,

0.63–0.99; P = .04) with combination therapy. A smaller randomized trial, however, showed no difference in PFS or OS between bevacizumab and bevacizumab/erlotinib maintenance therapy in patients with KRAS wildtype tumors.671 A meta-analysis identif ied three randomized trials (682

patients) and concluded that maintenance therapy with

bevacizumab/erlotinib significantly increases OS and PFS, with

manageable toxicity.672

Another phase III trial investigated the role of capecitabine in the

maintenance phase, after initial treatment with FOLFOX or CAPEOX.673 PFS, the primary endpoint, was 6.4 months in the capecitabine

maintenance group and 3.4 months in the group that was observed until progression (HR, 0.54; 95% CI, 0.42–0.70; P < .001). A non-statistically significant difference in the median OS was also seen (HR, 0.85; 95% CI,

0.64–1.11; P = .2247). Toxicities associated with the capecitabine

maintenance therapy were acceptable.

A systematic review and network meta-analysis of 12 randomized clinical trials comprising 5540 patients with mCRC concluded that a maintenance strategy with a fluoropyrimidine, with or without bevacizumab, led to a

significant improvement in PFS, but not in OS.674 Given the PFS benefit seen in some studies, but the probable lack of OS benefit, maintenance therapy may be discussed as part of shared decision-making with patients, with observation as an acceptable alternative.

Biosimilars

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 two biologics that are recommended in the NCCN Guidelines for Colon Cancer: bevacizumab and trastuzumab. The NCCN Panel has agreed that an U.S. Food and Drug Administration (FDA)-approved biosimilar may be substituted for either bevacizumab or trastuzumab wherever these

therapies are recommended within the NCCN Guidelines for Colon

Cancer.

Biomarkers for Systemic Therapy

As the role of targeted therapy for treatment of advanced CRC or mCRC has become increasingly prominent, the NCCN Panel has expanded its recommendations regarding biomarker testing. Currently, determination of tumor gene status for KRAS/NRAS and BRAF mutations, as well as HER2 amplif ications and MSI/MMR status (if not previously done), are

recommended for patients with mCRC. Testing may be carried out for

individual genes or as part of an NGS panel, with NGS being preferred. NGS panels have the advantage of being able to pick up rare and

actionable genetic alterations, such as NTRK and RET fusions and may be carried out using either a tissue or blood-based (eg, liquid) biopsy.675 Specific information about each of these biomarkers may be found in the sections below.

Biomarkers for Systemic Therapy

##### KRAS and NRAS Mutations

Repeat molecular testing should not be performed after standard cytotoxic chemotherapy as significant molecular changes are rarely observed. For patients with tumors initially harboring molecular alterations eligible for

targeted therapy, repeat testing may be considered to assess for a change in the molecular profile that may guide future targeted therapy decisions. A study of paired plasma samples from patients with RAS/BRAF/EGFR wildtype mCRC who received EGFR inhibitors compared to those who

received combination cytotoxic chemotherapy found that those who

received the targeted therapy were more likely to develop acquired

mutations (46%) than those who received cytotoxic chemotherapy (9%).676

KRAS and NRAS Mutations

The MAPK pathway of RAS/RAF/MEK/ERK is downstream of EGFR;

mutations in components of this pathway are now established to be strong negative predictive markers, essentially precluding efficacy of these

therapies. A sizable body of literature has shown that tumors with a

mutation in exons 2, 3, or 4 of either the KRAS or NRAS genes are

essentially insensitive to cetuximab or panitumumab therapy.677-687 The Panel therefore strongly recommends RAS (KRAS/NRAS) genotyping of tumor (either primary tumor or metastasis) in all patients with mCRC.

Patients with known KRAS- or NRAS-mutant tumors should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified. An exception to this is when cetuximab or panitumumab is given in combination with

sotorasib or adagrasib for tumors with KRAS G12C mutation (see

Systemic Therapy Options for KRAS G12C Mutation-Positive Disease in the Non–First-Line Setting, below). ASCO released a Provisional Clinical Opinion Update on extended RAS testing in patients with mCRC that is consistent with the NCCN Panel’s recommendations.688 A guideline on

molecular biomarkers for CRC developed by the ASCP, CAP, AMP, and

ASCO also recommends RAS testing consistent with the NCCN

recommendations.30

Studies have reported that around 40% of mCRC have KRAS mutations in codons 12 and 13.689,690 Of these mutations, KRAS G12D was mostly

commonly found (36%), followed by G12V (21.8%), and G13D (18.8%).690 KRAS G12C has been reported in around 17% of KRAS-mutated mCRC cases.691 Results are mixed as far as the prognostic value of KRAS

mutations. In the Alliance N0147 trial, patients with KRAS exon 2-mutant tumors experienced a shorter DFS than patients with tumors without such mutations.692 Other studies have also reported worse outcomes with

KRAS mutations.689,693,694

In the AGITG MAX study, 10% of patients with tumors with wild-type

KRAS exon 2 had mutations in KRAS exons 3 or 4 or in NRAS exons 2, 3, and 4.695 In the PRIME trial, 17% of 641 patients with tumors without

KRAS exon 2 mutations were found to have mutations in exons 3 and 4 of KRAS or mutations in exons 2, 3, and 4 of NRAS. A predefined

retrospective subset analysis of data from PRIME revealed that PFS (HR,

1.31; 95% CI, 1.07–1.60; P = .008) and OS (HR, 1.21; 95% CI, 1.01–1.45; P = .04) were decreased in patients with tumors with any KRAS or NRAS mutation who received panitumumab plus FOLFOX compared to those who received FOLFOX alone.686 These results show that panitumumab does not benefit patients with KRAS- or NRAS-mutant tumors and may even have a detrimental effect in these patients.

Updated analysis of the FIRE-3 trial (discussed in Cetuximab or

Panitumumab vs. Bevacizumab in First-Line Therapy, below) has been published.696 When all RAS (KRAS/NRAS) mutations were considered, PFS was significantly worse in patients with RAS-mutant tumors receiving FOLFIRI plus cetuximab than in patients with RAS-mutant tumors

receiving FOLFIRI plus bevacizumab (6.1 vs. 12.2 months; P = .004). On the other hand, patients with KRAS/NRAS wild-type tumors showed no

difference in PFS between the regimens (10.4 vs. 10.2 months; P = .54). This result indicates that cetuximab likely has a detrimental effect in

patients with KRAS- or NRAS-mutant tumors. The FDA indication for

panitumumab was, therefore, updated to state that panitumumab is not indicated for the treatment of patients with KRAS or NRAS mutationpositive disease in combination with oxaliplatin-based chemotherapy.697 A retrospective study by De Roock et al698 raised the possibility that codon 13 mutations (G13D) in KRAS may not be absolutely predictive of nonresponse. Another retrospective study showed similar results.684 However, a later retrospective analysis of three randomized controlled phase III trials concluded that KRAS G13D-mutant tumors were unlikely to respond to panitumumab.699 Results from a prospective, phase II, single-arm trial

assessed the benefit of cetuximab monotherapy in 12 patients with

refractory mCRC whose tumors contained KRAS G13D mutations.700 The primary endpoint of 4-month progression-free rate was not met (25%), and no responses were seen. Preliminary results of the AGITG phase II ICE CREAM trial also did not see a benefit of cetuximab monotherapy in

patients with KRAS G13D-mutant tumors.701 However, partial responses were reported after treatment with irinotecan plus cetuximab in 9% of this irinotecan-refractory population. A meta-analysis of eight RCTs came to the same conclusion: that tumors with KRAS G13D mutations are no more likely to respond to EGFR inhibitors than tumors with other KRAS

mutations.702

The recommendation for RAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of RAS status is appropriate to plan for the

treatment continuum, so that the information may be obtained in a non–time-sensitive manner and the patient and provider can discuss the

implications of a RAS mutation, if present, while other treatment options still exist. Note that because anti-EGFR agents have no role in the

management of stage I, II, or III disease, RAS genotyping of CRCs at

these earlier stages is not recommended.

KRAS mutations are early events in CRC formation, and therefore a very tight correlation exists between mutation status in the primary tumor and the metastases.703-705 For this reason, RAS genotyping can be performed on archived specimens of either the primary tumor or a metastasis. Fresh biopsies should not be obtained solely for the purpose of RAS genotyping unless an archived specimen from either the primary tumor or a

metastasis is unavailable.

BRAF V600E Mutations

Although mutations in RAS indicate a lack of response to EGFR inhibitors, many tumors containing wild-type RAS still do not respond to these

therapies. Therefore, studies have addressed factors downstream of RAS as possible additional biomarkers predictive of response to cetuximab or panitumumab. Approximately 5% to 9% of CRCs are characterized by a specific mutation in the BRAF gene (V600E).706,707 BRAF mutations are, for all practical purposes, limited to tumors that do not have RAS

mutations.706-708 Activation of the protein product of the non-mutated BRAF gene occurs downstream of the activated KRAS protein in the EGFR

pathway. The mutated BRAF protein product is believed to be

constitutively active,709-711 thereby putatively bypassing inhibition of EGFR by cetuximab or panitumumab.

Limited data from unplanned retrospective subset analyses of patients

with mCRC treated in the first-line setting suggest that although a BRAF V600E mutation confers a poor prognosis regardless of treatment, patients with disease characterized by this mutation may receive some benefit from the addition of cetuximab to front-line therapy.707,712 A planned subset

analysis of the PRIME trial also found that mutations in BRAF indicated a poor prognosis but were not predictive of benefit to panitumumab added to FOLFOX in first-line treatment of mCRC.686 On the other hand, results

##### BRAF V600E Mutations

from the randomized phase III Medical Research Council (MRC) COIN trial suggest that cetuximab may have no effect or even a detrimental

effect in patients with BRAF-mutated tumors treated with CAPEOX or

FOLFOX in the first-line setting.708

In subsequent lines of therapy, retrospective evidence suggests that

mutated BRAF is a marker of resistance to anti-EGFR therapy in the non–first-line setting of metastatic disease.713-715 A retrospective study of 773 primary tumor samples from patients with chemotherapy-refractory

disease showed that BRAF mutations conferred a significantly lower

response rate to cetuximab (2/24; 8.3%) compared with tumors with wildtype BRAF (124/326; 38.0%; P = .0012).716 Furthermore, data from the multicenter randomized controlled PICCOLO trial are consistent with this conclusion, with a suggestion of harm seen for the addition of

panitumumab to irinotecan in the non–first-line setting in the small subset of patients with BRAF-mutant tumors.717

A meta-analysis published in 2015 identif ied nine phase III trials and one phase II trial that compared cetuximab or panitumumab with standard

therapy or best supportive care including 463 patients with metastatic

colorectal tumors with BRAF mutations (first-line, second-line, or refractory settings).718 The addition of an EGFR inhibitor did not improve PFS (HR,

0.88; 95% CI, 0.67–1.14; P = .33), OS (HR, 0.91; 95% CI, 0.62–1.34; P = .63), or ORR (RR, 1.31; 95% CI, 0.83–2.08; P = .25) compared with

control arms. Similarly, another meta-analysis identif ied seven RCTs and found that cetuximab and panitumumab did not improve PFS (HR, 0.86; 95% CI, 0.61–1.21) or OS (HR, 0.97; 95% CI, 0.67–1.41) in patients with BRAF-mutant tumors.719

While the evidence suggests that BRAF V600E mutation makes response to panitumumab or cetuximab unlikely, the impact of other BRAF

mutations was less clear. A multicenter pooled study included 40 patients with mCRC harboring oncogenic non-V600 BRAF mutations (30% class 2

mutations, 70% class 3) who received anti-EGFR antibody treatment.720 Of the patients with class 2 BRAF mutations, only 1 out of 12 had disease response to anti-EGFR therapy, compared to 50% of those with class 3 mutations (P = .02). Therefore, it is reasonable to consider anti-EGFR

therapy for patients with BRAF mutations other than V600E, especially for class 3 mutations.

In addition to its role as a predictive marker for BRAF-targeted therapy, it is clear that mutations in BRAF are a strong prognostic marker.339,707,708,721-726 A prospective analysis of tissues from patients with stage II and III

colon cancer enrolled in the PETACC-3 trial showed that the BRAF

mutation is prognostic for OS in patients with MSI-L or MSS tumors (HR,

2.2; 95% CI, 1.4–3.4; P = .0003).339 Moreover, an updated analysis of the CRYSTAL trial showed that patients with metastatic colorectal tumors

carrying a BRAF mutation have a worse prognosis than those with the

wild-type gene.707 Additionally, BRAF mutation status predicted OS in the AGITG MAX trial, with an HR of 0.49 (95% CI, 0.33–0.73; P = .001).722 The OS for patients with BRAF-mutant tumors in the COIN trial was 8.8 months, while those with KRAS exon 2 mutations and wild-type KRAS

exon 2 tumors had OS times of 14.4 months and 20.1 months,

respectively.708 In addition, a secondary analysis of the N0147 and C-08 trials found that BRAF mutations were significantly associated with worse survival after recurrence of resected stage III colon cancer, with a stronger association for primary tumors located in the distal colon.727 Results from a systematic review and meta-analysis of 21 studies, including 9885

patients, suggest that BRAF mutation may accompany specific high-risk clinicopathologic characteristics.728 In particular, an association was

observed between BRAF mutation and proximal tumor location (OR, 5.22; 95% CI, 3.80–7.17; P < .001), T4 tumors (OR, 1.76; 95% CI, 1.16–2.66; P = .007), and poor differentiation (OR, 3.82; 95% CI, 2.71–5.36; P < .001).

##### HER2 Amplification/Overexpression

Overall, the Panel believes that evidence increasingly suggests that BRAF V600E mutation makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely,

unless given as part of a BRAF inhibitor regimen (see Encorafenib Plus Cetuximab or Panitumumab for BRAF V600E Mutation-Positive Disease in the Non–First-Line Setting, below). The Panel recommends BRAF

genotyping of tumor tissue (either primary tumor or metastasis729) at

diagnosis of stage IV disease. If a tumor is determined to be both MSIH/dMMR and BRAF V600E, first-line therapy with a checkpoint inhibitor would generally be preferred and a BRAF inhibitor regimen could be used in a later line of therapy, as directed in the algorithm.

HER2 Amplification/Overexpression

HER2 is a member of the same family of signaling kinase receptors as

EGFR and has been successfully targeted in breast cancer in both the advanced and adjuvant settings. HER2 is rarely amplif ied/overexpressed in CRC (approximately 3% overall), but the prevalence is higher in

RAS/BRAF–wild type tumors (reported at 5%–14%).730,731 Specific

molecular diagnostic methods have been proposed for HER2 testing in CRC,732 and HER2-targeted therapies are now recommended as

subsequent therapy options in patients with tumors that have HER2

overexpression (see Systemic Therapy Options for HER2-Amplified

Disease, below).730,733 Based on this, the NCCN Guidelines for Colon

Cancer recommend testing for HER2 amplif ications for all patients with mCRC. More information on HER2 testing methodology can be found in the Principles of Pathologic and Molecular Review section of the

algorithm.

Evidence does not support a prognostic role of HER2 overexpression.734 In addition to its role as a predictive marker for HER2-targeted therapy, initial results indicate HER2 amplif ication/overexpression may be

predictive of resistance to EGFR-targeting monoclonal antibodies.731,735,736

For example, in a cohort of 98 patients with RAS/BRAF–wild type mCRC, median PFS on therapy without an EGFR inhibitor was similar regardless of HER2 status.736 However, in therapy with an EGFR inhibitor, the PFS

was significantly shorter in those with HER2 amplif ication compared with those without HER2 amplif ication (2.8 vs. 8.1 months; HR, 7.05; 95% CI,

3.4–14.9; P < .001).

dMMR/MSI-H Status

The percentage of stage IV colorectal tumors characterized as MSI-H or dMMR ranged from 3.5% to 5.0% in clinical trials and was 6.5% in the

Nurses' Health Study and Health Professionals Follow-up Study.340,737,738 dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. However, programmed death ligands 1 and 2 (PD-L1 and PD-L2) on tumor cells can suppress the immune response by binding to the

programmed cell death protein 1 (PD-1) receptor on T-effector cells. This system evolved to protect the host from an unchecked immune response. Many tumors upregulate PD-L1 and thus evade the immune system.739 It was therefore hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors. Subsequently, this hypothesis was confirmed in clinical trials, leading to the addition of recommendations for checkpoint inhibitors for dMMR/MSI-H disease (see Checkpoint Inhibitor Immunotherapy for

dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the First-Line Setting and in the Non–First-Line Settings, below). The NCCN Guidelines for Colon Cancer recommend universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer. In addition to its role as a predictive marker for immunotherapy use in the advanced CRC setting, MMR/MSI status can also help to identify individuals with Lynch syndrome (see Lynch Syndrome, above), and to inform adjuvant therapy decisions for patients with stage II disease (see Microsatellite Instability under

Adjuvant Chemotherapy for Resectable Colon Cancer, above). It is

##### dMMR/MSI-H Status

##### POLE/POLD1 Mutations

important to note that there is currently no role for PD-L1 testing in CRC, outside a clinical trial, and that PD-L1 testing is not recommended.

POLE/POLD1 Mutations

The polymerase genes, POLE and POLD1, encode proteins with

proofreading functions that correct mistakes created during DNA

replication. Pathologic variants within the endonuclease domain of these proteins results in loss of the proofreading function, leading to subsequent acquisition of downstream mutations.740,741 Germline pathologic variants of POLE or POLD1 are found in polymerase proofreading-associated

polyposis (PPAP), which predisposes patients to colorectal adenomas and carcinomas. Management recommendations for PPAP are described in the NCCN Guidelines for Genetic/Familial High-Risk Assessment:

Determining Resectability

median OS compared to active surveillance (39.2 vs. 24.8 months;

adjusted HR, 0.66; 95% CI, 0.49–0.88; P = .006). The CAIRO6 study is a phase II randomized, parallel-group Dutch trial of 79 patients with isolated resectable peritoneal CRC metastases who were randomized to CRS with HIPEC, plus or minus perioperative systemic therapy.590 Comparable

proportions of patients on the study had macroscopic complete

CRS/HIPEC (89% vs. 86%) and major postoperative morbidity was 22% versus 33% between the perioperative systemic therapy and control arms, respectively. Grade ≥3 systemic therapy-related toxicity was observed in 35% of patients and ORRs were 28% (radiologic response) and 38%

(major pathologic response) following neoadjuvant therapy.

The Panel currently believes that complete CRS and/or intraperitoneal

chemotherapy can be considered in experienced centers for selected

patients with limited peritoneal metastases for whom R0 resection can be achieved. However, the significant morbidity and mortality associated with HIPEC, as well as the conflicting data on clinical efficacy, make this

approach very controversial.

Determining Resectability

The consensus of the Panel is that patients diagnosed with potentially

resectable mCRC should undergo an upfront evaluation by a

multidisciplinary team, including surgical consultation (ie, with an

experienced hepatic surgeon in cases involving liver metastases) to

assess resectability status. The criteria for determining patient suitability for resection of metastatic disease are the likelihood of achieving complete resection of all evident disease with negative surgical margins and

maintaining adequate liver reserve.591-594 When the remnant liver is

insufficient in size based on cross-sectional imaging volumetrics,

preoperative portal vein embolization of the involved liver can be done to expand the future liver remnant.595 It should be noted that size alone is rarely a contraindication to resection of a tumor. Resectability differs

fundamentally from endpoints that focus more on palliative measures.

Instead, the resectability endpoint is focused on the potential of surgery to cure the disease.596 Resection should not be undertaken unless complete removal of all known tumor is realistically possible (R0 resection), because incomplete resection or debulking (R1/R2 resection) has not been shown to be beneficial.420,591

The role of PET/CT in determining resectability of patients with mCRC is discussed in Workup and Management of Synchronous Metastatic

Disease, below.

Neoadjuvant Therapy and Conversion to Resectability

The majority of patients diagnosed with metastatic colorectal disease have unresectable disease. However, for those with liver-limited unresectable disease that, because of involvement of critical structures, cannot be

resected unless regression is accomplished, preoperative systemic

therapy is being increasingly considered in highly selected cases in an attempt to downsize colorectal metastases and convert them to a

resectable status. Patients presenting with large numbers of metastatic sites within the liver or lung are unlikely to achieve an R0 resection simply based on a favorable response to therapy, as the probability of complete eradication of a metastatic deposit by systemic therapy alone is low.

These patients should be regarded as having unresectable disease not amenable to conversion therapy. In some highly selected cases, however, patients with disease that has had significant response to conversion

therapy can be converted from unresectable to resectable disease

status.597

Any active metastatic systemic regimen can be used in an attempt to

convert a patient’s unresectable disease status to a resectable disease status, because the goal is not specifically to eradicate micrometastatic disease, but rather to obtain the optimal size regression of the visible

Neoadjuvant Therapy and Conversion to Resectability

metastases. An important point to keep in mind is that irinotecan- and

oxaliplatin-based chemotherapeutic regimens may cause liver

steatohepatitis and sinusoidal liver injury, respectively.598-602 Studies have reported that chemotherapy-associated liver injury (including severe

sinusoidal dilatation and steatohepatitis) is associated with morbidity and complications following hepatectomy for colorectal liver

metastases.598,599,602,603 To limit the development of hepatotoxicity, it is

therefore recommended that surgery be performed as soon as possible after the patient’s disease becomes resectable. Some of the trials

addressing various conversion therapy regimens are discussed below. In the study by Pozzo et al, it was reported that chemotherapy with

irinotecan combined with 5-FU/LV enabled a significant portion (32.5%) of the patients with initially unresectable liver metastases to undergo liver resection.593 The median time to progression was 14.3 months, with all of these patients alive at a median follow-up of 19 months. In a phase II

study conducted by the NCCTG,421 42 patients with unresectable liver

metastases were treated with FOLFOX. Twenty-five patients (60%) had tumor reduction and 17 patients (40%; 68% of the responders) were able to undergo resection after a median period of 6 months of chemotherapy. In another study, 1104 patients with initially unresectable colorectal liver metastases were treated with chemotherapy, which included oxaliplatin in the majority of cases, and 138 patients (12.5%) classified as “good

responders” underwent secondary hepatic resection.430 The 5-year DFS rate for these 138 patients was 22%. In addition, results from a

retrospective analysis of 795 previously untreated patients with mCRC enrolled in the Intergroup N9741 randomized phase III trial evaluating the efficacy of mostly oxaliplatin-containing chemotherapy regimens indicated that 24 patients (3.3%; 2 of the 24 had lung metastases) were able to

undergo curative resection after treatment.604 The median OS time in this group was 42.4 months.

