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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Colon Cancer

Version 2.2021 — January 21, 2021

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NCCN.org

NCCN Guidelines for Patients

available at www.nccn.org/patients

NCCN Guidelines Version 2.2021

Colon Cancer

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Table of Contents

Discussion

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NCCN Guidelines Panel Disclosures

ф Diagnostic/Interventional

radiology

¤ Gastroenterology

‡ Hematology/Hematology

oncology

Þ Internal medicine

† Medical oncology

≠ Pathology

¥ Patient advocacy

§ Radiotherapy/Radiation

oncology

¶ Surgery/Surgical oncology

* Discussion Section Writing

Committee

*Al B. Benson, III, MD/Chair †

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

*Alan P. Venook, MD/Vice-Chair † ‡

UCSF Helen Diller Family

Comprehensive Cancer Center

Mahmoud M. Al-Hawary, MD ф

University of Michigan Rogel Cancer Center

Mustafa A. Arain, MD ¤

UCSF Helen Diller Family

Comprehensive Cancer Center

*Yi-Jen Chen, MD, PhD §

City of Hope National Medical Center

Kristen K. Ciombor, MD †

Vanderbilt-Ingram Cancer Center

Stacey Cohen, MD †

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Harry S. Cooper, MD ≠

Fox Chase Cancer Center

Dustin Deming, MD †

University of Wisconsin Carbone Cancer Center

Linda Farkas, MD ¶

UT Southwestern Simmons

Comprehensive Cancer Center

Ignacio Garrido-Laguna, MD, PhD †

Huntsman Cancer Institute

at the University of Utah

Jean L. Grem, MD †

Fred & Pamela Buffett Cancer Center

Andrew Gunn, MD ф

O’Neal Comprehensive Cancer Center at UAB

J. Randolph Hecht, MD †

UCLA Jonsson Comprehensive Cancer Center

Sarah Hoffe, MD §

Moffitt Cancer Center

Joleen Hubbard, MD ‡

Mayo Clinic Cancer Center

Steven Hunt, MD ¶

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Kimberly L. Johung, MD, PhD §

Yale Cancer Center/Smilow Cancer Hospital

Natalie Kirilcuk, MD ¶

Stanford Cancer Institute

Smitha Krishnamurthi, MD † Þ

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

Wells A. Messersmith, MD †

University of Colorado Cancer Center

*Jeffrey Meyerhardt, MD, MPH †

Dana-Farber Brigham and Women’s

Cancer Center

*Eric D. Miller, MD, PhD §

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Mary F. Mulcahy, MD ‡ †

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

Steven Nurkin, MD, MS ¶

Roswell Park Comprehensive Cancer Center

Michael J. Overman, MD † ‡

The University of Texas

MD Anderson Cancer Center

Aparna Parikh, MD †