In addition, f irst-line FOLFOXIRI (infusional 5-FU, LV, oxaliplatin,

irinotecan) has been compared with FOLFIRI (infusional 5-FU, LV,

irinotecan) in two randomized clinical trials in patients with unresectable disease.605,606 In both studies, FOLFOXIRI led to an increase in R0

secondary resection rates: 6% versus 15%, P = .033 in the Gruppo

Oncologico Nord Ovest (GONO) trial605; and 4% versus 10%, P = .08 in the Gastrointestinal Committee of the HORG trial.606 In a follow-up study of the GONO trial, the 5-year survival rate was higher in the group receiving FOLFOXIRI (15% vs. 8%), with a median OS of 23.4 versus 16.7 months (P = .026).607

Chemotherapy regimens may be combined with bevacizumab or with

cetuximab or panitumumab for KRAS/NRAS/BRAF wild-type unresectable synchronous disease. In addition, checkpoint inhibitors may be considered for MSI-H/dMMR or POLE/POLD1 mutation-positive disease as an

alternative to chemotherapy-containing regimens. See the following

sections for data supporting these treatment approaches.

When systemic therapy is planned for patients with initially unresectable disease, the Panel recommends that a surgical re-evaluation be planned 2 months after initiation of therapy, and that those patients who continue to receive systemic therapy undergo surgical re-evaluation every 2 months thereafter.602,608-610 Reported risks associated with chemotherapy include the potential for development of liver sinusoidal dilatation, steatosis, or steatohepatitis.598,603,611 To limit the development of hepatotoxicity, it is therefore recommended that surgery be performed as soon as possible after the patient’s disease becomes resectable.

Neoadjuvant Bevacizumab for Metastatic Disease

The efficacy of bevacizumab in combination with chemotherapy in the

treatment of unresectable metastatic disease (see Systemic Therapy for Advanced or Metastatic Disease) has led to a study of its use in

combination with these regimens in the preoperative setting. However, the

Neoadjuvant Bevacizumab for Metastatic Disease

safety of administering bevacizumab preoperatively in combination with 5-FU–based regimens has not been adequately evaluated. A retrospective evaluation of data from two randomized clinical trials of 1132 patients

receiving chemotherapy with or without bevacizumab as initial therapy for mCRC indicated that the incidence of wound healing complications was increased for the group of patients undergoing a major surgical procedure while receiving a bevacizumab-containing regimen when compared to the group receiving chemotherapy alone while undergoing major surgery (13% vs. 3.4%, respectively; P = .28).612 However, when chemotherapy plus bevacizumab or chemotherapy alone was administered prior to surgery, the incidence of wound healing complications in either group of patients was low (1.3% vs. 0.5%; P = .63) The randomized phase III HEPATICA trial, which closed prematurely due to poor accrual, found that global

quality-of-life scores were higher in patients receiving CAPEOX plus

bevacizumab than in those receiving CAPEOX alone after resection of

liver metastases, but no conclusions could be drawn regarding the primary endpoint of DFS.613

The role of bevacizumab in the patient with unresectable mCRC, whose disease is felt to be potentially convertible to resectability with a reduction in tumor size, has also been studied. Data seem to suggest that

bevacizumab modestly improves the response rate to irinotecan-based regimens.614,615 Thus, when an irinotecan-based regimen is selected for an attempt to convert unresectable disease to resectability, the use of

bevacizumab would seem to be an appropriate consideration. The data on use of bevacizumab with oxaliplatin-based therapy in the conversion to resectability setting are mixed. On one hand, a 1400-patient, randomized, double-blind, placebo-controlled trial of CAPEOX or FOLFOX with or

without bevacizumab showed absolutely no benefit in terms of response rate or tumor regression for the addition of bevacizumab, as measured by both investigators and an independent radiology review committee.616 On the other hand, the randomized BECOME trial of 241 patients with initially

unresectable RAS-mutant CRC liver metastases showed improvement in the resectability of liver metastases as well as response rates and survival with mFOLFOX6 plus bevacizumab compared to mFOLFOX6 alone.617 R0 resection rates were 22.3% in the bevacizumab combo versus 5.8% with

mFOLFOX6 alone (P < .01). Because it is not known in advance whether resectability will be achieved, the use of bevacizumab with oxaliplatinbased therapy in this setting is acceptable.

A pooled analysis of the phase III TRIBE and TRIBE2 studies compared upfront FOLFOXIRI plus bevacizumab to chemotherapy doublets

(FOLFOX or FOLFIRI) plus bevacizumab for oligometastatic mCRC.618 In agreement with the primary outcomes from these studies, the benefits of using the chemotherapy triplet compared to the doublet were retained in the patient population that had oligometastatic disease, with interaction P scores above significance for PFS, OS, and ORR outcome measures.

Therefore, the authors of this study conclude that FOLFOXIRI provides a benefit for oligometastatic CRC, including when used as upfront treatment in conjunction with locoregional treatments, such as resection. The

randomized, phase III CAIRO5 study also compared FOLFOXIRI to

chemotherapy doublets, when combined with bevacizumab for patients with initially unresectable right-sided tumors in one of its cohorts.619 This study found that the group treated with FOLFOXIRI in combination with bevacizumab had a longer PFS compared with the doublets (10.6 months vs. 9.0 months; P = .032). Furthermore, an analysis of individual patient data from five trials that compared upfront FOLFOXIRI plus bevacizumab to doublet chemotherapy plus bevacizumab reported a higher R0

resection rate in the FOLFOXIRI arm.620

The Panel recommends against the use of bevacizumab as neoadjuvant treatment of patients with resectable metastatic colon cancer. For patients who receive bevacizumab for unresectable disease and are converted to a resectable state, the Panel recommends at least a 6-week interval (which

Neoadjuvant Cetuximab and Panitumumab for Metastatic Disease

corresponds to two half-lives of the drug621) between the last dose of

bevacizumab and surgery. Re-initiation of bevacizumab should be delayed at least 6 to 8 weeks postoperatively.

Neoadjuvant Cetuximab and Panitumumab for Metastatic Disease

More recent favorable results of randomized clinical trials evaluating

FOLFIRI, FOLFOX, or FOLFOXIRI in combination with anti-EGFR

inhibitors for the purpose of conversion of unresectable disease to

resectable disease have been reported. For instance, in the CELIM phase II trial, patients were randomized to receive cetuximab with either

FOLFOX6 or FOLFIRI.622 Retrospective analysis showed that in both

treatment arms combined resectability increased from 32% to 60% after chemotherapy in patients with wild-type KRAS exon 2 tumors with the

addition of cetuximab (P < .0001). Final analysis of this trial showed that the median OS of the entire cohort was 35.7 months (95% CI, 27.2–44.2 months), with no difference between the arms.623 Another RCT compared chemotherapy (mFOLFOX6 or FOLFIRI) plus cetuximab to chemotherapy alone in patients with unresectable CRC metastatic to the liver.624 The

primary endpoint was the rate of conversion to resectability based on

evaluation by a multidisciplinary team. After evaluation, 20 of 70 (29%)

patients in the cetuximab arm and 9 of 68 (13%) patients in the control arm were determined to be eligible for curative-intent hepatic resection. R0 resection rates were 25.7% in the cetuximab arm and 7.4% in the control arm (P < .01). In addition, surgery improved the median survival time

compared to unresected participants in both arms, with longer survival in patients receiving cetuximab (46.4 vs. 25.7 months; P = .007 for the

cetuximab arm and 36.0 vs. 19.6 months; P = .016 for the control arm). The phase III CAIRO5 trial included a cohort of patients with initially

unresectable RAS/BRAF wild-type, left-sided tumors who were

randomized to receive either bevacizumab or panitumumab in combination with a chemotherapy doublet (FOLFOX or FOLFIRI).619 While these arms

Neoadjuvant Checkpoint Inhibitors for Metastatic Disease

of the study were closed prematurely for futility, collected results showed no significant difference between the two arms.

The randomized, phase II VOLFI trial compared the efficacy and safety of mFOLFOXIRI in combination with panitumumab to FOLFOXIRI alone in patients with RAS wild-type, primarily non-resectable mCRC.625 Of the

cohort with unresectable, potentially convertible metastases, 75% were ultimately converted to resectable with FOLFOXIRI + panitumumab

compared to 36.4% with FOLFOXIRI alone. ORR was also improved in the combination compared to FOLFOXIRI alone while PFS was similar

between the two treatments and OS showed a trend in favor of the

combination. A meta-analysis of four RCTs concluded that the addition of cetuximab or panitumumab to chemotherapy significantly increased the response rate, the R0 resection rate (from 11%–18%; RR, 1.59; P =

.04), and PFS, but not OS in patients with wild-type KRAS exon 2-containing

tumors.626

The randomized, phase III TRIPLETE study compared mFOLFOXIRI plus panitumumab to mFOLFOX6 plus panitumumab as initial therapy for 435 patients with unresectable RAS and BRAF wild-type mCRC.627,628 This trial found that intensification of the chemotherapy regimen did not provide additional benefit when combined with panitumumab and led to higher

rates of gastrointestinal (GI) toxicity. Response rates (73% vs. 76%), early tumor shrinkage (57% vs. 58%), depth of response (48% vs. 47%), R0 resection rate (25% vs. 29%), and median PFS (12.7 vs. 12.3 months) were similar between mFOLFOXIRI plus panitumumab and mFOLFOX

plus panitumumab, respectively. Reflecting these data, the NCCN Panel does not recommend the combination of FOLFIRINOX with cetuximab or panitumumab for unresectable mCRC, while the FOLFIRI or FOLFOX

combinations are included as recommendations within the same setting.

Neoadjuvant Checkpoint Inhibitors for Metastatic Disease

While there is a lack of data in this setting, the Panel considers

pembrolizumab, dostarlimab-gxly, or nivolumab, as a monotherapy or in combination with ipilimumab, as preferred options for neoadjuvant therapy of resectable dMMR/MSI-H or POLE/POLD1 mutation-positive mCRC. While there are no clinical trial data supporting this approach, a few case studies have reported notable responses to pembrolizumab and

nivolumab when used as a neoadjuvant therapy for dMMR advanced CRC or mCRC.629-631 The Panel notes that special caution should be taken to monitor for signs of progression, which could potentially cause a

previously resectable tumor to become unresectable. While this is a

concern for any regimen being used as neoadjuvant therapy in the

resectable mCRC setting, the risk is possibly higher with immunotherapy compared to traditional chemotherapy options.

Perioperative Therapy for Resectable Metachronous Metastatic Disease

Perioperative administration of chemotherapy is recommended for most patients undergoing liver or lung resection for metachronous metastases with the goal of increasing the likelihood that residual microscopic disease will be eradicated. A meta-analysis identif ied three randomized clinical

trials comparing surgery alone to surgery plus systemic therapy with 642 evaluable patients with colorectal liver metastases.632 The pooled analysis showed a benefit of chemotherapy in PFS (pooled HR, 0.75; CI, 0.62–

0.91; P = .003) and DFS (pooled HR, 0.71; CI, 0.58–0.88; P = .001), but not in OS (pooled HR, 0.74; CI, 0.53–1.05; P = .088). Another metaanalysis published in 2015 combined data on 1896 patients from 10

studies and also found that perioperative chemotherapy improved DFS (HR, 0.81; 95% CI, 0.72–0.91; P = .0007) but not OS (HR, 0.88; 95% CI,

0.77–1.01; P = .07) in patients with resectable colorectal liver

metastases.633 Additional meta-analyses have also not observed a

statistically significant OS benefit with the addition of adjuvant

chemotherapy in resectable mCRC.634-636

The choice of regimen in the perioperative setting depends on several factors, including the patient’s history of treatment with chemotherapy or immunotherapy and the response rates and safety/toxicity issues

associated with the regimens, as outlined in the guidelines. Biologics are not recommended in the perioperative metastatic setting, with the

exception of initial therapy in patients with unresectable disease that may be converted to a resectable state or checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation-positive disease.

The phase III EORTC 40983 study, evaluating use of perioperative

FOLFOX (6 cycles before and 6 cycles after surgery) for patients with resectable liver metastases, showed absolute improvements in 3-year

PFS of 8.1% (P = .041) and 9.2% (P = .025) for all eligible patients and all patients with resected disease, respectively, when chemotherapy in

conjunction with surgery was compared with surgery alone.637 The partial response rate after preoperative FOLFOX was 40%, and operative

mortality was <1% in both treatment groups. However, no difference in OS was seen between the groups, perhaps because second-line therapy was given to 77% of the patients in the surgery-only arm and 59% of the

patients in the chemotherapy arm.638 Furthermore, a multi-institutional

phase II study investigating the feasibility and efficacy of preoperative

mFOLFOX6 for patients with resectable liver metastases demonstrated the feasibility of this approach.639 Three-year OS and PFS rates were

81.9% and 47.4%, respectively.

The New EPOC trial, which was stopped early because it met protocoldefined futility criteria, found a lack of benefit to cetuximab with

chemotherapy in the perioperative metastatic setting (>85% received

FOLFOX or CAPEOX; patients with prior oxaliplatin received FOLFIRI).640 In fact, with less than half of expected events observed, PFS was

significantly reduced in the cetuximab arm (14.8 vs. 24.2 months; HR,

1.50; 95% CI, 1.00–2.25; P < .048). A subsequent analysis of New EPOC, carried out 5 years after the last patient was recruited, reported a reduced median OS for chemotherapy plus cetuximab compared to chemotherapy alone (55.4 vs. 81.0 months; HR, 1.45; 95% CI, 1.02–2.05; P = .036).641 The Panel thus recommends against panitumumab and cetuximab as

perioperative treatment for resectable metachronous metastatic disease. The Panel also notes that cetuximab and panitumumab should be used with caution in patients with unresectable disease that could potentially be converted to a resectable status.

The optimal sequencing of systemic therapy and resection remains

unclear. Patients with resectable disease may undergo resection first,

followed by postoperative adjuvant chemotherapy. Alternatively,

perioperative (neoadjuvant plus postoperative) systemic therapy can be used.642,643

Potential advantages of preoperative therapy include: earlier treatment of micrometastatic disease, determination of responsiveness to therapy

(which can be prognostic and help in planning postoperative therapy), and avoidance of local therapy for those patients with early disease

progression. Potential disadvantages include missing the “window of

opportunity” for resection because of the possibility of disease progression or achievement of a complete response, thereby making it diff icult to

identify areas for resection.423,644,645 In fact, results from studies of patients with CRC receiving preoperative therapy indicated that viable cancer was still present in most of the original sites of metastases when these sites were examined pathologically despite achievement of a complete

response as evaluated on CT scan.645-647 Therefore, during treatment with preoperative systemic therapy, frequent evaluations must be undertaken and close communication must be maintained among medical oncologists, radiologists, surgeons, and patients so that a treatment strategy can be

developed that optimizes exposure to the preoperative regimen and

facilitates an appropriately timed surgical intervention.598

Other reported risks associated with the preoperative therapy approach include the potential for development of liver steatohepatitis and sinusoidal

liver injury when irinotecan- and oxaliplatin-based chemotherapeutic

regimens are administered, respectively.598-602 To reduce the development of hepatotoxicity, the neoadjuvant period is usually limited to 2 to 3

months, and patients should be carefully monitored by a multidisciplinary team.

Systemic Therapy for Advanced or Metastatic Disease

The current management of disseminated mCRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity

profiles of the constituent drugs. Although the specific regimens listed in the guideline are designated according to lines of therapy, it is important to clarify that these recommendations represent a continuum of care and that these lines of treatment are blurred rather than discrete.648 For example, if oxaliplatin is administered as part of an initial treatment regimen but is

discontinued after ≤12 weeks for escalating neurotoxicity, continuation of the remainder of the treatment regimen would still be considered initial therapy.

Principles to consider at the start of therapy include: 1) preplanned

strategies for altering therapy for disease exhibiting a tumor response or for disease characterized as stable or progressive; and 2) plans for

adjusting therapy for patients who experience certain toxicities. For

example, decisions related to therapeutic choices after first progression of disease should be based, in part, on the prior therapies received (ie,

exposing the patient to a range of cytotoxic agents). Furthermore, an

Systemic Therapy for Advanced or Metastatic Disease

Sequencing and Timing of Therapies

evaluation of the efficacy and safety of these regimens for a patient must consider not only the component drugs, but also the doses, schedules, and methods of administration of these agents, and the potential for

surgical cure and the performance status of the patient.

Sequencing and Timing of Therapies

Few studies have addressed the sequencing of therapies in advanced metastatic disease. Prior to the use of targeted agents, several studies randomized patients to different schedules.649-652 The data from these trials suggest that there is little difference in clinical outcomes if intensive

therapy is given in first line or if less intensive therapy is given first

followed by more intensive combinations.

Results from a randomized study to evaluate the efficacy of FOLFIRI and FOLFOX regimens as initial therapy and to determine the effect of using sequential therapy with the alternate regimen after first progression

showed neither sequence to be significantly superior with respect to PFS or median OS.652 A combined analysis of data from seven phase III clinical trials in advanced CRC provided support for a correlation between an

increase in median survival and administration of all three cytotoxic agents (ie, 5-FU/LV, oxaliplatin, irinotecan) at some point in the continuum of

care.653 Furthermore, OS was not found to be associated with the order in which these drugs were received.

Colorectal, Endometrial, and Gastric. Somatic POLE pathologic variants occur in approximately 2% to 8% of patients with MSS/pMMR CRC while somatic POLD1 pathologic variants are extremely rare.740,742

Similar to dMMR/MSI-H, CRC with POLE/POLD1 pathologic variants has a more favorable prognosis for stage II/III, likely due to enhanced immune response, although this association may be strongest for stage II

disease.743 Since POLE/POLD1 pathologic variants also cause a

hypermutated phenotype in CRC, similar to dMMR/MSI-H, it was theorized that pMMR CRC with POLE/POLD1 pathologic variants may also benefit from checkpoint inhibitor therapy.744 A retrospective analysis of 458

patients with POLE mutation-positive tumors tested this.745 Of the

identif ied POLE mutations, 15.0% were pathogenic, 15.9% were benign, and 69.1% were of unknown significance. Eighty-two patients received a PD-1/PD-L1 inhibitor, either as monotherapy or in combination. Compared to those with benign variants, patients with POLE pathogenic variants had improved clinical benefit rates (82.4% vs. 30.0%; P = .013), improved

median PFS (15.1 vs. 2.2 months; P < .001), longer OS (29.5 vs. 6.8

months; P < .001), and longer treatment duration (15.5 vs. 2.5 months).

Based on these results, the NCCN Panel recommends that mCRC with functional POLE/POLD1 pathologic variants should be treated consistently with the recommendations for dMMR/MSI-H disease (see Checkpoint

Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 MutationPositive Disease in the First-Line Setting and the Non–First-Line Settings, below).

##### NTRK Fusions

Three NTRK genes encode the TRK proteins. TRK expression is primarily in the nervous system where these kinases help to regulate pain,

perception of movement/position, appetite, and memory. NTRK gene

fusions lead to overexpression of the TRK fusion protein, resulting in

constitutively active downstream signaling.746 Studies have estimated that about 0.2% to 1% of CRCs carry NTRK gene fusions.747,748 A study of

2314 CRC specimens, of which 0.35% had NTRK fusions, found that

NTRK fusions were limited to cancers that were wild-type for KRAS,

NRAS, and BRAF. Furthermore, a majority of the CRCs harboring NTRK fusions were also MMR-deficient.749 Similarly, in a smaller study that

aimed to characterize the molecular and clinical landscape of

ALK, ROS1, and NTRK rearranged mCRC, 76.9% of NTRK rearranged tumors were MMR-deficient.750 NTRK inhibitors are treatment options for patients with mCRC that is NTRK gene fusion-positive (see Systemic

Therapy Options for NTRK Fusion-Positive Disease in the Non-First-Line Setting, below).

RET is a transmembrane glycoprotein receptor-tyrosine kinase that plays an important role in the homeostasis of several different types of tissues, including neural, hematopoietic, and neuroendocrine tissues.751 RET gene fusions lead to constitutively active, ligand-independent activation of the RET pathway.752 RET gene fusions are implicated in the pathogenesis of several solid tumors including thyroid and non-small-cell lung cancer, as

##### RET Fusions

##### Tumor Mutational Burden

well as in a small subset (<1%) of CRCs.751,753 A systematic review

analyzed data from 24 RET gene fusion-positive mCRC cases from three screening sources and found RET gene fusions to be more prevalent with increased age (median age, 66 vs. 60 years; P = .052), in those with

ECOG PS of 1–2 compared to those with ECOG PS of 0 (90 % vs. 50%; P = .02), in those with right-sided tumors (55% vs. 32%; P = .013), and in those with unresected primary tumors (58% vs. 21%; P < .001).753 MSI-H

status was also found to be more prevalent in RET gene fusion-positive samples compared to RET-negative samples (48% vs. 7%; P < .001). All RET gene fusion-positive samples were RAS and BRAF wild-type.753 The highly selective RET kinase inhibitor, selpercatinib, is a treatment option for patients with mCRC that is RET gene fusion-positive (see Selpercatinib for RET Gene Fusion-Positive Disease in the Non-First-Line Setting,

below).

Tumor Mutational Burden

Tumor mutational burden (TMB) measures the total amount of somatic

coding mutations within a given coding area of the tumor genome and can be quantif ied using NGS techniques.754 Research has identif ied TMB as a potential biomarker for response to immunotherapy and pembrolizumab has been FDA-approved for patients with unresectable or metastatic,

TMB-high (TMB-H) solid tumors that have progressed following prior

treatment and have no satisfactory alternative treatment options.755 TMB-H is defined in the label as ≥10 mutations/megabase by an FDA-approved test. This approval was based on results of the phase 2, KEYNOTE-158 study that enrolled patients with advanced solid tumors.756 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 on this study, none had CRC. The phase II TAPUR basket study included a cohort of 28 patients with TMB-H advanced CRC who were treated with pembrolizumab.757 For the

CRC cohort, the disease control rate (DCR) was 31% and the ORR was 11%. Another abstract on the TAPUR study, reporting results for 12

patients with TMB-H advanced CRC treated with nivolumab plus

ipilimumab, concluded that the combination therapy does not have

sufficient clinical activity in MSS, TMB-H CRC.758

Based on the limited data in the CRC population, the NCCN Panel does not currently recommend TMB biomarker testing, unless measured as part of a clinical trial.

Severe Fluoropyrimidine-Associated Toxicity

Dihydropyrimidine dehydrogenase (DPYD) is the enzyme that catabolizes fluoropyrimidines.759,760 Certain variants of the DPYD gene result in a

truncated protein, which may lead to prolonged systemic exposure to

fluoropyrimidine761-765 and may herald an increased risk of severe

toxicity.766-768 The actual incidence of specific gene alterations of these variants across different populations is unknown. A systematic review of the published literature found that, across 13,929 patients, such DPYD variants (hetero- or homozygous) were identif ied in 4.1% of patients.768 Treatment-related deaths were reported in 0.1% in patients without

identif ied DPYD variants and in 2.3% of those with known DPYD variants (95% CI, 1.3%–3.9%).

While not all patients known to have DPYD variants are necessarily at

increased risk of toxicity, such individuals could receive dose reductions or could be offered non-fluoropyrimidine regimens.760 Prospective studies have shown DPYD genotyping to be feasible in clinical practice and that dose reductions in the setting of variant DPYD genes diminish the risk of substantial toxicity.769-771 In a prospective study, 22 patients with the

DPYD*2A variant allele (of 2038 patients screened; 1.1%) received dosereduced fluoropyrimidine, which led to a significant reduction in the risk of grade ≥3 toxicity compared with historic controls (28% vs. 73%; P <

.001).771 None of the patients died from drug toxicity, compared with a

Severe Fluoropyrimidine-Associated Toxicity

10% death rate in the historical control group. However, there was great heterogeneity in the specific treatment regimens and dosing decisions within the treated cohorts. Capecitabine was the fluoropyrimidine given to the majority of patients, but the various combinations also included other chemotherapeutics as well as bolus and infusional 5-FU. Also, the protocol left the specific dosing decision to the physician and fluoropyrimidine dose reductions ranged from 17% to 91% (median 48%).771 A cost-effectiveness modeling within this study concluded that pre-treatment testing was costeffective, largely based on the assumptions that intensive care unit (ICU) hospitalizations and the cost of uridine triacetate (approximately $75,000 per cycle) as a treatment in very ill patients could be avoided. Efficacy was not an endpoint in this study. Another prospective study identif ied 85

patients with any of the four most common DPYD variant alleles (8% of 1103 patients screened) who received an initial f luoropyrimidine dose

reduction of either 25% or 50% depending on the specific allele.770 This study reported that the RR of severe fluoropyrimidine-related toxicity was reduced for genotype-guided dosing for all studied alleles compared to the historical cohorts.

In an effort to standardize the dose adjustments indicated by the specific variants, the Clinical Pharmacogenetics Implementation Consortium

(CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing provides dosing recommendations for 5-FU and 5-FU prodrug-based regimens based on DPYD.772 A reduced starting dose of fluoropyrimidines is recommended for intermediate metabolizers (those who are heterozygous for DPYD decreased/no function variants). Some patients with decreased/no function variants tolerate normal doses of

fluoropyrimidines; thus, the CPIC Guidelines recommend increasing doses in subsequent cycles for patients with minimal or no toxicity in the first two cycles of treatment. Further dose reduction is recommended for those who do not tolerate the reduced starting dose. For those classified as poor

metabolizers, the CPIC Guidelines recommend avoiding fluoropyrimidines.

These guidelines reflect common sense dose adjustments rather than

methodically derived dosing based on actual pharmacokinetics. Also, the dose adjustment paradigm does not distinguish between IV bolus or

infusional 5-FU or the pro-drug capecitabine. The pharmacokinetics of IV 5-FU vary greatly based on the rate of infusion and there are many more factors involved in determining an individual’s tolerance of capecitabine,which is uniformly used at reduced dose in the United States compared to Europe.773

While dose adjustment of f luoropyrimidines based on DPYD genotype has been shown to diminish toxicity, it is not certain that dose reductions do not result in inferior efficacy. A prospective multicenter study of 156 DPYD variant carriers and 775 DPYD wild-type controls, most with advanced or metastatic disease, sought to test this.774 In this study, DPYD variant

carriers received either a 25% or 50% fluoropyrimidine dose reduction, depending on the exact variant. Each DPYD variant carrier was matched to three wild-type controls treated with the standard dose. For pooled

DPYD variant carriers, PFS and OS were not significantly affected by

these lower fluoropyrimidine doses, although a shorter PFS (HR, 1.43; 95% CI, 1.10–1.86; P = .007) was found in the 61 carriers of the

c.1236G>A variant who were treated with the reduced dose. These

findings raise the possibility that dose reduction may diminish the efficacy of the fluoropyrimidine with at least this variant of DPYD. While the impact in patients with advanced CRC may not be significant, reduced efficacy of fluoropyrimidines when used in the adjuvant setting could be very

meaningful.775 Because fluoropyrimidines are a pillar of therapy in CRC and it is not known with certainty that given DPYD variants are associated with this risk and/or that dose adjustments do not impact efficacy, the

NCCN Panel does not recommend universal pretreatment DPYD

genotyping at this time. However, as with all guideline decisions, the Panel reviews all new data and considers input from stakeholders in real time and guidelines are continuously reassessed.

Regimens Not Recommended

Uridine triacetate is an orally administered pyrimidine analog that is

believed to compete for receptors on normal cells and, as such, decreases the toxic effects of excessive fluoropyrimidines. It is FDA approved for the emergency treatment of both adult and pediatric patients exhibiting earlyonset, severe or life-threatening toxicity within 96 hours of the completion of 5-FU or capecitabine administration.776 Uridine triacetate was evaluated in two single-arm, multicenter open-label trials in which a total of 135

patients were treated with uridine triacetate following 5-FU or capecitabine overdose or upon early onset of severe toxicities.777,778 In these studies, a total of 96% of the patients treated with uridine triacetate survived and

exhibited rapid reversal of severe cardiac and neurologic toxicities. Thirtyeight percent of these patients were able to resume chemotherapy within 30 days, with a mean time to resumption of chemotherapy of 19.6 days.777 The importance of administration of uridine triacetate within the first 96 hours must be noted. While most patients on these trials were treated

within the first 96 hours, 50% of the four patients who were treated beyond 96 hours died.778

Regimens Not Recommended

The consensus of the Panel is that infusional 5-FU regimens seem to be less toxic than bolus regimens and that any bolus regimen of 5-FU is

inappropriate when administered with either irinotecan or oxaliplatin.

Therefore, the Panel no longer recommends using the IFL regimen (which was shown to be associated with increased mortality and decreased

efficacy relative to FOLFIRI in the BICC-C trial614,779 and inferior to

FOLFOX in the Intergroup trial780) at any point in the therapy continuum. 5-FU in combination with irinotecan or oxaliplatin should be administered via an infusional biweekly regimen,312 or capecitabine can be used with

oxaliplatin.781

The Dutch CAIRO trial showed promising results for the use of

capecitabine/irinotecan (CapeIRI) in the first-line treatment of mCRC.650

However, in the American BICC-C trial, CapeIRI showed worse PFS than FOLFIRI (5.8 vs. 7.6 months; P = .015), and was considerably more toxic with higher rates of severe vomiting, diarrhea, and dehydration.614 In this trial, the CapeIRI arm was discontinued. The EORTC study 40015 also compared FOLFIRI with CapeIRI and was discontinued after enrollment of only 85 patients because seven deaths were determined to be treatmentrelated (five in the CapeIRI arm).782 Several European studies have

assessed the safety and efficacy of CapeIRI in combination with

bevacizumab (CapeIRI/Bev) in the first-line metastatic setting. A small

Spanish study of 46 patients who received CapeIRI/Bev showed

encouraging results with good tolerability.783 A similar trial by the Spanish group found similar results in 77 patients.784 Preliminary results from a

randomized phase II study conducted in France were presented in 2009,

showing a manageable toxicity profile for CapeIRI/Bev in this setting.785

Additionally, a randomized phase III HeCOG trial compared CapeIRI/Bev and FOLFIRI/Bev in the first-line metastatic setting and found no

significant differences in efficacy between the regimens.786 Despite the differing toxicity profiles reported, the toxicities seemed to be reasonable in both arms. Finally, a randomized phase II study of the AIO colorectal study group compared CAPEOX plus bevacizumab with a modified

CapeIRI regimen plus bevacizumab and found similar 6-month PFS and similar toxicities.787 Because of the concerns about the toxicity of the

CapeIRI combination, which may differ between patients of American and European descent, the Panel does not recommend CapeIRI or

CapeIRI/Bev for the first-line treatment of mCRC.

Other drug combinations that have produced negative results in phase III trials for the treatment of advanced CRC include sunitinib plus FOLFIRI, cetuximab plus brivanib, erlotinib plus bevacizumab, cediranib plus

FOLFOX/CAPEOX, and atezolizumab plus cobimetinib.788-792 These

regimens are not recommended for the treatment of patients with CRC.

##### FOLFOX for First-Line Therapy

Results from two randomized phase III trials have shown that combination therapy with more than one biologic agent is not associated with improved outcomes and can cause increased toxicity.793,794 In the PACCE trial, the addition of panitumumab to a regimen containing oxaliplatin- or irinotecanbased chemotherapy plus bevacizumab was associated with significantly shorter PFS and higher toxicity in both KRAS exon 2 wild-type and mutant gene groups.793 Similar results were observed in the CAIRO2 trial with the addition of cetuximab to a regimen containing capecitabine, oxaliplatin,

and bevacizumab.794 Therefore, the Panel strongly recommends against the use of therapy involving the concurrent combination of an anti-EGFR agent (cetuximab or panitumumab) and an anti-vascular endothelial

growth factor (VEGF) agent (bevacizumab).

First-Line Systemic Therapy

FOLFOX for First-Line Therapy

The addition of bevacizumab is an option when FOLFOX is chosen as

initial therapy,616,795 as is the addition of panitumumab or cetuximab for

patients with disease characterized by wild-type KRAS, NRAS, and BRAF. With respect to the treatment of metastatic disease with bevacizumabcontaining regimens or chemotherapy without an additional biologic agent, Panel consensus is that FOLFOX and CAPEOX can be used

interchangeably. Results from a registry-based cohort analysis of >2000 patients support the equivalence of these combinations.798

Use of oxaliplatin has been associated with an increased incidence of

peripheral sensory neuropathy.799 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

receiving FOLFOX as initial therapy for metastatic disease.800 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.801 A meta-analysis of RCTs also

concluded that intermittent delivery of systemic therapy does not

compromise OS compared to continuous treatment.802 Therefore, the

Panel recommends adjusting the schedule/timing of the administration of this drug as a means of limiting this AE. 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.

In the phase II OPTIMOX2 trial, patients were randomized to receive

either an OPTIMOX1 approach (discontinuation of oxaliplatin after 6

cycles of FOLFOX to prevent or reduce neurotoxicity with continuance of 5-FU/LV followed by reintroduction of oxaliplatin on disease progression)or an induction FOLFOX regimen (6 cycles) followed by discontinuation of all chemotherapy until tumor progression reached baseline, followed by reintroduction of FOLFOX.803 Results of the study showed no difference in OS for patients receiving the OPTIMOX1 approach compared with those undergoing an early, pre-planned, chemotherapy-free interval (median

OS, 23.8 vs. 19.5 months; P = .42). However, the median duration of

disease control, which was the primary endpoint of the study, reached

statistical significance at 13.1 months in patients undergoing maintenance therapy and 9.2 months in patients with a chemotherapy-free interval (P =.046).803

The CONcePT trial also tested an intermittent oxaliplatin approach in

patients with advanced CRC and found that it improved acute peripheral sensory neuropathy (P = .037) over continuous oxaliplatin.804 The addition of oxaliplatin breaks also improved time to treatment failure (HR, 0.581; P = .0026) and time to tumor progression (HR, 0.533; P = .047).

##### CAPEOX for First-Line Therapy

Early data suggested that calcium/magnesium infusion might prevent

oxaliplatin-related neurotoxicity.805-812 However, the phase III, randomized, double-blind N08CB study, which randomized 353 patients with colon

cancer receiving adjuvant FOLFOX to calcium/magnesium infusion or

placebo, found that calcium/magnesium did not reduce cumulative

sensory neurotoxicity.813 The Panel therefore recommends against

calcium/magnesium infusions for this purpose.

CAPEOX for First-Line Therapy

The combination of capecitabine and oxaliplatin, known as CAPEOX or XELOX, has been studied as an active first-line therapy for patients with mCRC.814-818 In a randomized phase III trial comparing CAPEOX and

FOLFOX in 2034 patients, the regimens showed similar median PFS

intervals of 8.0 and 8.5 months, respectively, and CAPEOX was

determined to be noninferior to FOLFOX as first-line treatment of

metastatic disease.814 Meta-analyses of RCTs also showed that CAPEOX and FOLFOX had similar benefits for patients with mCRC.819,820

peripheral sensory neuropathy (see FOLFOX, above). Discontinuation of oxaliplatin from FOLFOX or CAPEOX should be strongly considered after 3 months of therapy (the OPTIMOX1 approach800), or sooner for

unacceptable neurotoxicity, with other drugs in the regimen maintained until tumor progression. A Turkish Oncology Group Trial showed that this stop-and-go approach is safe and effective in first-line therapy with

CAPEOX/bevacizumab.821 The randomized FOCUS4-N trial compared

capecitabine maintenance therapy to active monitoring in patients with

disease responding to first-line therapy.822 While there was no significant difference in OS between the two groups (15.2 months in the capecitabine arm vs. 14.8 months in the active monitoring arm [adjusted HR, 0.93; P = .66]), median PFS was longer in the capecitabine arm (3.88 months

##### FOLFIRI for First-Line Therapy

compared to 1.87 months in the active monitoring arm [adjusted HR, 0.40; P < .0001]).

Patients experiencing neurotoxicity on oxaliplatin should not receive

subsequent oxaliplatin therapy until and unless they experience near-total resolution of that neurotoxicity. The Panel recommends against the use of calcium/magnesium infusion to prevent oxaliplatin-related neurotoxicity.813 Regarding the toxicities associated with capecitabine use, the Panel noted that: 1) patients with diminished creatinine clearance may accumulate

levels of the drug, and therefore may require dose modification; 2) the incidence of hand-foot syndrome was increased for patients receiving

capecitabine-containing regimens versus either bolus or infusional

regimens of 5-FU/LV795; and 3) patients of North American descent may experience a higher incidence of AEs with certain doses of capecitabine compared with patients from other countries.773 These toxicities may

necessitate modifications in the dosing of capecitabine.795,823 Patients on capecitabine should be monitored closely so that dose adjustments can be made at the earliest signs of certain side effects, such as hand-foot

syndrome. Interestingly, an analysis of patients from the AIO’s KRK-0104 trial and the Mannheim rectal cancer trial found that capecitabine-related hand-foot skin reactions were associated with an improved OS (75.8 vs.

41.0 months; P = .001; HR, 0.56).824

The addition of bevacizumab is an option if CAPEOX is chosen as initial therapy.616,795 With respect to the treatment of metastatic disease with

bevacizumab-containing regimens or chemotherapy without an additional biologic agent, the consensus of the Panel is that FOLFOX and CAPEOX can be used interchangeably. Results from a registry-based cohort

analysis of >2000 patients support the equivalence of these

combinations.798

FOLFIRI for First-Line Therapy

Evidence for the comparable efficacy for FOLFOX and FOLFIRI comes from a crossover study in which patients received either FOLFOX or

FOLFIRI as initial therapy and were then switched to the other regimen at disease progression.652 Similar response rates and PFS times were

obtained when these regimens were used as first-line therapy. Further support for this conclusion has come from results of a phase III trial

comparing the efficacy and toxicity of FOLFOX and FOLFIRI regimens in previously untreated patients with mCRC.825 No differences were observed in response rate, PFS times, and OS between the treatment arms.

A randomized phase III study compared FOLFIRI to 5-FU/LV in first-line treatment of patients ≥75 years with mCRC.826 In this population of

patients, grade 3–4 toxicities were increased with the addition of irinotecan (52.2% vs. 76.3%), without an improvement in PFS or OS.

Toxicities associated with irinotecan include both early and late forms of diarrhea, dehydration, and severe neutropenia.827 Irinotecan is inactivated by the enzyme uridine diphosphate

glucuronosyltransferase 1A1

(UGT1A1), which is also involved in converting substrates such as bilirubin into more soluble forms through conjugation with certain glycosyl groups. Deficiencies in UGT1A1 can be caused by certain genetic polymorphisms and can result in conditions associated with accumulation of unconjugated hyperbilirubinemias, such as types I and II of the Crigler-Najjar and Gilbert syndromes. Thus, irinotecan should be used with caution and at a

decreased dose in patients with Gilbert syndrome or elevated serum

bilirubin. Similarly, certain genetic polymorphisms in the gene encoding for UGT1A1 can result in a decreased level of glucuronidation of the active metabolite of irinotecan, resulting in an accumulation of the drug and

increased risk for toxicity,827-829 although severe irinotecan-related toxicity is not experienced by all patients with these polymorphisms.829 Results from a dose-finding and pharmacokinetic study suggest that dosing of

irinotecan should be individualized based on UGT1A1 genotype.830 The maximum tolerated dose of IV irinotecan every 3 weeks was 850 mg, 700 mg, and 400 mg in patients with the *1/*1, *1/*/28, and *28/*28 genotypes, respectively.

bevacizumab, along with improved outcomes for ORR and median OS in the per-protocol population with cetuximab.910 PFS was similar between the groups and the advantage for cetuximab only occurred in patients with left-sided primary tumors.

The phase III PARADIGM trial evaluated the use of panitumumab versus bevacizumab when combined with FOLFOX as first-line therapy in 823 patients with RAS wild-type mCRC.911 In the as-treated population, 75.3% had left-sided tumors. After a median follow-up of 61 months,

panitumumab showed a significantly higher median OS when used as part of the first-line regimen compared to bevacizumab. This was true for both the left-sided tumor population (37.9 vs. 34.3 months; P = .03) as well as the full analysis set (36.2 vs. 31.3 months; P = .03). While PFS was similar

Commercial tests are available to detect the UGT1A1*28 allele, which is associated with decreased gene expression and, hence, reduced levels of UGT1A1 expression. Also, a warning was added to the label for irinotecan indicating that a reduced starting dose of the drug should be used in

patients known to be homozygous for UGT1A1*28.831 A practical approach to the use of UGT1A1*28 allele testing with respect to patients receiving irinotecan has been presented,829 although guidelines for use of this test in clinical practice have not been established. Furthermore, UGT1A1 testing on patients who experience irinotecan toxicity is not recommended,

because they will require a dose reduction regardless of the UGT1A1 test result.

Results from a phase IV trial in 209 patients with mCRC who received

bevacizumab in combination with FOLFIRI as first-line therapy showed

that this combination was as effective and well-tolerated as bevacizumab with other 5-FU–based therapies.832 A phase III trial in Japan also showed that FOLFIRI plus bevacizumab is noninferior to mFOLFOX6 plus

bevacizumab with regard to PFS.833 Therefore, the addition of

bevacizumab to FOLFIRI is recommended as an option for initial therapy; alternatively, cetuximab or panitumumab (only for left-sided tumors

characterized by wild-type RAS/BRAF) can be added to this

regimen.685,707,796,834,835

Infusional 5-FU/LV and Capecitabine for First-Line Therapy

For patients with impaired tolerance to aggressive initial therapy, the

guidelines recommend infusional 5-FU/LV or capecitabine with or without bevacizumab as an option.312,781,795,836-838 Patients with metastatic cancer with no improvement in functional status after this less intensive initial

##### Infusional 5-FU/LV and Capecitabine for First-Line Therapy

##### FOLFOXIRI or FOLFIRINOX for First-Line Therapy

therapy should receive best supportive care. Patients showing

improvement in functional status should be treated with one of the options specified for initial therapy for advanced or metastatic disease. Toxicities associated with capecitabine use are discussed earlier (see CAPEOX). In a pooled analysis of results from two randomized clinical trials involving patients with a potentially curative resection of liver or lung metastases randomly assigned to either postoperative systemic chemotherapy with 5-FU/LV or observation alone after surgery, the median PFS was 27.9

months in the chemotherapy arm and 18.8 months for those undergoing surgery alone (HR, 1.32; 95% CI, 1.00–1.76; P = .058), with no significant difference in OS.839

Results were published from the open-label phase III AVEX trial, in which 280 patients ≥70 years were randomized to capecitabine with or without bevacizumab.840 The trial met its primary endpoint, with the addition of

bevacizumab giving a significantly improved median PFS (9.1 vs. 5.1

months; HR, 0.53; 95% CI, 0.41–0.69; P < .0001).

FOLFOXIRI or FOLFIRINOX for First-Line Therapy

Use of FOLFOXIRI compared with FOLFIRI as initial therapy for the

treatment of metastatic disease has been investigated in two randomized phase III trials.605,606 In a trial by the GONO group, statistically significant improvements in PFS (9.8 vs. 6.9 months; HR, 0.63; P = .0006) and

median OS (22.6 vs. 16.7 months; HR, 0.70; P = .032) were observed in the FOLFOXIRI arm,605 although no OS difference was seen between

treatment arms in the HORG study (median OS was 19.5 and 21.5 months for FOLFIRI and FOLFOXIRI, respectively; P = .337).606 Both studies

showed some increased toxicity in the FOLFOXIRI arm (eg, significant increases in neurotoxicity and neutropenia,605 diarrhea, alopecia, and

neurotoxicity606), but no differences in the rate of toxic death were reported in either study. Long-term outcomes of the GONO trial with a median

follow-up of 60.6 months were later reported.607 The improvements in PFS and OS were maintained.

The Panel includes the possibility of adding bevacizumab to FOLFIRINOX for initial therapy of patients with unresectable metastatic disease. Results of the GONO group’s phase III TRIBE trial showed that

FOLFOXIRI/bevacizumab significantly increased PFS (12.1 vs. 9.7

months; HR, 0.75; 95% CI, 0.62–0.90; P = .003) and response rate (65% vs. 53%; P = .006) compared to FOLFIRI/bevacizumab in patients with unresectable mCRC.841 Subgroup analyses indicated that no benefit to the addition of oxaliplatin was seen in patients who received prior adjuvant therapy (64% of cases included oxaliplatin in the adjuvant regimen).

Diarrhea, stomatitis, neurotoxicity, and neutropenia were significantly more prevalent in the FOLFOXIRI arm. In an updated analysis on the TRIBE trial, investigators reported the median OS at 29.8 months (95% CI, 26.0–

34.3) in the FOLFOXIRI plus bevacizumab arm and 25.8 months (95% CI,

22.5–29.1) in the FOLFIRI plus bevacizumab arm (HR, 0.80; 95% CI,

0.65–0.98; P = .03).842

The randomized, phase III TRIBE2 compared first-line FOLFOXIRI plus bevacizumab to a sequential strategy of f irst-line FOLFOX plus

bevacizumab followed by FOLFIRI plus bevacizumab after progression in 679 patients with unresectable, previously untreated mCRC.843 The

primary endpoint of median PFS was 19.2 months for FOLFOXIRI

compared to 16.4 months for the sequential strategy (HR, 0.74; 95% CI,

0.63–0.88; P = .0005). Serious AEs were reported in 25% of patients in the FOLFOXIRI group compared to 17% in the sequential therapy group. Results from the randomized phase II OLIVIA trial, which compared

mFOLFOX6/bevacizumab to FOLFOXIRI/bevacizumab in patients with

unresectable colorectal liver metastases, were also reported.844

Improvement in R0 resection rate was seen in the

FOLFOXIRI/bevacizumab arm (49% vs. 23%; 95% CI, 4%–48%) and in

##### Bevacizumab for First-Line Therapy

the primary endpoint of overall (R0/R1/R2) resection rate (61% vs. 49%; 95% CI, −11%–36%). Other phase II trials, including CHARTA and

STEAM, have also reported improved outcomes for FOLFOXIRI plus

bevacizumab when compared to a chemotherapy doublet plus

bevacizumab for first-line treatment of mCRC.620,845

A pooled analysis of TRIBE and TRIBE2846 and a meta-analysis of

individual patient data from CHARTA, OLIVIA, STEAM, TRIBE, and

TRIBE2620 reached similar conclusions as the clinical trials. These

analyses concluded that first-line treatment with FOLFOXIRI plus

bevacizumab yields significantly better outcomes, albeit at the expense of higher toxicity, compared to sequential treatment with chemotherapy

doublets in combination with bevacizumab. An additional pooled analysis of TRIBE and TRIBE2847 evaluated toxicity based on age with FOLFOXIRI plus bevacizumab and found lower risks of grade 3 or higher neutropenia (P = .07), diarrhea (P = .04), and asthenia (P = .008) in patients aged <50 years but higher rates of any grade nausea (P < .01) and vomiting (P < .01) in this age group. There was no impact on PFS (P = .81), OS (P = .44), or ORR (P = .50) based on age. Based on these results, the NCCN Panel strongly recommends first-line FOLFIRINOX for patients with

excellent performance status who can withstand the higher toxicity of the triplet regimen.

The Panel recommends FOLFIRINOX instead of FOLFOXIRI because FOLFOXIRI uses a high dose of 5-FU (3200 mg/m2 over 48 hours).

Patients in the United States have been shown to have greater toxicity

with 5-FU. The dose of 5-FU (2400 mg/m2 over 46 hours) is a starting

dose consistent with the dose recommended in FOLFOX or FOLFIRI and should be strongly considered for patients in the United States.

Bevacizumab for First-Line Therapy

Bevacizumab is a humanized monoclonal antibody that blocks the activity of VEGF, a factor that plays an important role in tumor angiogenesis.621

The NCCN Panel notes that FDA-approved biosimilars may be substituted for bevacizumab wherever the therapy is recommended within these

Guidelines (see Biosimilars, above, for more information). Pooled results from several randomized phase II studies have shown that the addition of bevacizumab to first-line 5-FU/LV improved OS in patients with

unresectable mCRC compared with those receiving these regimens

without bevacizumab.615,848,849 A combined analysis of the results of these trials showed that the addition of bevacizumab to 5-FU/LV was associated with a median survival of 17.9 versus 14.6 months for regimens consisting of 5-FU/LV or 5-FU/LV plus irinotecan without bevacizumab (P = .008).837 A study of previously untreated patients receiving bevacizumab plus IFL also provided support for the inclusion of bevacizumab in initial therapy.615 In that pivotal trial, a longer survival time was observed with the use of

bevacizumab (20.3 vs. 15.6 months; HR, 0.66; P < .001).

Results have also been reported from a large, head-to-head, randomized, double-blind, placebo-controlled, phase III study (NO16966) in which

CAPEOX (capecitabine dose, 1000 mg/m2, twice daily for 14 days) with bevacizumab or placebo was compared with FOLFOX with bevacizumab or placebo in 1400 patients with unresectable metastatic disease.616 The addition of bevacizumab to oxaliplatin-based regimens was associated

with a more modest increase of 1.4 months in PFS compared with these regimens without bevacizumab (HR, 0.83; 97.5% CI, 0.72–0.95; P =

.0023), and the difference in OS, which was also a modest 1.4 months, did not reach statistical significance (HR, 0.89; 97.5% CI, 0.76–1.03; P =

.077).616 Researchers have suggested that differences observed in crossstudy comparisons of NO16966 with other trials might be related to

differences in the discontinuation rates and durations of treatment

between trials, although these hypotheses are conjectural.616 However, in this 1400-patient randomized study, absolutely no difference in response rate was seen with and without bevacizumab, and this finding could not have been influenced by the early withdrawal rates, which would have

occurred after the responses would have occurred. Results of subset

analyses evaluating the benefit of adding bevacizumab to either FOLFOX or CAPEOX indicated that bevacizumab was associated with

improvements in PFS when added to CAPEOX but not FOLFOX.616

The combination of FOLFIRI and bevacizumab in the first-line treatment of advanced CRC has been studied, although no RCTs have compared

FOLFIRI with and without bevacizumab. A systematic review with a pooled analysis (29 prospective and retrospective studies, 3502 patients) found that the combination gave a response rate of 51.4%, a median PFS of

10.8 months (95% CI, 8.9–12.8), and a median OS of 23.7 months (95% CI, 18.1–31.6).850 FOLFIRINOX with bevacizumab is also an accepted

combination (see FOLFOXIRI or FOLFIRINOX for First-Line Therapy,

above), although no RCTs have compared FOLFIRINOX with and without bevacizumab.

A prospective observational cohort study (ARIES) included 1550 patients who received first-line therapy with bevacizumab with chemotherapy for mCRC and 482 patients treated with bevacizumab in second-line.851

Median OS was 23.2 months (95% CI, 21.2–24.8) for the first-line cohort and 17.8 months (95% CI, 16.5–20.7) for the second-line group. A similar cohort study (ETNA) of f irst-line bevacizumab use with irinotecan-based therapy reported a median OS of 25.3 months (95% CI, 23.3–27.0).852 Several meta-analyses have shown a benefit for the use of bevacizumab in first-line therapy for mCRC.853-861 A meta-analysis of six randomized

clinical trials (3060 patients) that assessed the efficacy of bevacizumab in first-line treatment of mCRC found that bevacizumab gave a PFS (HR,

0.72; 95% CI, 0.66–0.78; P < .00001) and OS (HR, 0.84; 95% CI, 0.77–

0.91; P < .00001) advantage.862 However, subgroup analyses showed that the advantage was limited to irinotecan-based regimens. In addition, an analysis of the SEER-Medicare database found that bevacizumab added a modest improvement to OS of patients with stage IV CRC diagnosed

between 2002 and 2007 (HR, 0.85; 95% CI, 0.78–0.93).863 The survival advantage was not evident when bevacizumab was combined with

oxaliplatin-based chemotherapy, but was evident in irinotecan-based

regimens. Limitations of this analysis have been discussed,864,865 but,

overall, the addition of bevacizumab to first-line chemotherapy appears to offer a modest clinical benefit.

A meta-analysis of RCTs showed that the addition of bevacizumab to

chemotherapy is associated with a higher incidence of treatment-related mortality than chemotherapy alone (RR, 1.33; 95% CI, 1.02–1.73; P =

.04), with hemorrhage (23.5%), neutropenia (12.2%), and GI perforation (7.1%) being the most common causes of fatality.866 Venous

thromboembolisms, on the other hand, were not increased in patients

receiving bevacizumab with chemotherapy versus those receiving

chemotherapy alone.867 Another meta-analysis showed that bevacizumab was associated with a significantly higher risk of hypertension, GI

hemorrhage, and perforation, although the overall risk for hemorrhage and perforation is quite low.868 The risk of stroke and other arterial events is increased in patients receiving bevacizumab, especially in those ≥65

years. GI perforation is a rare but important side effect of bevacizumab therapy in patients with CRC.612,795 Extensive prior intra-abdominal

surgery, such as peritoneal stripping, may predispose patients to GI

perforation. A small cohort of patients with advanced ovarian cancer had an unacceptably high rate of GI perforation when treated with

bevacizumab.869 This result illustrated that peritoneal debulking surgery may be a risk factor for GI perforation, whereas the presence of an intact primary tumor does not seem to increase the risk for GI perforation. The FDA approved a safety label warning of the risk for necrotizing fasciitis, sometimes fatal and usually secondary to wound healing complications; GI perforation; or fistula formation after bevacizumab use.621

Use of bevacizumab may interfere with wound healing.612,621,795 A

retrospective evaluation of data from two randomized trials of 1132

patients undergoing chemotherapy with or without bevacizumab as initial therapy for mCRC indicated that the incidence of wound healing

complications was increased for the group of patients undergoing a major surgical procedure while receiving a bevacizumab-containing regimen

compared with the group receiving chemotherapy alone while undergoing major surgery (13% vs. 3.4%, respectively; P = .28).612 However, when chemotherapy plus bevacizumab or chemotherapy alone was

administered after surgery, with a delay between surgery and

bevacizumab administration of at least 6 weeks, the incidence of wound healing complications in either group of patients was low (1.3% vs. 0.5%; P = .63). Similarly, results of a single-center, nonrandomized phase II trial of patients with potentially resectable liver metastases showed no increase in bleeding or wound complications when the bevacizumab component of CAPEOX plus bevacizumab therapy was stopped 5 weeks before surgery (ie, bevacizumab excluded from the sixth cycle of therapy).870 In addition, no significant differences in bleeding, wound, or hepatic complications were seen in a retrospective trial evaluating the effects of preoperative bevacizumab stopped at ≤8 weeks versus at ≥8 weeks before resection of liver colorectal metastases in patients receiving oxaliplatin- or irinotecancontaining regimens.871 The Panel recommends an interval of at least 6 weeks (which corresponds to two half-lives of the drug621) between the last dose of bevacizumab and any elective surgery. Additionally, re-initiation of bevacizumab should be delayed at least 6 to 8 weeks postoperatively.

Preclinical studies suggested that cessation of anti-VEGF therapy might be associated with accelerated recurrence, more aggressive tumors on recurrence, and increased mortality. A retrospective meta-analysis of f ive placebo-controlled, randomized, phase III trials including 4205 patients with metastatic colorectal, breast, renal, or pancreatic cancer found no

difference in time to disease progression and mortality with discontinuation

of bevacizumab versus discontinuation of placebo.872 Although this metaanalysis has been criticized,873,874 the results are supported by results from the NSABP Protocol C-08 trial.404 This trial included patients with stage II and stage III CRC, and no differences in recurrence, mortality, or mortality 2 years after recurrence were seen between patients receiving

bevacizumab versus patients in the control arm. These results suggest that no “rebound effect” is associated with bevacizumab use.

Cetuximab or Panitumumab for First-Line Therapy in KRAS/NRAS WildType Disease

Cetuximab and panitumumab are monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways. Panitumumab is a fully human monoclonal antibody, whereas cetuximab is a chimeric

monoclonal antibody.875 Cetuximab and panitumumab have been studied in combination with FOLFIRI and FOLFOX as initial therapy options for treatment of mCRC. The randomized, phase II PLANET-TTD trial

comparing patients treated with panitumumab plus either FOLFOX or

FOLFIRI found no significant differences in efficacy between the two

regimens.876

Meta-analyses of RCTs have concluded that EGFR inhibitors provide a clear clinical benefit in the treatment in patients with RAS wild-type

mCRC.687,877 Patients with known KRAS- or NRAS-mutant tumors should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justif ied (see Biomarkers for Systemic Therapy, KRAS and NRAS

Mutations, above for more information). Individual trials are discussed

below.

Administration of either cetuximab or panitumumab has been associated with severe infusion reactions, including anaphylaxis, in 3% and 1% of patients, respectively.875 Based on case reports and a small trial,

##### Cetuximab or Panitumumab for First-Line Therapy in KRAS/NRAS Wild-Type Disease

administration of panitumumab seems to be feasible for patients

experiencing severe infusion reactions to cetuximab.878-880 Skin toxicity is a side effect of both of these agents and is not considered part of the

infusion reactions. The incidence and severity of skin reactions with

cetuximab and panitumumab seem to be very similar. Furthermore, the presence and severity of skin rash in patients receiving either of these drugs have been shown to predict increased response and

survival.683,685,881-884 An NCCN task force addressed the management of dermatologic and other toxicities associated with anti-EGFR inhibitors.885 Cetuximab and panitumumab have also been associated with a risk for

venous thromboembolic and other serious AEs.886,887

Based on the results of the PACCE and CAIRO2 trials, the Panel strongly advises against the concurrent use of bevacizumab with either cetuximab or panitumumab (see Bevacizumab, above).793,794 Several trials that

assessed EGFR inhibitors in combination with various chemotherapy

agents are discussed below.

Cetuximab/Panitumumab and Primary Tumor Sidedness: A growing body of data has shown that the location of the primary tumor can be both

prognostic and predictive of response to EGFR inhibitors in mCRC.888-896 For example, outcomes of 75 patients with mCRC treated with cetuximab, panitumumab, or cetuximab/irinotecan in first-line or subsequent lines of therapy at three Italian centers were analyzed based on sidedness of the primary tumor.889 No responses were seen in the patients with right-sided primary tumors compared with a response rate of 41% in those with leftsided primaries (P = .003). The median PFS was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (HR, 3.97;

95% CI, 2.09–7.53; P < .0001).

The strongest evidence for the predictive value of primary tumor

sidedness and response to EGFR inhibitors is in the first-line treatment of patients in the phase III CALGB/SWOG 80405 trial.893 The study showed

that patients with RAS wild-type, right-sided primary tumors (cecum to

hepatic flexure) had longer OS if treated with bevacizumab than if treated with cetuximab in first line (HR, 1.36; 95% CI, 0.93–1.99; P = .10),

whereas patients with all RAS wild-type, left-sided primary tumors (splenic flexure to rectum) had longer OS if treated with cetuximab than if treated with bevacizumab (HR, 0.77; 95% CI, 0.59–0.99; P = .04).897 OS was

prolonged with cetuximab versus bevacizumab in the left-sided primary group (39.3 vs. 32.6 months) but shortened in the right-sided primary

group (13.6 vs. 29.2 months). Retrospective analyses of other

contemporary studies have confirmed this finding.896

These and other data suggest that cetuximab and panitumumab confer little if any benefit to patients with mCRC if the primary tumor originated on the right side. The Panel believes that primary tumor sidedness is a

surrogate for the non-random distribution of molecular subtypes across the colon and that the ongoing analysis of genomic differences between rightand left-sided tumors898 will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy, 888,889,891 but the Panel awaits more

definitive studies. Until such data are available, all patients with

RAS/BRAF wild-type tumors can be considered for panitumumab or

cetuximab in subsequent lines of therapy if neither was previously given. Cetuximab with FOLFIRI: Use of cetuximab as initial therapy for metastatic disease was investigated in the CRYSTAL trial, in which patients were

randomly assigned to receive FOLFIRI with or without cetuximab.685

Retrospective analyses of the subset of patients with known KRAS exon 2 tumor status showed a statistically significant improvement in median PFS

with the addition of cetuximab in the wild-type (9.9 vs. 8.7 months; HR,

0.68; 95% CI, 0.50–0.94; P = .02).685 The statistically significant benefit in PFS for patients with KRAS exon 2 wild-type tumors receiving cetuximab was confirmed in a publication of an updated analysis of the CRYSTAL data.707 This study included a retrospective analysis of OS in the KRAS exon 2 wild-type population and found an improvement with the addition of cetuximab (23.5 vs. 20.0 months; P = .009). Importantly, the addition of cetuximab did not affect the quality of life of participants in the CRYSTAL trial.899 As has been seen with other trials, when DNA samples from the CRYSTAL trial were re-analyzed for additional KRAS and NRAS

mutations, patients with RAS wild-type tumors derived a clear OS benefit (HR, 0.69; 95% CI, 0.54–0.88), whereas those with any RAS mutation did not (HR, 1.05; 95% CI, 0.86–1.28).900

Panitumumab with FOLFIRI: FOLFIRI with panitumumab is listed as an option for first-line therapy in mCRC based on extrapolation from data in second-line treatment.717,835,901,902

Cetuximab with FOLFOX: Several trials have assessed the combination of FOLFOX and cetuximab in first-line treatment of mCRC. In a retrospective evaluation of the subset of patients with known tumor KRAS exon 2 status enrolled in the randomized phase II OPUS trial, addition of cetuximab to FOLFOX was associated with an increased ORR (61% vs. 37%; OR, 2.54; P = .011) and a very slightly lower risk of disease progression (7.7 vs. 7.2 months [a 15-day difference]; HR, 0.57; 95% CI, 0.36–0.91; P = .016)

compared with FOLFOX alone in the subset of patients with KRAS exon 2 wild-type tumors.679 Although data supporting the statistically significant benefits in ORR and PFS for patients with tumors characterized by KRAS wild-type exon 2 were upheld in an update of this study, no median OS benefit was observed for the addition of cetuximab to chemotherapy (22.8 months in the cetuximab arm vs. 18.5 months in the arm undergoing

chemotherapy alone; HR, 0.85; P = .39).903

Furthermore, in the randomized phase III MRC COIN trial, no benefit in OS (17.9 vs. 17.0 months; P = .067) or PFS (8.6 months in both groups; P = .60) was seen with the addition of cetuximab to FOLFOX or CAPEOX as first-line treatment of patients with locally advanced CRC or mCRC and wild-type KRAS exon 2.708 Exploratory analyses of the COIN trial,

however, suggest that there may be a benefit to the addition of cetuximab in patients who received FOLFOX instead of CAPEOX.708

Notably, additional trials examining the efficacity of the addition of

cetuximab to oxaliplatin-containing regimens in the first-line treatment of patients with advanced CRC or mCRC and wild-type KRAS exon 2 have not shown any benefit. The addition of cetuximab to the Nordic FLOX

regimen showed no benefit in OS or PFS in this population of patients in the randomized phase III NORDIC VII study of the Nordic Colorectal

Cancer Biomodulation Group.904

However, results from the randomized phase III CALGB/SWOG 80405 trial of >1000 patients (discussed in Cetuximab or Panitumumab vs.

Bevacizumab in First-Line Therapy, below) showed that the combination of FOLFOX with cetuximab can be effective in first-line treatment of

mCRC.797 The phase III open-label, randomized TAILOR trial confirmed this result, reporting benefits in PFS (9.2 vs. 7.4 months; P = .004), OS (20.7 vs. 17.8 months; P = .02), and ORR (61.1% vs. 39.5%; P < .001) with first-line cetuximab plus FOLFOX compared to FOLFOX alone in

patients with RAS wild-type mCRC.905 Therefore, the Panel recommends cetuximab plus FOLFOX as an initial therapy option for RAS/BRAF wildtype patients with advanced or metastatic disease.

Panitumumab with FOLFOX: Panitumumab in combination with either

FOLFOX686,796 or FOLFIRI834 has also been studied in the first-line

treatment of patients with mCRC. Results from the large, open-label,

randomized PRIME trial comparing panitumumab plus FOLFOX versus FOLFOX alone in patients with KRAS/NRAS wild-type advanced CRC

showed a statistically significant improvement in PFS (HR, 0.72; 95% CI,

0.58–0.90; P = .004) and OS (HR, 0.77; 95% CI, 0.64–0.94; P = .009) with the addition of panitumumab.686 Therefore, the combination of FOLFOX and panitumumab remains an option as initial therapy for patients with

advanced or metastatic disease. Importantly, the addition of panitumumab had a detrimental impact on PFS for patients with tumors characterized by mutated KRAS/NRAS in the PRIME trial (discussed further in KRAS and NRAS Mutations within Biomarkers for Systemic Therapy, above).686

The phase III randomized GONO TRIPLETE study compared

mFOLFOXIRI plus panitumumab with mFOLFOX6 plus panitumumab as initial therapy in patients with unresectable RAS/BRAF wild-type mCRC and found that more intensive mFOLFOXIRI plus panitumumab did not provide additional benefit and resulted in non-negligible increases in GI toxicity.906 The two groups had similar OR rates, at 76% for mFOLFOX6 plus panitumumab versus 73% for mFOLFOXIRI plus panitumumab (OR,

0.87; 95% CI, 0.56–1.34; P = .526). Median PFS was also similar at a

median follow-up of 26.5 months, at 12.7 months for mFOLFOX6 plus panitumumab versus 12.3 months for mFOLFOXIRI plus panitumumab (HR, 0.88; 95% CI, 0.70–1.11; P = .277). There were also no significant differences in early tumor shrinkage (58% vs. 57%; P = .878) or deepness of response (47% vs. 48%; P = .845) noted. Grade >2 diarrhea occurred in 7% of patients in the mFOLFOX6 plus panitumumab versus 23% of

patients in the mFOLFOXIRI plus panitumumab group.

Cetuximab with CAPEOX: In a trial comparing CAPEOX/cetuximab versus FOLFOX/cetuximab, 88 patients with extended RAS/BRAF/PIK3CA wildtype mCRC were evaluated.907 There was no significant difference in

response rate between the CAPEOX/cetuximab versus

FOLFOX/cetuximab arms, at 61.5% and 66.7%, respectively (P = .298). DCRs were also similar, at 86.5% (95% CI, 74.2%–94.4%) for the

CAPEOX/cetuximab group versus 88.9% (95% CI, 73.9%–96.9%) for the

FOLFOX/cetuximab group. Based on these data, the Panel now

recommends CAPEOX plus cetuximab or panitumumab in addition to

FOLFOX plus cetuximab or panitumumab for initial therapy for advanced CRC or mCRC.

Cetuximab or Panitumumab vs. Bevacizumab in First-Line Therapy: The randomized, open-label, multicenter FIRE-3 trial from the German AIO

group compared the efficacy of FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in first-line, KRAS exon 2 wild-type, metastatic disease.696 This trial did not meet its primary endpoint of investigator-read ORR in the 592 patients (62.0% vs. 58.0%; P = .18). PFS was nearly identical

between the study arms, but a statistically significant improvement in OS was reported in the cetuximab arm (28.7 vs. 25.0 months; HR, 0.77; 95% CI, 0.62–0.96; P = .017). The Panel has several criticisms of the trial,

including the lack of third-party review and low rates of second-line

therapy.908,909 While the rate of AEs was similar between the arms, more skin toxicity was observed in those receiving cetuximab. A final survival analysis of the FIRE-3 study reported a median OS in the RAS wild-type population of 31 months with cetuximab versus 26 months with

between the treatment groups, RR and R0 resection rates were higher with panitumumab. The Panel notes that since the OS curves do not

separate until well after the median PFS, the improvement in OS with

panitumumab may be related to what the patients received in later lines of therapy rather than the choice of f irst-line therapy.

Results of the phase III CALGB/SWOG 80405 trial, comparing

FOLFOX/FOLFIRI with cetuximab or bevacizumab, were reported.797 In this study, patients with wild-type KRAS exon 2 tumors received either FOLFOX (73%) or FOLFIRI (27%) and were randomized to receive

cetuximab or bevacizumab. The primary endpoint of OS was equivalent between the arms, at 29.0 months in the bevacizumab arm versus 30.0 months in the cetuximab arm (HR, 0.88; 95% CI, 0.77–1.01; P = .08).

Results for the randomized multicenter phase II PEAK trial, which

compared FOLFOX/panitumumab with FOLFOX/bevacizumab in first-line treatment of patients with wild-type KRAS exon 2 tumors, were also

published.912 In the subset of 170 participants with wild-type KRAS/NRAS based on extended tumor analysis, PFS was better in the panitumumab arm (13.0 vs. 9.5 months; HR, 0.65; 95% CI, 0.44–0.96; P = .03). A trend towards improved OS was seen (41.3 vs. 28.9 months; HR, 0.63; 95% CI,

0.39–1.02; P = .06). The final analysis of the PEAK trial confirmed that FOLFOX/panitumumab showed a longer PFS compared to

FOLFOX/bevacizumab in patients with wild-type RAS tumors (12.8 vs.

10.1 months; HR, 0.68; 95% CI, 0.48–0.96; P = .029).913 Although these data are intriguing, definitive conclusions are hindered by the small sample size and limitations of subset analyses.914

Economic analyses suggest that bevacizumab may be more cost-effective than EGFR inhibitors in first-line therapy for mCRC,915 although more

recent analyses have shown the opposite.916,917

At this time, the Panel considers the addition of cetuximab, panitumumab, or bevacizumab to chemotherapy as equivalent choices in the first-line, RAS/BRAF wild-type, metastatic setting.

Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the First-Line Setting

The phase III, randomized, open-label KEYNOTE-177 study evaluated the use of pembrolizumab compared to chemotherapy with or without

bevacizumab or cetuximab as first-line therapy for 307 patients with MSIH/dMMR mCRC.918 Median PFS was found to be longer with

pembrolizumab compared to chemotherapy (16.5 vs. 8.2 months; HR,

0.60; 95% CI, 0.45–0.80; P = .0002). Confirmed ORR was 43.8% with

pembrolizumab versus 33.1% with chemotherapy. Grade ≥3 treatmentrelated AEs were reported in 22% of patients treated with pembrolizumab compared to 66% of those treated with chemotherapy. In an updated final analysis of KEYNOTE-177, with a median follow-up of 44.5 months,

median OS was NR with pembrolizumab (NR; 95% CI, 49.2–NR)

compared to 36.7 months (NR; 95% CI, 27.6–NR) with chemotherapy

(HR, 0.74; 95% CI, 0.53–1.03; P = .036).919 While the survival difference was not significant between the two arms, the study did report a 60%

crossover rate, with 60% of patients on the chemotherapy-first arm

crossing over to pembrolizumab or another checkpoint inhibitor during the course of the study.

A follow-up health-related quality-of-life analysis of 294 patients treated as part of KEYNOTE-177 revealed a clinically meaningful improvement in

quality of life with pembrolizumab versus chemotherapy based on

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (P = .0002).920

Likewise, the phase II CheckMate-142 trial evaluated the role of nivolumab in combination with ipilimumab for first-line treatment of dMMR/MSI-H

mCRC.921 In the first-line cohort, ORR was found to be 69% (95% CI,

##### Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the First-Line Setting

53%–82%) and DCR 84% (95% CI, 70.5%–93.5%), with a median followup of 29 months. Thirteen percent of patients had complete disease

response and the median duration of response, median PFS, and median OS had not been reached. Twenty percent of patients had grade 3 or 4 treatment-related AEs and AEs led to discontinuation in 13% of patients. A 2022 abstract reported 5-year follow-up results of CheckMate-142.922 ORR by investigator assessment increased to 71% (95% CI, 56–84), with

progressive disease rate of 16%. PFS and OS rates at 48 months were 51% and 72%, respectively. Additional results from CheckMate-142

(including nivolumab alone or in combination with ipilimumab as

subsequent therapy) are discussed in Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the Non–First-Line Setting, below.

CheckMate 8HW is an ongoing phase III study comparing nivolumab in combination with ipilimumab to nivolumab alone or chemotherapy for

dMMR/MSI-H mCRC. In a prespecified interim analysis, PFS was

compared between nivolumab plus ipilimumab (202 patients) and

chemotherapy (101 patients) in the first-line setting.923 With a median

follow-up of 24.3 months, the combination of nivolumab plus ipilimumab showed a significant improvement in PFS compared to chemotherapy,

with a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.14–0.32; P < .0001). No new safety signals were observed, and nivolumab plus ipilimumab had a lower percentage of grade ≥3 treatmentrelated AEs compared to chemotherapy (23% vs. 48%), although there were two treatment-related deaths on the immunotherapy combination and none with chemotherapy. OS data have not yet been presented.

Although PD-1 immune checkpoint inhibitors are generally well tolerated, serious adverse reactions—many immune-mediated—occur in as many as 21% to 41% of patients.924-927 The most common immune-mediated side effects are to the skin, liver, kidneys, GI tract, lungs, and endocrine

systems.928-930 Pneumonitis, occurring in approximately 3% to 7% of

patients on checkpoint inhibitor therapy, is one of the most serious side effects of PD-1 inhibitors.928,931-933

Based on these data, the Panel recommends pembrolizumab;

dostarlimab-gxly; or nivolumab, alone or in combination with ipilimumab, as first-line treatment options for patients with MSI-H/dMMR mCRC,

regardless of whether intensive therapy is recommended. The

recommendation for nivolumab plus ipilimumab is category 2B when

intensive therapy is not recommended due to concerns about potential

toxicity from the combination therapy. While dostarlimab-gxly does not

have clinical trial data for untreated mCRC, the Panel feels that the

checkpoint inhibitors may be used interchangeably for dMMR/MSI-H

mCRC and the clinical trial data for dostarlimab-gxly in both the previously untreated, locally advanced and the previously treated mCRC settings

support its use in the first-line setting. As discussed in the Biomarkers for Systemic Therapy section, above, checkpoint inhibitor immunotherapy is also recommended for mCRC with functional POLE/POLD1 mutations.

Second-Line or Subsequent Systemic Therapy

The recommended therapy options after first progression for patients who have received prior therapy are dependent on the initial treatment regimen and are outlined in the guidelines. Single-agent irinotecan administered after f irst progression has been shown to significantly improve OS relative to best supportive care 934 or infusional 5-FU/LV.935 In the study of Rougier et al,935 median PFS was 4.2 months for irinotecan versus 2.9 months for 5-FU (P = .030), whereas Cunningham et al934 reported a survival rate at 1 year of 36.2% in the group receiving irinotecan versus 13.8% in the

supportive care group (P = .0001). A meta-analysis of f ive RCTs showed that there was no OS benefit to FOLFIRI over that obtained with irinotecan alone.936 Furthermore, no significant differences in OS were observed in

Second-Line or Subsequent Systemic Therapy

##### Cetuximab and Panitumumab in the Non–First-Line Setting

the Intergroup N9841 trial when FOLFOX was compared with irinotecan monotherapy after first progression of mCRC.937

A meta-analysis of randomized trials found that the addition of a targeted agent after f irst-line treatment improves outcomes but also increases

toxicity.938 Another meta-analysis showed an OS and PFS benefit to

continuing an anti-angiogenic agent after progression on an antiangiogenic agent in first-line.939 Data relating to specific biologic therapies are discussed below.

Cetuximab and Panitumumab in the Non–First-Line Setting

For patients with wild-type KRAS/NRAS/BRAF tumors who experienced progression on therapies not containing an EGFR inhibitor, cetuximab or panitumumab plus irinotecan, cetuximab or panitumumab plus FOLFIRI, or single-agent cetuximab or panitumumab681 is recommended. For

patients with wild-type KRAS/NRAS/BRAF tumors progressing on

therapies that did contain an EGFR inhibitor, administration of an EGFR inhibitor is not recommended in subsequent lines of therapy, except for anti-EGFR rechallenge. No data support switching to either cetuximab or panitumumab after disease progression on the other drug, and the Panel recommends against this practice. While there is limited evidence

suggesting that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy, the Panel awaits more definitive studies to set this limitation. Until such data are available, all patients with

cetuximab in subsequent lines of therapy if neither was previously given. See section on Cetuximab/Panitumumab and Primary Tumor Sidedness, above, for discussion of data.

Panitumumab has been studied as a single agent in the setting of mCRC for patients with disease progression on oxaliplatin/irinotecan-based

chemotherapy in an open-label phase III trial.940 In a retrospective analysis of the subset of patients in this trial with known KRAS exon 2 tumor status,

the benefit of panitumumab versus best supportive care was shown to be enhanced in patients with KRAS exon 2 wild-type tumors.677 PFS was 12.3 weeks versus 7.3 weeks in favor of the panitumumab arm. Response

rates to panitumumab were 17% versus 0% in the wild-type and mutant arms, respectively.677 A more recent phase III trial compared single-agent panitumumab to best supportive care in patients with wild-type KRAS exon 2 mCRC and disease progression on oxaliplatin- and irinotecan-based

chemotherapy.941 The primary endpoint of OS was improved with

panitumumab (10.0 vs. 7.4 months; HR, 0.73; 95% CI, 0.57–0.93; P <

.01).

Panitumumab has also been studied in combination therapy in the setting of progressing mCRC. Among patients with KRAS exon 2 wild-type tumors enrolled in the large Study 181 comparing FOLFIRI alone versus FOLFIRI plus panitumumab as second-line therapy for mCRC, addition of the

biologic agent was associated with improvement in median PFS (5.9 vs.

3.9 months; HR, 0.73; 95% CI, 0.59–0.90; P = .004), although differences in OS between the arms did not reach statistical significance.835 These

results were confirmed in the final results of Study 181.902 Furthermore, reanalysis of samples from the trial showed that the benefit of the

combination was limited to participants with no RAS mutations.942 In

addition, secondary analysis from the STEPP trial showed that

panitumumab in combination with irinotecan-based chemotherapy in

second-line therapy has an acceptable toxicity profile.901 The randomized multicenter PICCOLO trial, which assessed the safety and efficacy of

irinotecan/panitumumab, did not meet its primary endpoint of improved OS in patients with wild-type KRAS/NRAS tumors.717

Cetuximab has been studied both as a single agent681,881,943,944 and in

combination with irinotecan943 in patients experiencing disease

progression on initial therapy not containing cetuximab or panitumumab for metastatic disease. Results of a large phase III study comparing

irinotecan with or without cetuximab did not show a difference in OS, but showed significant improvement in response rate and in median PFS with irinotecan and cetuximab compared with irinotecan alone.945 Importantly, KRAS status was not determined in this study and toxicity was higher in the cetuximab-containing arm (eg, rash, diarrhea, electrolyte

imbalances).945 In a re-analysis of RAS status, median PFS (5.4 vs. 2.6 months; HR, 0.57; 95% CI, 0.46–0.69; P < .0001) and ORR (29.4% vs.

5.0%; OR, 8.12; 95% CI, 4.04–17.40; P < .0001) were improved with

cetuximab plus irinotecan compared to irinotecan alone.946 Median OS

was similar between the two groups (12.3 months for cetuximab plus

irinotecan vs. 12.0 months for irinotecan alone [HR, 0.91; 95% CI, 0.71–

1.17; P = .4645]). Almost 50% of patients in the irinotecan alone arm

received cetuximab post-study, potentially masking an OS benefit with the addition of cetuximab.

In a retrospective analysis of the subset of patients with known KRAS

exon 2 tumor status receiving cetuximab monotherapy as second-line

therapy,881 the benefit of cetuximab versus best supportive care was

shown to be enhanced in patients with KRAS exon 2 wild-type tumors.681 For those patients, median PFS was 3.7 versus 1.9 months (HR, 0.40; 95% CI, 0.30–0.54; P < .001) and median OS was 9.5 versus 4.8 months (HR, 0.55; 95% CI, 0.41–0.74; P < .001), in favor of the cetuximab arm.681 The randomized, multicenter, open-label, noninferiority phase III

ASPECCT trial compared single-agent cetuximab with single-agent

panitumumab in the chemotherapy-refractory metastatic setting.947 The primary noninferiority OS endpoint was reached, with a median OS of 10.4 months (95% CI, 9.4–11.6) with panitumumab and 10.0 months (95% CI,

9.3–11.0) with cetuximab (HR, 0.97; 95% CI, 0.84–1.11). The incidence of AEs was similar between the groups. The final analysis of ASPECCT

came to the same conclusion, reporting a median OS of 10.2 months with

panitumumab and 9.9 months with cetuximab (HR, 0.98; 95% CI, 0.82–

1.07).948

The randomized, multicenter, phase II SPIRITT trial randomized 182

patients with KRAS wild-type tumors whose disease progressed on firstline oxaliplatin-based therapy plus bevacizumab to FOLFIRI plus

bevacizumab or FOLFIRI plus panitumumab.949 No difference was seen in the primary endpoint of PFS between the arms (7.7 months in the

panitumumab arm vs. 9.2 months in the bevacizumab arm; HR, 1.01; 95% CI, 0.68–1.50; P = .97).

A pooled analysis of the TRIBE and TRIBE2 studies assessed treatments administered after second disease progression in 1187 patients with

mCRC who received upfront FOLFOXIRI/ bevacizumab versus FOLFOX or FOLFIRI/bevacizumab.950 In third-line therapy, patients with RAS/BRAF wild-type tumors achieved longer PFS with EGFR inhibitors compared to other therapies (6.4 vs. 3.9 months, P = .02)

Bevacizumab in the Non–First-Line Setting

In the TML (ML18147) trial, patients with mCRC who progressed on

regimens containing bevacizumab received second-line therapy consisting of a different chemotherapy regimen with or without bevacizumab.951 This study met its primary endpoint, with patients continuing on bevacizumab having a modest improvement in OS (11.2 vs. 9.8 months; HR, 0.81; 95% CI, 0.69–0.94; P = .0062). Subgroup analyses from this trial found that these treatment effects were independent of KRAS exon 2 status.952

Similar results were reported from the GONO group’s phase III

randomized BEBYP trial, in which the PFS of patients who continued on bevacizumab plus a different chemotherapy regimen following progression on bevacizumab was 6.8 months compared to 5.0 months in the control arm (HR, 0.70; 95% CI, 0.52–0.95; P = .001).953 An improvement in OS was also seen in the bevacizumab arm (HR, 0.77; 95% CI, 0.56–1.06; P =

##### Bevacizumab in the Non–First-Line Setting

.04). The EAGLE trial randomized 387 patients with disease progression following oxaliplatin-based therapy with bevacizumab to second-line

therapy with FOLFIRI plus either 5 or 10 mg/kg bevacizumab.954 No

difference was seen in PFS or time to treatment failure between the arms, indicating that 5 mg/kg of bevacizumab is an appropriate dose in secondline treatment of mCRC.

The continuation of bevacizumab following progression on bevacizumab was also studied in a community oncology setting through a retrospective analysis of 573 patients from the US Oncology iKnowMed electronic

medical record system.955 Bevacizumab beyond progression was

associated with a longer OS (HR, 0.76; 95% CI, 0.61–0.95) and a longer post-progression OS (HR, 0.74; 95% CI, 0.60–0.93) on multivariate

analysis. Analyses of the ARIES observational cohort found similar results, with longer post-progression survival with continuation of bevacizumab (HR, 0.84; 95% CI, 0.73–0.97).956

Overall, these data (along with data from the VELOUR trial, discussed

below) show that the continuation of VEGF blockade in second-line

therapy offers a very modest but statistically significant OS benefit. The Panel added the continuation of bevacizumab to the second-line treatment options in the 2013 versions of the NCCN Guidelines for Colon and Rectal Cancers. It may be added to any regimen that does not contain another targeted agent. The Panel recognizes the lack of data suggesting a benefit to bevacizumab with irinotecan alone in this setting, but believes that the option is acceptable, especially in patients whose disease progressed on a 5-FU– or capecitabine-based regimen. When an angiogenic agent is used in second-line therapy, bevacizumab is preferred over ziv-aflibercept and ramucirumab (discussed below), based on toxicity and/or cost.957 Beyond the second-line setting, bevacizumab may be combined with trif luridinetipiracil [see Trifluridine-Tipiracil (TAS-102), below, for more information].

It may also be appropriate to consider using bevacizumab with second-line therapy after progression on a first-line regimen that did not contain

bevacizumab.958 However, there are no data to support adding

bevacizumab to a regimen after progression on that same regimen. The randomized phase III ECOG E3200 study in patients who experienced disease progression through a first-line non-bevacizumab–containing

regimen showed that the addition of bevacizumab to second-line FOLFOX modestly improved survival.958 Median OS was 12.9 months for patients receiving FOLFOX plus bevacizumab compared with 10.8 months for

patients treated with FOLFOX alone (P = .0011).958 Use of single-agent bevacizumab is not recommended because it was shown to have inferior efficacy compared with the FOLFOX alone or FOLFOX plus bevacizumab treatment arms.958

Ziv-Aflibercept

Ziv-aflibercept is a recombinant protein that has part of the human VEGF receptors (VEGFR) 1 and 2 fused to the Fc portion of human

immunoglobulin G1 (IgG1). It is designed to function as a VEGF trap to prevent activation of VEGFR and thus inhibit angiogenesis. The VELOUR trial tested second-line ziv-aflibercept in patients with mCRC that

progressed after one regimen containing oxaliplatin. The trial met its

primary endpoint with a small improvement in OS (13.5 months for

FOLFIRI/ziv-aflibercept vs. 12.1 months for FOLFIRI/placebo; HR, 0.82; 95% CI, 0.71–0.94; P = .003).959 A prespecified subgroup analysis from the VELOUR trial found that median OS in the ziv-aflibercept arm versus the placebo arm was 12.5 months (95% CI, 10.8–15.5) versus 11.7

months (95% CI, 9.8–13.8) in patients with prior bevacizumab treatment and 13.9 months (95% CI, 12.7–15.6) versus 12.4 months (95% CI, 11.2–

13.5) in patients with no prior bevacizumab treatment.960

AEs associated with ziv-aflibercept treatment in the VELOUR trial led to discontinuation in 26.6% of patients compared to a 12.1% discontinuation

##### Ramucirumab

in the placebo group.959 The most common causes for discontinuation

were asthenia/fatigue, infections, diarrhea, hypertension, and venous

thromboembolic events.

Ziv-aflibercept has only shown activity when given in conjunction with

FOLFIRI in patients without prior exposure to FOLFIRI. No data suggest activity of FOLFIRI plus ziv-aflibercept in patients whose disease

progressed on FOLFIRI plus bevacizumab or vice-versa, and no data

suggest activity of single-agent ziv-aflibercept. Furthermore, the addition of ziv-aflibercept to FOLFIRI in first-line therapy of patients with mCRC in the phase II AFFIRM study had no benefit and increased toxicity.961 Thus, the Panel added ziv-aflibercept as a second-line treatment option in

combination with FOLFIRI or irinotecan only following progression on

therapy not containing irinotecan. However, the Panel prefers

##### Ziv-Aflibercept

bevacizumab over ziv-aflibercept and ramucirumab (discussed below) in this setting, based on toxicity and/or cost.957

Ramucirumab

Another anti-angiogenic agent, ramucirumab, is a human monoclonal

antibody that targets the extracellular domain of VEGFR 2 to block VEGF signaling. In the multicenter, phase III RAISE trial, 1072 patients with

mCRC whose disease progressed on first-line therapy with

fluoropyrimidine/oxaliplatin/bevacizumab were randomized to FOLFIRI

with either ramucirumab or placebo.962 The primary endpoint of OS in the ITT population was met at 13.3 months and 11.7 months in the

ramucirumab and placebo groups, respectively, for an HR of 0.84 (95% CI, 0.73–0.98; P = .02). PFS was also improved with the addition of

ramucirumab, at 5.7 months and 4.5 months for the two arms (HR, 0.79; 95% CI, 0.70–0.90; P < .0005). A subgroup analysis of the RAISE trial

subsequently reported similar efficacy and safety among patient

subgroups with different KRAS mutation tumor status, time to progression on first-line therapy, and age.963

Rates of discontinuation due to AEs in the RAISE trial were 11.5% in the ramucirumab arm and 4.5% in the placebo arm. The most common grade 3 or worse AEs were neutropenia, hypertension, diarrhea, and fatigue. In addition, a meta-analysis of six phase III trials showed that ramucirumab did not increase the risk of arterial thromboembolic events, venous

thromboembolic events, high-grade bleeding, or high-grade GI bleeding compared to placebo controls.964 These results suggest that ramucirumab may be distinct among antiangiogenic agents in that it does not increase the risk of these events.

Considering the results of the RAISE trial, the Panel added ramucirumab as a second-line treatment option in combination with FOLFIRI or

irinotecan following progression on therapy not containing irinotecan. As with ziv-aflibercept, no data suggest activity of FOLFIRI plus ramucirumab in patients whose disease progressed on FOLFIRI plus bevacizumab or vice-versa, and no data suggest activity of single-agent ramucirumab.

When an angiogenic agent is used in this setting, the Panel prefers

bevacizumab over ziv-aflibercept and ramucirumab, because of toxicity and/or cost.957

##### Encorafenib Plus Cetuximab or Panitumumab for BRAF V600E Mutation-Positive Disease in the Non–First-Line Setting

Encorafenib Plus Cetuximab or Panitumumab for BRAF V600E MutationPositive Disease in the Non–First-Line Setting

A combination of the BRAF inhibitor, encorafenib, and the MEK inhibitor,

binimetinib, with cetuximab has been investigated in the randomized,

phase III BEACON trial for metastatic, BRAF V600E mutation-positive

CRC.965,966 The safety lead-in of the BEACON trial showed promising

efficacy results with an ORR of 48% (95% CI, 29.4%–67.5%) among the 29 patients included in the efficacy analysis. Among the 30 treated

patients in the safety lead-in, the most common grade 3 or 4 AEs were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate transaminase (AST) (10%), and urinary tract

infections (10%).965

##### Systemic Therapy Options for HER2-Amplified Disease

Subsequently, the randomized portion of the BEACON trial reported

similarly encouraging results, including a positive OS result.966 Within this portion of the study, 665 patients were randomized to receive either the triplet combination, an encorafenib and cetuximab doublet, or a control regimen of cetuximab plus either irinotecan or FOLFIRI. Updated results of BEACON reported a median OS of 5.9 months, 9.3 months, and 9.3

months for the control, doublet, and triplet arms, respectively.967 The

confirmed ORRs were 1.8%, 19.5%, and 26.8%, respectively, and grade 3 or higher AE rates were highest in the triplet arm, although the addition of binimetinib did not improve OS over the doublet. Quality-of-life

assessments showed that the doublet and triplet regimens led to a

similarly longer maintenance of quality of life compared with control.968

Based on these reports, the NCCN Panel concluded that only the doublet regimen of encorafenib with either cetuximab or panitumumab should be recommended for patients with BRAF V600E-mutated mCRC.

Data exist on the use of cetuximab or panitumumab in combination with irinotecan and vemurafenib969 or dabrafenib plus trametinib970 for BRAF V600E mutation-positive mCRC. However, based on superior data and/or lower toxicity with the encorafenib-containing doublets, the Panel voted to

not include recommendations for these regimens within the current version of the guidelines.

Systemic Therapy Options for HER2-Amplified Disease

Four different regimens are recommended by the Panel as options for subsequent treatment of mCRC with HER2 amplif ications: famtrastuzumab deruxtecan-nxki (T-DXd) monotherapy or trastuzumab in

combination with pertuzumab, lapatinib, or tucatinib. These regimens (with the exception of T-DXd) may also be appropriate for patients with

previously untreated HER2-amplif ied mCRC when intensive therapy is not recommended. The NCCN Panel notes that FDA-approved biosimilars

may be substituted for trastuzumab wherever the therapy is recommended

within these Guidelines (see Biosimilars, above, for more information). The results of clinical trials supporting each of these regimens are detailed

Trastuzumab Plus Pertuzumab: A combination regimen of the HER2

inhibitors trastuzumab and pertuzumab was studied in a subset analysis of MyPathway, a phase IIa multiple basket study.971 This subset included 57 patients with previously treated, HER2-amplif ied mCRC who were treated with the combination of pertuzumab and trastuzumab. ORR was 32%

(95% CI, 20–45), with 1 complete response and 17 partial responses.

Thirty-seven percent of patients treated with trastuzumab plus pertuzumab had grade 3 or 4 AEs, with hypokalemia and abdominal pain being most common. Another phase II basket study, TAPUR, also investigated the combination of trastuzumab and pertuzumab in HER2-amplif ied mCRC.972 In this study, 28 patients with heavily pretreated, HER2-amplif ied

advanced CRC were treated with the combination. The DCR was 54% and OR was observed in 25% of patients. The median PFS and median OS were 9.6 weeks and 28.8 weeks, respectively. Four patients had at least one grade 3 AE or serious AE, including anemia, infusion reaction, left ventricular dysfunction, and decreased lymphocyte count.

Trastuzumab Plus Lapatinib: The combination of trastuzumab plus the dual HER2/EGFR inhibitor, lapatinib, was studied in the multicenter, phase II HERACLES trial.730 This trial included 27 patients with previously

treated, HER2-positive tumors that were treated with trastuzumab and

lapatinib. ORR was 30% (95% CI, 14–50), with one complete response, seven partial responses, and 12 patients with stable disease. Twenty-two percent of patients treated with trastuzumab plus lapatinib had grade 3 AEs, including fatigue (four patients), skin rash (one patient), and

increased bilirubin (one patient).730

Trastuzumab Plus Tucatinib: A combination regimen of the HER2

inhibitors trastuzumab and tucatinib was studied in the multicenter, phase

II MOUNTAINEER trial.973 This trial included 117 patients with

chemotherapy-refractory, HER2-positive, RAS wild-type mCRC. Initially, all patients on this study were treated with the combination (cohort A),

while later, patients were randomized to receive either tucatinib

monotherapy (cohort C) or the combination of tucatinib and trastuzumab (cohort B). Of the 84 patients who received the combination in cohorts A and B, the confirmed ORR was 38.1% (95% CI, 27.7-49.3), with three

patients having a complete response to the treatment. In all three cohorts, the most common AE was diarrhea. Three percent of patients who

received the combination had tucatinib-related serious AEs (acute kidney injury, colitis, and fatigue).

T-DXd: The HER2-directed antibody and topoisomerase inhibitor

conjugate was studied in the phase 2, multicenter DESTINY-CRC01 trial of 78 patients with HER2-expressing, RAS/BRAF wild-type unresectable CRC and/or mCRC that had already progressed on at least two prior

regimens.974 Patients were split into three cohorts based on the level of tumor HER2 expression (cohort A: IHC 3+ or IHC 2+/ISH+; cohort B: IHC 2+/ISH-; cohort C: IHC 1+). In cohort A, the primary endpoint of ORR was

45.3%, with one complete response and 23 partial responses. Median

PFS in this group was 6.9 months, and median OS had not yet been

reached at the time of data cutoff. No responses were reported in cohorts B or C. Thirty percent of patients in cohort A had received prior anti-HER2 therapy; for these patients ORR was 43.8%. The most common grade ≥3 treatment-emergent AEs were decreased neutrophil count (22%) and

NAVIGATE study reported a median PFS of 5.3 months (95% CI, 2.2–9.0) and a median OS of 33.4 months (95% CI, 2.8–36.5).990 Responses were ongoing for f ive patients, leading their results to be censored. Of the 8 patients with colon cancer, 50% showed a partial response and 50% had stable disease.

Entrectinib: 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.991 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–NE) by independent

review. Median duration of response was 10 months (95% CI, 7.1–NE). Of the four patients with CRC in 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.

Repotrectinib: 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 f irst NTRK TKI treatment, and 48 patients in the NTRK TKI-pretreated cohort, who had already received larotrectinib or entrectinib.992 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.

Selpercatinib for RET Gene Fusion-Positive Disease in the Non-FirstLine Setting

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.752 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 efficacyevaluable patients, the ORR for the entire cohort by independent review

##### Selpercatinib for RET Gene Fusion-Positive Disease in the Non-First-Line Setting

##### Regorafenib

was 43.9% (95% CI, 28.5–60.3) and 20% in the colon cancer subgroup (95% CI, 2.5–55.6). There were 2 complete responses (5%), although neither patient had colon cancer. 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–NE), and median duration of response was 24.5 months (95% CI, 9.2–NE). For the colon cancer subgroup, median

duration of response was 9.4 months (95% CI, 5.6–13.3). 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.993

Regorafenib

Regorafenib is a small-molecule inhibitor of multiple kinases (including

VEGFR, fibroblast growth factor [FGF] receptors, platelet-derived growth factor [PDGF] receptors, BRAF, KIT, and RET) that are involved with

various processes including tumor growth and angiogenesis.994 The phase III CORRECT trial randomized 760 patients whose disease progressed on standard therapy to best supportive care with placebo or regorafenib.995 The trial met its primary endpoint of OS (6.4 months for regorafenib vs. 5.0 months for placebo; HR, 0.77; 95% CI, 0.64–0.94; P = .005). PFS was also significantly but modestly improved (1.9 vs. 1.7 months; HR, 0.49; 95% CI, 0.42–0.58; P < .000001).

The randomized, double-blind, phase III CONCUR trial was performed in China, Hong Kong, South Korea, Taiwan, and Vietnam.996 Patients with progressive mCRC were randomized 2:1 to receive regorafenib or placebo after two or more previous treatment regimens. After a median follow-up of

7.4 months, the primary endpoint of OS was met in the 204 randomized patients (8.8 months in the regorafenib arm vs. 6.3 months in the placebo arm; HR, 0.55; 95% CI, 0.40–0.77; P < .001).

The most common grade 3 or higher AEs in the regorafenib arm of the CORRECT trial were hand-foot skin reaction (17%), fatigue (10%),

hypertension (7%), diarrhea (7%), and rash/desquamation (6%).995 Severe and fatal liver toxicity occurred in 0.3% of 1100 patients treated with

regorafenib across all trials.994 In a meta-analysis of four studies that

included 1078 patients treated with regorafenib for CRC, GI stromal tumor

(GIST), renal cell carcinoma, or hepatocellular carcinoma, the overall

incidence of all-grade and high-grade hand-foot skin reactions was 60.5% and 20.4%, respectively.997 In the subset of 500 patients with CRC, the incidence of all-grade hand-foot skin reaction was 46.6%.

Other studies have also investigated regorafenib for treatment of refractory mCRC. The phase IIIb CONSIGN trial assessed the safety of regorafenib in 2872 patients from 25 countries with refractory mCRC.998 The

REBECCA study assessed the safety and efficacy of regorafenib in a

cohort of 654 patients with mCRC within a compassionate use program.999 The prospective, observational CORRELATE study assessed the safety and efficacy of regorafenib in 1037 patients with mCRC in real-world

clinical practice.1000 The safety and efficacy profiles of regorafenib in all of these trials were consistent with that seen in the CORRECT trial.

The randomized, phase II ReDOS trial investigated the use of an

alternative dose schedule to reduce the toxicities related to regorafenib treatment.1001 Of the 116 evaluable patients, the dose-escalation group had a higher percentage of patients who initiated cycle 3 of regorafenib (43%) compared to the standard dosing group (26%). Rates of several of the most common AEs were also lower among the dose-escalation group compared to the standard dosing group. Based on these results, the Panel agreed that a dose-escalation strategy is an appropriate alternative

##### Trifluridine-Tipiracil (TAS-102)

approach for regorafenib dosing. The phase II REARRANGE study has also supported alternative dosing schedules for regorafenib as feasible and safe in patients with previously treated mCRC.1002

Regorafenib has only shown activity in patients whose disease has

progressed on all standard therapy. Therefore, the Panel added

regorafenib as an additional line of therapy for patients with mCRC

refractory to chemotherapy. It can be given before or after trif luridinetipiracil or fruquintinib; no data inform the best order of these therapies.

Trifluridine-Tipiracil (TAS-102)

Trifluridine-tipiracil is an oral combination drug, consisting of a cytotoxic thymidine analog, trif luridine, and a thymidine phosphorylase inhibitor,

tipiracil hydrochloride, which prevents the degradation of trif luridine. Early clinical studies of the drug in patients with CRC were promising.1003,1004 Results of the double-blind, randomized, controlled, international phase III RECOURSE trial were published in 2015,1005 followed shortly thereafter by approval of trif luridine-tipiracil by the FDA.1006 With 800 patients with

mCRC who progressed through at least two prior regimens randomized 2:1 to receive trif luridine-tipiracil or placebo, the primary endpoint of OS was met (5.3 vs. 7.1 months; HR, 0.68; 95% CI, 0.58–0.81; P < .001).1005 Improvement was also seen in the secondary endpoint of PFS (1.7 vs. 2.0 months; HR, 0.48; 95% CI, 0.41–0.57; P < .001). The most common AEs associated with trif luridine-tipiracil in RECOURSE were neutropenia

(38%), leukopenia (21%), and febrile neutropenia (4%); one drug-related death occurred.1005 A postmarketing surveillance study did not reveal any unexpected safety signals1007 and a subgroup analysis of the RECOURSE trial reported similar efficacy and safety regardless of age, geographical origin, or KRAS mutation status.1008

The combination of trif luridine-tipiracil and bevacizumab has also been studied in the non-first-line setting. The regimen was initially studied in the

phase I/II C-TASK FORCE trial1009 and a subsequent randomized phase II trial that compared trif luridine-tipiracil with and without bevacizumab.1010 Following positive results on these early trials, the phase III SUNLIGHT trial was conducted to compare trif luridine-tipiracil plus bevacizumab to trif luridine-tipiracil alone in 492 patients with previously treated mCRC.1011 Nearly all patients on the trial had previously received a fluoropyrimidine, irinotecan, and oxaliplatin; 72% had received an anti-VEGF antibody; and

93.7% of those with RAS wild-type disease had received an anti-EGFR antibody. Median OS was longer for the bevacizumab combination

compared to trif luridine-tipiracil alone (10.8 vs. 7.5 months; HR, 0.61; 95% CI, 0.49–0.77; P < .001). Median PFS was also longer for the combination

at 5.6 months versus 2.4 months for trif luridine-tipiracil alone (HR, 0.44; 95% CI, 0.36–0.54; P < .001). The most common Aes reported for both groups were neutropenia, nausea, and anemia and no treatment-related deaths occurred in either group. A retrospective study of 57 patients with refractory mCRC showed similar results to the clinical trial data, with an improved median OS for trif luridine-tipiracil with bevacizumab versus

without (14.4 vs. 4.5 months; P < .001).1012 Another retrospective study similarly reported improved OS and time to treatment discontinuation for trif luridine-tipiracil plus bevacizumab compared to either trif luridine-tipiracil alone or regorafenib.1013

Based on these data, the Panel added trif luridine-tipiracil, with or without bevacizumab, as a treatment option for patients whose disease has

progressed through standard therapies. The bevacizumab combination is preferred over trif luridine-tipiracil alone. It can be given before or after regorafenib or fruquintinib; no data inform the best order of these

therapies, although real-world data have shown that patients show better adherence to trif luridine-tipiracil compared to regorafenib.1014 The 144

patients in RECOURSE who had prior exposure to regorafenib obtained similar OS benefit from trif luridine-tipiracil (HR, 0.69; 95% CI, 0.45–1.05) as the 656 patients who did not (HR, 0.69; 95% CI, 0.57–0.83).

##### Fruquintinib

The combination of trif luridine-tipiracil and bevacizumab has also been studied in the first-line setting in both the phase III SOLSTICE study1015 and the phase II TASCO1 study.1016,1017 Both of these studies compared trif luridine-tipiracil plus bevacizumab to capecitabine plus bevacizumab in patients who were not candidates for intensive therapy and have shown similar OS and PFS results between the two treatment groups. Based on concerns about the hematologic and financial toxicities with trif luridinetipiracil compared to capecitabine, the NCCN Panel does not currently

recommend trif luridine-tipiracil, with or without bevacizumab, as first-line therapy for mCRC.

Fruquintinib

Fruquintinib is an orally administered kinase inhibitor that targets VEGFR 1, 2, and 3. Its efficacy and safety has been evaluated in two randomized, double-blind, phase 3 clinical trials, FRESCO and FRESCO-2.1018,1019

FRESCO was conducted at 28 hospitals in China and randomized 416

patients with mCRC that had progressed after at least 2 lines of

chemotherapy, but had not received VEGFR inhibitor therapy, to either fruquintinib or placebo.1019 Patients treated with fruquintinib had

significantly longer median OS compared to those who received placebo (9.3 vs. 6.6 months; HR, 0.65; P < .001). Median PFS was also longer with fruquintinib (3.7 vs. 1.8 months; HR, 0.26; P < .001). FRESCO-2 was a larger study, conducted at 124 hospitals and cancer centers across 14 countries, and enrolled 691 patients with mCRC who had previously

received all available cytotoxic and targeted therapies and had progressed on or were intolerant to trif luridine-tipiracil and/or regorafenib.1018 Patients were randomized to receive fruquintinib or placebo, plus best supportive care. Patients in the FRESCO-2 study had received a median of 4

previous lines of systemic therapy for metastatic disease and 73% had received >3 lines of therapy. As opposed to FRESCO, 97% of patients had received prior VEGF inhibitor therapy and nearly half had progressed on both trif luridine-tipiracil and regorafenib. Patients received fruquintinib

for a median of 3.1 months (compared to 1.8 months on placebo) and just 20% discontinued fruquintinib due to toxicities. Median OS was 7.4

months with fruquintinib compared to 4.8 months with placebo (HR, 0.66; 95% CI, 0.55–0.80; P < .0001). Grade ≥3 AEs occurred in 63% of patients who received fruquintinib compared to 50% who received placebo. The most common grade ≥3 AEs with fruquintinib were hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). Based on these data, the NCCN Panel recommends fruquintinib as a treatment option for mCRC that has progressed through all other available regimens. It can be given before or after trif luridine-tipiracil or regorafenib; no data inform the best order of these therapies.

Workup and Management of Synchronous Metastatic Disease

The workup for patients in whom metastatic synchronous adenocarcinoma from the large bowel (eg, colorectal liver metastases) is suspected should include a total colonoscopy, CBC, chemistry profile, CEA determination, biopsy if indicated, and CT scan with IV contrast of the chest, abdomen, and pelvis.244 MRI with IV contrast should be considered if CT is

inadequate. The Panel also recommends testing for tumor KRAS/NRAS and BRAF gene status and HER2 amplif ications at diagnosis of metastatic disease (see Biomarkers for Systemic Therapy, above). However, if the tumor is known to have a RAS or BRAF mutation, HER2 testing is not

indicated, as amplif ication is very rare in this subset.730,731 NGS panels can be used to detect these biomarkers and have the advantage of also

detecting other rare and actionable mutations (eg, NTRK and RET

fusions).

The Panel strongly discourages the routine use of PET/CT scanning for staging, baseline imaging, or routine follow-up. However, the Panel

recommends consideration of a preoperative PET/CT scan at baseline in selected cases if prior anatomic imaging indicates the presence of

potentially surgically curable M1 disease. The purpose of this PET/CT

Workup and Management of Synchronous Metastatic Disease

scan is to evaluate for unrecognized metastatic disease that would

preclude the possibility of surgical management. A randomized clinical trial of patients with resectable metachronous metastases assessed the role of PET/CT in the workup of potential curable disease.1020 While there was no impact of PET/CT on survival, surgical management was changed in 8% of patients after PET/CT. For example, resection was not undertaken for

2.7% of patients because additional metastatic disease was identif ied (ie, bone, peritoneum/omentum, abdominal nodes). In addition, 1.5% of

patients had more extensive hepatic resections and 3.4% had additional organ surgery. An additional 8.4% of patients in the PET/CT arm had

anemia (14%). In the final analysis of DESTINY-CRC01, no responses

occurred in cohorts B or C.975 In cohort A, confirmed ORR was 45.3%, all of which were partial responses, with a median duration of response of 7.0 months. Median PFS and OS were 6.9 and 15.5 months, respectively. Of note, across all three cohorts, eight patients on this trial developed

interstitial lung disease or pneumonitis related to T-DXd, including three deaths due to this complication (3.5% of all patients).

The ongoing DESTINY-CRC02 trial includes patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) mCRC, with either RAS wild-type or mutant

disease.976 Patients were randomized to either 5.4 or 6.4 mg/kg T-DXd. An abstract presented primary results, reporting an ORR of 37.8% for the 5.4 mg/kg dose and 27.5% for 6.4 mg/kg. T-DXd showed antitumor activity irrespective of RAS mutation status and in those who were previously

treated with anti-HER2 therapy, suggesting that this agent may be

considered as an option for HER2-amplif ied mCRC regardless of RAS

mutation status or previous HER2 targeted therapy.

Systemic Therapy Options for KRAS G12C Mutation-Positive Disease in the Non–First-Line Setting

Two KRAS G12C inhibitors, sotorasib and adagrasib, are recommended for treatment of previously treated mCRC, which harbors this mutation. Sotorasib or adagrasib should be given in combination with cetuximab or panitumumab or may be considered as a single agent if there are

concerns about toxicities from EGFR inhibitors. Mechanisms for acquired resistance to adagrasib and sotorasib have been described.977

The phase I portion of the CodeBreaK 100 trial was a basket study of

sotorasib monotherapy. It included 129 patients with solid tumors

harboring the KRAS G12C mutation, 42 with CRC.978 Of the subgroup with CRC, 7.1% had a confirmed response and 73.8% had disease control. A prespecified subset analysis of the phase II portion of CodeBreaK 100 investigated sotorasib monotherapy for previously treated mCRC with

KRAS G12C mutation.979 OR was observed in 9.7% of the 62 treated

patients. Grade ≥3 treatment-related AEs occurred in 11.6% of patients treated with sotorasib monotherapy. The phase Ib/2 CodeBreaK 101 trial looked at various doublets including sotorasib. One cohort of this trial

investigated the combination of sotorasib plus panitumumab in 40 patients with previously treated KRAS G12C-mutated mCRC. Results from the

dose expansion cohort reported a confirmed ORR of 30% (95% CI,

##### Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the Non–First-Line Setting

16.6%–46.5%).980 Median PFS and OS were 5.7 and 15.2 months,

respectively. Grade ≥3 treatment-related AEs occurred in 27% of patients who received the combination therapy.

KRYSTAL-1 is a phase 1/2 clinical trial evaluating the safety and efficacy of adagrasib, alone or in combination with other anticancer therapies, in patients with advanced solid tumors that had been previously treated. One publication of this study reported results for patients with KRAS G12Cmutated mCRC treated with adagrasib alone (n = 44) or adagrasib in

combination with cetuximab (n = 32).981 In this subgroup, disease

##### Systemic Therapy Options for KRAS G12C Mutation-Positive Disease in the Non–First-Line Setting

response was reported in 19% of patients treated with adagrasib

monotherapy, with a median duration of response of 4.3 months (95% CI, 8–33) and median PFS of 5.6 months (95% CI, 2.3–8.3). For the

combination of adagrasib and cetuximab, responses were noted in 46% of patients, with a median response duration of 7.6 months (95% CI, 5.7–not estimable [NE]) and median PFS of 6.9 months (95% CI, 5.4–8.1). Grade ≥3 treatment-related AEs were reported in 34% of patients who received the monotherapy and 16% of those who received the combination. A 2024 American Association for Cancer Research (AACR) abstract on this study presented updated results from 94 patients who received the combination of adagrasib and cetuximab.982 With a median follow-up of 11.9 months, the ORR was 34.0%, DCR was 85.1%, and median duration of response was 5.8 months. Median PFS was 6.9 months and median OS was 15.9 months.

Checkpoint Inhibitor Immunotherapy for dMMR/MSI-H or POLE/POLD1 Mutation-Positive Disease in the Non–First-Line Setting

The Panel currently recommends that dMMR/MSI-H or POLE/POLD1

mutation-positive mCRC be treated with a checkpoint inhibitor as first-line therapy if no prior immunotherapy has been received and the patient is a candidate for immunotherapy. However, if a different therapy was used in

the first-line setting, checkpoint inhibitor immunotherapy is also

appropriate for use in the non–first-line setting.

Pembrolizumab is a humanized, IgG4 monoclonal antibody that binds to PD-1 with high affinity, preventing its interaction with PD-L1 and PD-L2 and thus allowing immune recognition and response.755 A phase II study evaluated the activity of pembrolizumab in 11 patients with dMMR CRC, 21 patients with pMMR CRC, and nine patients with dMMR noncolorectal carcinomas.924 All patients had progressive metastatic

disease; the patients in the colorectal arms had progressed through two to four previous therapies. The primary endpoints were the immunerelated ORR and the 20-week immune-related PFS rate. The immunerelated ORRs were 40% (95% CI, 12–74) in the dMMR CRC group, 0% (95% CI, 0–20) in the pMMR CRC group, and 71% (95% CI, 29–96) in the dMMR non-colorectal group. The 20-week immune-related PFS rates were 78% (95% CI, 40–97), 11% (95% CI, 1–35), and 67% (95% CI, 22–96), respectively. These results indicate that MSI is a predictive marker for the effectiveness of pembrolizumab across tumor types. Furthermore, the median PFS and OS were NR in the arm with dMMR CRC and were

2.2 and 5.0 months, respectively, in the pMMR CRC group (HR for

disease progression or death, 0.10; P < .001). Another phase II study, KEYNOTE-164, investigated the efficacy of pembrolizumab in 124

patients with MSI-H/dMMR mCRC that had been treated with at least

one previous line of therapy.983 The patients on this study were divided into two cohorts based on whether they had received ≥2 lines of therapy including fluoropyrimidine, oxaliplatin, and irinotecan (cohort A) or ≥1

lines of therapy (cohort B). ORR was reported as 33% for both cohorts, with the median duration of response not reached at the time of

publication. Median PFS was 2.3 months and 4.1 months, for cohorts A and B, respectively. Median OS was 31.4 months for cohort A and had not been reached for cohort B. Treatment-related AEs of grade ≥3

occurred in 16% of patients in cohort A and 13% in cohort B, with

pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase being most common.

Nivolumab is another humanized IgG4 PD-1 blocking antibody,984 which was studied with or without ipilimumab in patients with mCRC in the phase II, multi-cohort, CheckMate-142 trial.926,927 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 most common.926 Emerging 5-year long-term data revealed an ORR of 39% (95% CI, 28–51).922 PFS and OS at 48 months were 36% and

49%, respectively.

Another cohort of the CheckMate-142 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 DCR 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.927 An in-depth analysis of the safety profile of nivolumab plus ipilimumab on the CheckMate-142 trial reported that

AEs predefined in the study protocol as being of special clinical interest (eg, endocrine, GI, hepatic, pulmonary, renal, and skin events) tended to occur early in treatment, were managed using evidence-based treatment algorithms, and resolved.985 Emerging 5-year long-term data from this

cohort revealed an ORR of 65% (95% CI, 55–73).922 PFS and OS at 48 months were 54% and 71%, respectively.

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.986 The safety and efficacy of dostarlimab-gxly was evaluated in the phase I GARNET study of patients with advanced solid tumors who had previously received systemic therapy for advanced disease.987 Cohort F of this trial enrolled patients with dMMR- or POLE-mutant non-endometrial solid

tumors, the majority of which were GI cancers. Of the 115 patients with CRC in the efficacy analysis, confirmed ORR was 43.5% (95% CI, 34.3–

53.0), with 12.2% achieving complete response. Median PFS for this

group was 8.4 months and median DOR and OS were not yet reached. Treatment-related AEs grade ≥3 were reported in 16.3% of 363 patients included in the safety analysis. Dostarlimab-gxly was discontinued in 25 patients due to a treatment-related AE.

Based on these data, the Panel recommends pembrolizumab, nivolumab, nivolumab plus ipilimumab, or dostarlimab-gxly as subsequent-line

treatment options in patients with metastatic dMMR/MSI-H CRC who have not previously received checkpoint inhibitor immunotherapy. As discussed in the Biomarkers for Systemic Therapy section above, checkpoint

inhibitor immunotherapy is also recommended for mCRC with functional POLE/POLD1 mutations.

Systemic Therapy Options for NTRK Gene Fusion-Positive Disease in the Non–First-Line Setting

Studies have estimated that about 0.2% to 1% of CRCs carry NTRK gene fusions.747,748 Three targeted therapies: larotrectinib, entrectinib, and

repotrectinib have been FDA-approved for the treatment of patients with metastatic, unresectable solid tumors that have an NTRK gene fusion and no satisfactory alternative treatment options, regardless of the location of the primary tumor. The Panel recommends larotrectinib, entrectinib, or

##### Systemic Therapy Options for NTRK Gene Fusion-Positive Disease in the Non–First-Line Setting

repotrectinib as subsequent treatment options for patients with NTRK

gene fusion-positive disease, acknowledging that these therapies will not be appropriate for most patients due to the rarity of the NTRK fusion in CRC.

Larotrectinib: A pooled analysis of three studies (a phase I including

adults, a phase I/II involving children, and the phase II NAVIGATE study involving adolescents and adults) studied the safety and efficacy of

larotrectinib in 55 patients with NTRK gene fusion-positive tumors,

including four patients with colon cancer.746 For the whole population, the ORR was 75% (95% CI, 61–85) by independent review and 80% (95% CI, 67–90) by investigator assessment,746 although the package insert cites a 25% ORR for colon tumors specifically.988 Larotrectinib 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.746 A subsequent analysis of these three studies included 159 patients, eight with colon cancer, and reported similar results compared to the earlier

analysis.989 In this later analysis, the ORR was 79% (95% CI, 72–85) by investigator assessment with 16% complete responses. An analysis of 14 patients with GI cancer who were treated with larotrectinib in the

false-positive results, many of which were investigated with biopsies or additional imaging. A meta-analysis of 18 studies including 1059 patients with hepatic colorectal metastases found that PET or PET/CT results

changed management in 24% of patients.1021

Patients with clearly unresectable metastatic disease should not have

baseline PET/CT scans. The Panel also notes that PET/CT scans should not be used to assess response to chemotherapy, because a PET/CT

scan can become transiently negative after chemotherapy (eg, in the

presence of necrotic lesions).1022 False-positive PET/CT scan results can occur in the presence of tissue inflammation after surgery or infection.1022 An MRI with IV contrast can be considered as part of the preoperative

evaluation of patients with potentially surgically resectable M1 liver

disease. For example, an MRI with contrast may be of use when the PET and CT scan results are inconsistent with respect to the extent of disease in the liver.

The criterion of potential surgical cure includes patients with metastatic disease that is not initially resectable but for whom a surgical cure may

become possible after preoperative chemotherapy. In most cases,

however, the presence of extrahepatic disease will preclude the possibility of resection for cure; conversion to resectability for the most part refers to

a patient with liver-only disease that, because of involvement of critical structures, cannot be resected unless regression is accomplished with chemotherapy (see Neoadjuvant Therapy and Conversion to Resectability, above).

Close communication among members of the multidisciplinary treatment team is recommended, including an upfront evaluation by a surgeon

experienced in the resection of hepatobiliary or lung metastases.

Recommendations for Resectable Synchronous Liver or Lung Metastases

When patients present with CRC and synchronous liver metastases,

resection of the primary tumor and liver can be performed in a

simultaneous or staged approach.1023-1032 Historically, in the staged

approach, the primary tumor was usually resected first. However, the

approach of liver resection before resection of the primary followed by adjuvant chemotherapy is now well-accepted.1024,1026,1033,1034 In addition, emerging data suggest that systemic therapy, followed by resection of liver metastases before resection of the primary tumor, might be an effective approach in some patients, although more studies are needed.1035-1042

Adjuvant chemotherapy following resection of the primary and metastases may be recommended for pMMR/MSS disease or dMMR/MSIH/POLE/POLD1 disease where checkpoint inhibitor immunotherapy was not given neoadjuvantly, although the benefit of adjuvant chemotherapy in this setting remains controversial. The phase II/III JCOG0603 trial of 300 patients with liver-only CRC metastases compared hepatectomy alone to hepatectomy followed by 12 courses of adjuvant mFOLFOX6.1043 Fiveyear DFS was significantly longer with adjuvant chemotherapy compared to hepatectomy alone (49.8% vs. 38.7%; HR, 0.67; 95% CI, 0.50–0.92; P = .006). However, the 5-year OS rate was higher with hepatectomy alone compared to hepatectomy with adjuvant chemotherapy (83.1% vs. 71.2%).

Recommendations for Resectable Synchronous Liver or Lung Metastases

If a patient with resectable liver or lung metastases is a candidate for

surgery, the Panel recommends the following options for pMMR/MSS

disease: 1) synchronous or staged colectomy with liver or lung

resection425,433 followed by adjuvant chemotherapy (FOLFOX [preferred], CAPEOX [preferred], 5-FU/LV, or capecitabine308,637); 2) neoadjuvant

chemotherapy for 2 to 3 months (ie, FOLFOX [preferred],424 CAPEOX

[preferred], FOLFIRI [category 2B], or FOLFIRINOX [category 2B]618)

followed by synchronous or staged colectomy with liver or lung resection, then adjuvant chemotherapy; or 3) colectomy followed by chemotherapy (see neoadjuvant options above) and a staged resection of metastatic

disease, then adjuvant chemotherapy. Based on the limited data that are available, as well as their own institutional practice patterns, the NCCN

Panel has included FOLFIRI and FOLFIRINOX as options for neoadjuvant treatment of resectable synchronous mCRC. These recommendations’ category 2B rating reflects the relative scarcity of data supporting these treatment options.

For dMMR/MSI-H or POLE/POLD1 mutation-positive disease, the first

option listed above is an option, although neoadjuvant immunotherapy

with a checkpoint inhibitor is the preferred approach. While resection of metastatic disease is the preferred approach, local therapy for metastases may be considered in addition, or instead of, resection in select cases. For dMMR/MSI-H or POLE/POLD1 mutation-positive disease, any of the

checkpoint inhibitor regimens that are recommended for metastatic

disease may be used in the neoadjuvant setting. Overall, combined

neoadjuvant and adjuvant treatments should not exceed 6 months.

In the case of liver metastases only, HAIC with or without systemic 5-

FU/LV (category 2B) remains an option at centers with experience in the surgical and medical oncologic aspects of this procedure.

Recommendations for Unresectable Synchronous Metastases

Patients with dMMR/MSI-H or POLE/POLD1 mutation-positive

synchronous unresectable metastatic disease should preferentially receive checkpoint inhibitor immunotherapy as their f irst-line option as long as the patient is a candidate for immunotherapy and no prior immunotherapy has been received. Disease status should be reevaluated every 2 to 3 months, followed by a continuation of immunotherapy; resection, with or without RT; surveillance; or additional lines of systemic therapy based on disease response.

For patients with pMMR/MSS metastatic disease that is deemed to be

potentially convertible (see Neoadjuvant Therapy and Conversion to

Resectability, above),1044 chemotherapy regimens with high response

rates should be considered, and these patients should be reevaluated for resection after 2 months of preoperative chemotherapy and every 2

months thereafter while undergoing this therapy. If bevacizumab is

included as a component of the conversion therapy, an interval of at least 6 weeks between the last dose of bevacizumab and surgery should be applied, with a 6- to 8-week postoperative period before re-initiation of bevacizumab. Patients with disease converted to a resectable state should undergo synchronized or staged resection of colon and metastatic cancer, including treatment with pre- and postoperative chemotherapy for a

preferred total perioperative therapy duration of 6 months. Recommended options for adjuvant therapy for these patients include active systemic

therapy regimens for advanced or metastatic disease (category 2B for the use of biologic agents in this setting); observation or a shortened course of chemotherapy can also be considered for patients who have completed preoperative chemotherapy. In the case of liver metastases only, HAIC with or without systemic 5-FU/LV (category 2B) remains an option at

centers with experience in the surgical and medical oncologic aspects of this procedure. Ablative therapy of metastatic disease, either alone or in combination with resection, can also be considered when all measurable

Recommendations for Unresectable Synchronous Metastases

metastatic disease can be treated (see Management of Metastatic

Disease). Patients with disease that is not responding to therapy should receive systemic therapy for advanced or metastatic disease with

treatment selection based partly on whether intensive therapy is

recommended. Debulking surgery or ablation without curative intent is not recommended.

Results from one study suggest that there may be some benefit in both OS and PFS from resection of the primary in the setting of unresectable colorectal metastases.1045 Other systematic reviews and retrospective

analyses also have shown a potential benefit.1045-1051 Separate analyses of the SEER database and the National Cancer Database also identif ied a survival benefit of primary tumor resection in this setting.1052,1053

On the other hand, a different analysis of the National Cancer Database came to the opposite conclusion.1054 The randomized phase III JCOG1007 study also concluded that primary tumor resection followed by

chemotherapy in patients with synchronous unresectable metastases

conferred no survival benefit over chemotherapy alone.1055 For the 160 patients enrolled in this study, median OS was 25.9 months with primary tumor resection plus chemotherapy compared to 26.7 months for

chemotherapy alone. Three patients on this study died following primary tumor resection due to postoperative complications. The phase III CAIRO4 study has also shown a higher 60-day mortality rate in patients with

unresectable mCRC randomized to primary tumor resection followed by systemic therapy (11%) compared to those who were randomized to

systemic therapy alone (3%).1056 Furthermore, the prospective, multicenter phase II NSABP C-10 trial showed that patients with an asymptomatic

primary colon tumor and unresectable metastatic disease who received mFOLFOX6 with bevacizumab experienced an acceptable level of

morbidity without upfront resection of the primary tumor.1057 The median

OS was 19.9 months. Notably, symptomatic improvement in the primary is often seen with systemic chemotherapy even within the first 1 to 2 weeks. Complications from the intact primary lesion are uncommon in this

setting,461 and its removal delays initiation of systemic chemotherapy. In fact, a systematic review concluded that resection of the primary does not reduce complications and does not improve OS.1058 Another systematic review and meta-analysis identif ied five studies that compared open to

laparoscopic palliative colectomies in this setting.1059 The laparoscopic

approach resulted in shorter lengths of hospital stays (P < .001), fewer postoperative complications (P = .01), and lower estimated blood loss (P < .01).

Overall, the Panel believes that the risks of surgery outweigh the possible benefits of resection of asymptomatic primary tumors in the setting of

unresectable colorectal metastases. Routine palliative resection of a

synchronous primary lesion should therefore only be considered if the patient has an unequivocal imminent risk of obstruction, acute significant bleeding, perforation, or other significant tumor-related symptoms.

An intact primary is not a contraindication to bevacizumab use. The risk of GI perforation in the setting of bevacizumab is not decreased by removal of the primary tumor, because large bowel perforations, in general, and perforation of the primary lesion, in particular, are rare.

Recommendations for Synchronous Abdominal/Peritoneal Metastases

For patients with peritoneal metastases causing obstruction or that may cause imminent obstruction, palliative surgical options include colon

resection, diverting colostomy, a bypass of impending obstruction, or

stenting, followed by systemic therapy for advanced or metastatic disease. The primary treatment of patients with nonobstructing metastases is

chemotherapy. As mentioned above (see Cytoreductive Debulking with

Recommendations for Synchronous Abdominal/Peritoneal Metastases

Workup and Management of Metachronous Metastatic Disease

Hyperthermic Intraperitoneal Chemotherapy), the Panel currently believes that the treatment of disseminated carcinomatosis with complete CRS

and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for whom R0 resection can be achieved. However, the significant morbidity and

mortality associated with HIPEC, as well as the conflicting data on clinical efficacy, make this approach very controversial.

Workup and Management of Metachronous Metastatic Disease

On documentation of metachronous, potentially resectable, metastatic

disease with dedicated contrast-enhanced CT or MRI, characterization of the disease extent using PET/CT scan should be considered in select

cases if a surgical cure of M1 disease is feasible. PET/CT is used at this juncture to promptly characterize the extent of metastatic disease, and to identify possible sites of extrahepatic disease that could preclude

surgery.1020,1060,1061 Specifically, Joyce et al1060 reported that the

preoperative PET changed or precluded curative-intent liver resection in 25% of patients. A randomized clinical trial assessed the role of PET/CT in the workup of patients with resectable metachronous metastases.1020

While there was no impact of PET/CT on survival, surgical management was changed in 8% of patients after PET/CT. This trial is discussed in

more detail in Workup and Management of Synchronous Metastatic

Disease, above.

As with other conditions in which stage IV disease is diagnosed, a tumor analysis (metastases or original primary) for KRAS/NRAS and BRAF

mutations and HER2 amplif ications, as well as MSI/MMR testing if not

previously done, should be performed to define whether targeted therapies can be considered among the potential options (see Biomarkers for

Systemic Therapy).

Close communication between members of the multidisciplinary treatment team is recommended, including upfront evaluation by a surgeon

experienced in the resection of hepatobiliary and lung metastases. The management of metachronous metastatic disease is distinguished from that of synchronous disease through also including an evaluation of the chemotherapy or immunotherapy history of the patient and through the absence of colectomy.

Patients with resectable disease are classified according to whether they have undergone previous chemotherapy or immunotherapy. For patients who have resectable pMMR/MSS metastatic disease, treatment is

resection with 6 months of perioperative chemotherapy (pre- or

postoperative or a combination of both), with choice of regimens based on previous therapy. For patients with resectable dMMR/MSI-H or

POLE/POLD1 mutation-positive metastatic disease, neoadjuvant

immunotherapy with a checkpoint inhibitor is an option, if no previous

immunotherapy was given. Locally ablative procedures can be considered instead of or in addition to resection in cases of liver or lung

oligometastases (see Local Therapies for Metastases, above), but

resection is preferred. For patients without a history of chemotherapy use, FOLFOX or CAPEOX is preferred for pMMR/MSS disease, with

capecitabine or 5-FU/LV as additional category 2B options. There are also cases when perioperative chemotherapy is not recommended in

resectable metachronous disease. In particular, patients with a history of previous chemotherapy and an upfront resection can be observed or may be given an active regimen for advanced disease (category 2B for the use of biologic agents in these settings). Observation is preferred if oxaliplatinbased therapy was previously administered.

Patients determined to have unresectable disease through cross-sectional imaging scan (including those considered potentially convertible) should receive an active systemic therapy regimen based on prior chemotherapy

Endpoints for Advanced CRC Clinical Trials

or immunotherapy history (see Second-Line or Subsequent Systemic Therapy, above). In the case of liver metastases only, HAIC with or without systemic 5-FU/LV (category 2B) is an option at centers with experience in the surgical and medical oncologic aspects of this

procedure. Patients receiving palliative systemic therapy should be

monitored with CT or MRI scans approximately every 2 to 3 months.

Endpoints for Advanced CRC Clinical Trials

In the past few years, there has been much debate over what endpoints are most appropriate for clinical trials in advanced CRC.1062 Quality of life is an outcome that is rarely measured but of unquestioned clinical

relevance.1063 While OS is also of clear clinical relevance, it is often not used because large numbers of patients and long follow-up periods are required.1063 PFS is often used as a surrogate, but its correlation with OS is inconsistent at best, especially when subsequent lines of therapy are administered.1063-1065 In 2011, The Grupo Español Multidisciplinar en

Cancer Digestivo (GEMCAD) proposed particular aspects of clinical trial design to be incorporated into trials that use PFS as an endpoint.1066

A study, in which individual patient data from three RCTs were pooled, tested endpoints that take into account subsequent lines of therapy:

duration of disease control, which is the sum of PFS times of each active treatment; and time to failure of strategy, which includes intervals between treatment courses and ends when the planned lines of treatment end

(because of death, progression, or administration of a new agent).1064 The authors found a better correlation between these endpoints and OS than between PFS and OS. Another alternative endpoint, time to tumor growth, has also been suggested to predict OS.1067,1068 Further evaluation of these and other surrogate endpoints is warranted.

Post-Treatment Surveillance

After curative-intent surgery and adjuvant chemotherapy, if administered, post-treatment surveillance of patients with CRC is performed to evaluate for possible therapeutic complications, discover a recurrence that is

potentially resectable for cure, and identify new metachronous neoplasms at a preinvasive stage. An analysis of data from 20,898 patients enrolled in 18 large, adjuvant, randomized trials showed that 80% of recurrences

occurred in the first 3 years after surgical resection of the primary tumor,319 and a another study found that 95% of recurrences occurred in the first 5 years.1069

Surveillance for Locoregional Disease

Advantages of more intensive follow-up of patients with stage II and/or stage III disease have been shown prospectively in several older

studies1070-1072 and in multiple meta-analyses of RCTs designed to

compare low- and high-intensity programs of surveillance.1073-1078 Intensive postoperative surveillance has also been suggested to be of benefit to patients with stage I and IIA disease.1079 Furthermore, a population-based report indicates increased rates of resectability and survival in patients

treated for local recurrence and distant metastases of CRC in more recent years, thereby providing support for more intensive post-treatment followup in these patients.1080

Results from the randomized controlled FACS trial of 1202 patients with resected stage I to III disease showed that intensive surveillance imaging or CEA screening resulted in an increased rate of curative-intent surgical treatment compared with a minimum follow-up group that only received testing if symptoms occurred, but no advantage was seen in the CEA and CT combination arm (2.3% in the minimum follow-up group, 6.7% in the CEA group, 8% in the CT group, and 6.6% in the CEA plus CT group).1081 In this study, no mortality benefit to regular monitoring with CEA, CT, or both was observed compared with minimum follow-up (death rate, 18.2%

Surveillance for Locoregional Disease

vs. 15.9%; difference, 2.3%; 95% CI, −2.6%–7.1%). The authors

concluded that any strategy of surveillance is unlikely to provide a large survival advantage over a symptom-based approach. The randomized

COLOFOL trial of 2509 patients with stage II or III CRC looked at follow-up testing with CT of the thorax and abdomen and CEA screening, comparing a high-frequency surveillance approach (CT and CEA at 6, 12, 18, 24, and 36 months post-surgery) to a low-frequency approach (CT and CEA at 12 and 36 months post-surgery).1082 This trial reported no significant

difference in 5-year overall mortality or CRC-specific mortality between the two screening approaches.

The CEAwatch trial compared usual follow-up care to CEA measurements every 2 months, with imaging performed if CEA increases were seen

twice, in 3223 patients at 11 hospitals treated for non-mCRC in the

Netherlands.1083 The intensive CEA surveillance protocol resulted in the detection of more recurrences and recurrences that could be treated with curative intent than usual follow-up, and the time to detection of recurrent disease was shorter. Another randomized trial of 1228 patients found that more intensive surveillance led to earlier detection of recurrences than a less intensive program (less frequent colonoscopy and liver ultrasound and the absence of an annual chest x-ray) but did not affect OS.1084

The randomized phase III PRODIGE 13 trial is comparing 5-year OS after intensive radiologic monitoring (abdominal ultrasound,

chest/abdomen/pelvis CT, and CEA) with a lower intensity program

(abdominal ultrasound and chest x-ray) in patients with resected stage II or III colon or rectal tumors.1085 A 2020 abstract reporting results from

1995 patients on this trial concluded that the more intensive surveillance program did not provide any benefit in 5-year OS, but did result in more curative intent secondary surgeries for colon cancer. Surgical treatment of recurrence was performed in 40.9% of patients receiving minimal

surveillance (no CT, no CEA), 66.3% of patients receiving lower intensity

imaging plus CEA, 50.7% of patients receiving no CEA but higher intensity imaging, and 59.5% of patients in the maximum surveillance group with both CEA and CT (P = .0035).1086 A 2022 abstract that reported final RFS results from PRODIGE 13 found that, with a median follow-up of 7.8 years, cancer recurrence was detected in 22.3% of patients (89.5% metastatic recurrence, 10.5% local recurrence).1087 Five-year RFS rates were 73.2% with CT surveillance versus 68.2% without CT (P = .052) while they were

70.4% and 71.0% with and without CEA screening, respectively. The

authors concluded that intensive imaging, but not CEA screening,

provided an increased opportunity for curative-intent surgical treatment of recurrence and a trend toward better 5-year RFS with CT surveillance. Clearly, controversies remain regarding selection of optimal strategies for following up patients after potentially curative CRC surgery, and the

Panel’s recommendations are based mainly on consensus. The Panel

endorses surveillance as a means to identify patients with potentially

curable metastatic disease with surgical resection.

For patients with stage I disease, the Panel believes that a less intensive surveillance schedule is appropriate because of the low risk of recurrence and the harms associated with surveillance. Possible harms include

radiation exposure with repeated CT scans, psychological stress

associated with surveillance visits and scans, and stress and risks from following up on false-positive results. Therefore, for patients with stage I disease, the Panel recommends colonoscopy at 1 year after surgery.

Repeat colonoscopy is recommended at 3 years, and then every 5 years thereafter, unless advanced adenoma (villous polyp, polyp >1 cm, or highgrade dysplasia) is found. In this case, colonoscopy should be repeated in 1 year.1078

The following Panel recommendations for post-treatment surveillance

pertain to patients with stage II/III disease who have undergone successful treatment (ie, no known residual disease). History and physical

examination should be given every 3 to 6 months for 2 years, and then every 6 months for a total of 5 years. A CEA test (also see Managing an Increasing CEA Level, below) is recommended at baseline and every 3 to 6 months for 2 years,1088 then every 6 months for a total of 5 years for patients with stage III disease and those with stage II disease if the

clinician determines that the patient is a potential candidate for aggressive curative surgery.1073,1088 Colonoscopy is recommended at approximately 1 year after resection (or at 3–6 months postresection if not performed

preoperatively because of an obstructing lesion). Repeat colonoscopy is typically recommended at 3 years, and then every 5 years thereafter,

unless follow-up colonoscopy indicates advanced adenoma (villous polyp, polyp >1 cm, or high-grade dysplasia), in which case colonoscopy should be repeated in 1 year.1078 More frequent colonoscopies may be indicated in patients who present with colon cancer before 50 years of age. Chest, abdominal, and pelvic CT scan are recommended every 6 to 12 months (category 2B for more frequently than annually) for up to 5 years in

patients with stage III disease and those with stage II disease at a high

risk for recurrence.1073,1089 Routine CEA monitoring and CT scanning are not recommended beyond 5 years. Use of PET/CT to monitor for disease recurrence is not recommended.1089,1090 The CT that accompanies a

PET/CT is usually a noncontrast CT, and therefore not of ideal quality for routine surveillance.

Surveillance colonoscopies are primarily aimed at identifying and

removing metachronous polyps, because data show that patients with a history of CRC have an increased risk of developing second cancers,

particularly in the first 2 years after resection.1078,1091 Furthermore, use of post-treatment surveillance colonoscopy has not been shown to improve survival through the early detection of recurrence of the original CRC.1078 The recommended frequency of post-treatment surveillance

colonoscopies is higher (ie, annually) for patients with Lynch syndrome.31

CT scan is recommended to monitor for the presence of potentially

resectable metastatic lesions, primarily in the lung and liver.1073 Hence, CT scan is not routinely recommended in asymptomatic patients who are not candidates for potentially curative resection of liver or lung

metastases.1073,1089

The ASCO Clinical Practice Guidelines Committee has endorsed the

Follow-up Care, Surveillance Protocol, and Secondary Prevention

Measures for Survivors of Colorectal Cancer from Cancer Care Ontario (CCO).1092 These guidelines differ only slightly from the surveillance

recommendations in these NCCN Guidelines for Colon Cancer. While

ASCO/CCO recommend abdominal and chest CT annually for 3 years in patients with stage II and III disease, the NCCN Panel recommends semiannual to annual scans for 5 years (category 2B for more frequent than annual scanning). The Panel bases its recommendation on the fact that approximately 10% of patients will recur after 3 years.319,1069 The American Society of Colon and Rectal Surgeons also released surveillance

guidelines, which are also very similar to NCCN surveillance

recommendations.1093 One exception is the inclusion of intensive

surveillance for patients with resected stage I colon or rectal cancer if the provider deems the patient to be at increased risk for recurrence.

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112. Mills KT, Bellows CF, Hoffman AE, et al. Diabetes mellitus and

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114. Mei ZB, Zhang ZJ, Liu CY, et al. Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and metaanalysis. PLoS One 2014;9:e91818. Available at:

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115. Meng F, Song L, Wang W. Metformin improves overall survival of colorectal cancer patients with diabetes: A meta-analysis. J Diabetes Res 2017;2017:5063239. Available at:

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116. Kowall B, Stang A, Rathmann W, Kostev K. No reduced risk of

overall, colorectal, lung, breast, and prostate cancer with metformin

therapy in diabetic patients: database analyses from Germany and the UK.

Pharmacoepidemiol Drug Saf 2015;24:865-874. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/26132313.

117. Zanders MM, van Herk-Sukel MP, Vissers PA, et al. Are metformin,statin and aspirin use still associated with overall mortality among

colorectal cancer patients with diabetes if adjusted for one another? Br J Cancer 2015;113:403-410. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/26180924.

118. Hari DM, Leung AM, Lee JH, et al. AJCC Cancer Staging Manual 7th edition criteria for colon cancer: do the complex modifications improve

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119. Chu QD, Zhou M, Medeiros K, Peddi P. Positive surgical margins contribute to the survival paradox between patients with stage IIB/C

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2016;160:1333-1343. Available at:

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120. Kim MJ, Jeong SY, Choi SJ, et al. Survival paradox between stage IIB/C (T4N0) and stage IIIA (T1-2N1) colon cancer. Ann Surg Oncol

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121. Gunderson LL, Jessup JM, Sargent DJ, et al. Revised TN

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122. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal

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124. Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 2004;54:295-308. Available at:

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125. Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in

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126. Nissan A, Stojadinovic A, Shia J, et al. Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone. J Clin Oncol 2006;24:4078-4084. Available at:

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136. Budde CN, Tsikitis VL, Deveney KE, et al. Increasing the number of lymph nodes examined after colectomy does not improve colon cancer staging. J Am Coll Surg 2014;218:1004-1011. Available at:

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137. Parsons HM, Tuttle TM, Kuntz KM, et al. Association between lymph node evaluation for colon cancer and node positivity over the past 20

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138. Storli K, Sondenaa K, Furnes B, et al. Improved lymph node harvest from resected colon cancer specimens did not cause upstaging from TNM stage II to III. World J Surg 2011;35:2796-2803. Available at:

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143. Belt EJ, te Velde EA, Krijgsman O, et al. High lymph node yield is

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Surveillance for Metastatic Disease

Patients who had resection of mCRC can undergo subsequent curativeintent resection of recurrent disease (see Surgical Management of

Colorectal Metastases, above). A retrospective analysis of 952 patients who underwent resection at Memorial Sloan Kettering Cancer Center

showed that 27% of patients with recurrent disease underwent curativeintent resection and that 25% of those patients (6% of recurrences; 4% of the initial population) were free of disease for ≥36 months.1094

Surveillance for Metastatic Disease

Managing an Increasing CEA Level

Panel recommendations for surveillance of patients with stage IV CRC

with no evidence of disease (NED) after curative-intent surgery and

subsequent adjuvant treatment are similar to those listed for patients with stage II/III disease, except that certain evaluations are performed more frequently. Specifically, the Panel recommends that these patients

undergo contrast-enhanced CT scan of the chest, abdomen, and pelvis every 3 to 6 months in the first 2 years after adjuvant treatment (category 2B for frequency <6 months) and then every 6 to 12 months for up to a total of 5 years. CEA testing is recommended every 3 to 6 months for the first 2 years and then every 6 months for a total of 5 years, as in earlystage disease. Again, use of PET/CT scans for surveillance is not

recommended. An analysis of patients with resected or ablated colorectal liver metastases found that the frequency of surveillance imaging did not correlate with time to second procedure or median survival duration.1095 Those scanned once per year survived a median of 54 versus 43 months for those scanned 3 to 4 times per year (P = .08), suggesting that annual scans may be sufficient in this population.

Managing an Increasing CEA Level

Workup for patients with an elevated CEA level after resection should

include colonoscopy; chest, abdominal, and pelvic CT scans; physical

examination; and consideration of PET/CT scan. If imaging study results are normal in the face of a rising CEA, repeat CT scans are recommended every 3 months until either disease is identif ied or CEA level stabilizes or declines.

In a retrospective chart review at Memorial Sloan Kettering Cancer Center, approximately half of elevations in CEA levels after R0 resection of

locoregional CRC were false positives, with most being single high

readings or repeat readings in the range of 5 to 15 ng/mL.1096 In this study, false-positive results >15 ng/mL were rare, and all results >35 ng/mL

represented true positives. Following a systematic review and meta-

analysis, the pooled sensitivity and specificity of CEA at a cutoff of 10

ng/mL were calculated at 68% (95% CI, 53–79) and 97% (95% CI, 90–99), respectively.1097,1098 In the first 2 years post-resection, a CEA cutoff of 10 ng/mL is estimated to detect 20 recurrences, miss 10 recurrences, and result in 29 false positives.

Panel opinion was divided on the usefulness of PET/CT scan in the

scenario of an elevated CEA with negative, good-quality CT scans (ie,

some Panel members favored use of PET/CT in this scenario whereas others noted that the likelihood of PET/CT identifying surgically curable disease in the setting of negative good-quality CT scans is vanishingly

small). A systematic review and meta-analysis found 11 studies (510

patients) that addressed the use of PET/CT in this setting.1099 The pooled estimates of sensitivity and specificity for the detection of tumor recurrence were 94.1% (95% CI, 89.4–97.1) and 77.2% (95% CI, 66.4–85.9),

respectively. An analysis of outcomes of 88 patients treated for CRC

under surveillance who had normal or equivocal conventional imaging

results with an elevated CEA found that PET/CT had a sensitivity of 88% and a specificity of 88% for the detection of recurrences.1100

Use of PET/CT scans in this scenario is permissible within these

guidelines. The Panel does not recommend a so-called blind or CEAdirected laparotomy or laparoscopy for patients whose workup for an

increased CEA level is negative,1101 nor does it recommend use of antiCEA-radiolabeled scintigraphy.

Survivorship

The Panel recommends that a prescription for survivorship and transfer of care to the primary care physician be written.1102 The oncologist and

primary care provider should have defined roles in the surveillance period, with roles communicated to the patient. The care plan should include an overall summary of treatments received, including surgeries, radiation

Survivorship

treatments, and systemic therapies. The possible expected time to

resolution of acute toxicities, long-term effects of treatment, and possible late sequelae of treatment should be described. Finally, surveillance and health behavior recommendations should be part of the care plan.

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 (see the NCCN Guidelines for Survivorship). Additional health monitoring should be performed as indicated under the care of a primary care physician. Survivors are encouraged to maintain a therapeutic relationship with a primary care physician throughout their

lifetime.1103

Other recommendations include monitoring for late sequelae of colon

cancer or the treatment of colon cancer, such as chronic diarrhea or

incontinence (eg, patients with stoma).1104-1109 Other long-term problems common to CRC survivors include oxaliplatin-induced peripheral

neuropathy, fatigue, insomnia, cognitive dysfunction, body image issues (especially as related to an ostomy), and emotional or social distress.1110-1116 Specific management interventions to address these and other side effects are described in a review,1117 and a survivorship care plan for

patients with CRC have been published.1118

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. The NCCN Guidelines for Survivorship include many topics with potential relevance to survivors of CRC, including Anxiety, Depression, and Distress; Cognitive Dysfunction; Fatigue; Pain; Sexual Dysfunction; Healthy Lifestyles; and Immunizations. Concerns related to employment, insurance, and disability

are also discussed. The American Cancer Society has also established guidelines for the care of survivors of CRC, including surveillance for recurrence, screening for subsequent primary malignancies, the

management of physical and psychosocial effects of cancer and its

treatment, and promotion of healthy lifestyles.1103

Healthy Lifestyles for Survivors of CRC

Evidence indicates that certain lifestyle characteristics, such as smoking cessation, maintaining a healthy BMI, engaging in regular exercise, and making certain dietary choices are associated with improved outcomes

and quality of life after treatment for colon cancer.

In a prospective observational study of patients with stage III colon cancer enrolled in the CALGB 89803 adjuvant chemotherapy trial, DFS was found to be directly related to the amount of exercise in which the patients

engaged.1119 An analysis of physical activity in the CALGB/SWOG 80702 (Alliance) trial reported similar results.1120 In addition, a study of a large cohort of men treated for stage I through III CRC showed an association between increased physical activity and lower rates of CRC-specific

mortality and overall mortality.1121 More recent data support the conclusion that physical activity improves outcomes. In a cohort of >2000 survivors of non-mCRC, those who spent more time in recreational activity had a lower mortality than those who spent more leisure time sitting.1122 In addition, evidence suggests that both pre- and post-diagnosis physical activity

decreases CRC mortality. Women enrolled in the Women's Health

Initiative study who subsequently developed CRC had lower CRC-specific mortality (HR, 0.68; 95% CI, 0.41–1.13) and all-cause mortality (HR, 0.63; 95% CI, 0.42–0.96) if they reported high levels of physical activity.1123

Similar results were seen in other studies and in meta-analyses of

prospective studies.1124-1127 Dietary and physical activity interventions were also found to have positive effects on quality of life and depression for CRC survivors in a randomized study.1128

Healthy Lifestyles for Survivors of CRC

A retrospective study of patients with stage II and III colon cancer enrolled in NSABP trials from 1989 to 1994 showed that patients with a BMI of ≥35 kg/m2 had an increased risk of disease recurrence and death.1129 Data

from the ACCENT database also found that pre-diagnosis BMI has a

prognostic impact on outcomes in patients with stage II/III CRC

undergoing adjuvant therapy.1130 An analysis of participants in the Cancer Prevention Study-II Nutrition Cohort who subsequently developed nonmCRC found that pre-diagnosis obesity but not post-diagnosis obesity was associated with higher all-cause and CRC-specific mortality.1131 A metaanalysis of prospective cohort studies found that pre-diagnosis obesity was associated with increased CRC-specific and all-cause mortality.1132 Other analyses confirm the increased risk for recurrence and death in

patients with obesity.94,1133-1136

In contrast, pooled data from first-line clinical trials in the ARCAD

database indicate that a low BMI may be associated with an increased risk of progression and death in the metastatic setting, whereas a high BMI may not be.1137 In addition, results of one retrospective observational study of a cohort of 3408 patients with resected stage I to III CRC suggest that the relationship between mortality and BMI might be U shaped, with the lowest mortality for those with BMI 28 kg/m2.1138 However, several possible explanations for this so-called “obesity paradox” have been suggested.1139 Overall, the Panel believes that survivors of CRC should be encouraged to achieve and maintain a healthy body weight (see the NCCN Guidelines for Survivorship).

A diet consisting of more fruits, vegetables, poultry, and fish; less red

meat; more whole grains; and fewer refined grains and concentrated

sweets has been found to be associated with an improved outcome in

terms of cancer recurrence or death.1140 There is also some evidence that higher postdiagnosis intake of total milk and calcium may be associated with a lower risk of death in patients with stage I, II, or III CRC.100 Analysis

of the CALGB 89803 trial found that higher dietary glycemic load was also associated with an increased risk of recurrence and mortality in patients with stage III disease.1141 Another analysis of the data from CALGB 89803 found an association between high intake of sugar-sweetened beverages and an increased risk of recurrence and death in patients with stage III colon cancer.1142 The link between red and processed meats and mortality in survivors of non-mCRC has been further supported by data from the Cancer Prevention Study II Nutrition Cohort, in which survivors with

consistently high intake had a higher risk of CRC-specific mortality than those with low intake (RR, 1.79; 95% CI, 1.11–2.89).92

A discussion of lifestyle characteristics that may be associated with a

decreased risk of colon cancer recurrence, such as those recommended by the American Cancer Society,1143 also provides “a teachable moment” for the promotion of overall health, and an opportunity to encourage

patients to make choices and changes compatible with a healthy lifestyle. In addition, telephone-based health behavior coaching has been shown to have a positive effect on physical activity, diet, and BMI in survivors of

CRC, suggesting that survivors may be open to health behavior

change.1144

Therefore, survivors of CRC should be encouraged to maintain a healthy body weight throughout life; adopt a physically active lifestyle (at least 30 minutes of moderate-intensity activity on most days of the week); consume a healthy diet with emphasis on plant sources; eliminate or limit alcohol consumption; and quit smoking.1143 Activity recommendations may require

modification based on treatment sequelae (ie, ostomy, neuropathy), and diet recommendations may be modified based on the severity of bowel dysfunction.1145

Secondary Chemoprevention for CRC Survivors

Limited data suggest a link between post-colorectal-cancer-diagnosis

statin use and increased survival.117,1146,1147 A meta-analysis that included four studies found that post-diagnosis statin use increased OS (HR, 0.76; 95% CI, 0.68–0.85; P < .001) and cancer-specific survival (HR, 0.70; 95% CI, 0.60–0.81; P < .001).1146

Abundant data show that low-dose aspirin therapy after a diagnosis of

CRC decreases the risk of recurrence and death.1148-1154 For example, a population-based, observational, retrospective cohort study of 23,162

patients with CRC in Norway found that post-diagnosis aspirin use was associated with improved CRC-specific survival (HR, 0.85; 95% CI, 0.79–

0.92) and OS (HR, 0.95; 95% CI, 0.90–1.01).1148 Some evidence suggests that tumor mutations in PIK3CA may be predictive for response to aspirin, although the data are somewhat inconsistent and other predictive markers have also been suggested.1150,1155-1160 In addition, a meta-analysis of 15 RCTs showed that while non-aspirin NSAIDs were better for preventing recurrence, low-dose aspirin was safer and thereby had a more favorable risk-to-benefit profile.1161

Based on these data, the Panel believes that survivors of CRC can

consider taking 325 mg aspirin daily to reduce their risk of recurrence and death. Importantly, aspirin may increase the risk of GI bleeding and

hemorrhagic stroke, and these risks should be discussed with CRC

survivors.1162

Summary

The Panel believes that a multidisciplinary approach is necessary for

managing CRC. The Panel endorses the concept that treating patients in a clinical trial has priority over standard or accepted therapy. The Panel

stresses the importance of determining MSI and MMR status at diagnosis

as treatment recommendations can vary considerably at all stages of

colon cancer based on these biomarker results.

The recommended surgical procedure for resectable colon cancer is an en bloc resection and adequate lymphadenectomy. Adequate pathologic

assessment of the resected lymph nodes is important with a goal of

evaluating at least 12 nodes. Adjuvant chemotherapy is recommended for patients with stage III disease and is also an option for some patients with high-risk stage II disease. The preferred regimens for adjuvant therapy, as well as the recommended duration of therapy, depends on the pathologic stage of the tumor and the risk of recurrence. Patients with resectable T4b tumors or with bulky nodal disease may be treated with neoadjuvant

systemic therapy prior to colectomy.

Patients with metastatic disease in the liver or lung should be considered for surgical resection if they are candidates for surgery and if all original sites of disease are amenable to resection (R0) and/or ablation. Six

months of perioperative systemic therapy should be administered to

patients with synchronous or metachronous resectable metastatic disease. When a response to systemic therapy would likely convert a patient from an unresectable to a resectable disease state (ie, conversion therapy), this therapy should be initiated.

The recommended post-treatment surveillance program for patients with resected disease includes serial CEA determinations; periodic chest,

abdomen, and pelvis CT scans; colonoscopic evaluations; and a

survivorship plan to manage long-term side effects of treatment, facilitate disease prevention, and promote a healthy lifestyle.

Recommendations for patients with disseminated metastatic disease

represent a continuum of care in which lines of treatment are blurred

rather than discrete. Principles to consider at initiation of therapy include pre-planned strategies for altering therapy for patients in both the

presence and absence of disease progression, including plans for

adjusting therapy for patients who experience certain toxicities. In addition to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing

chemotherapy regimens, immunotherapy and targeted therapy regimens are becoming an increasingly important part of the mCRC treatment

landscape. Combination of a biologic agent (eg, bevacizumab, cetuximab, panitumumab) with some of the chemotherapy regimens is an option,

depending on available data. Systemic therapy options for patients with progressive disease depend on the choice of initial therapy and biomarker status of the tumor.

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引用 / 出处

NCCN临床实践指南：结肠癌（2025.V1）. 2025.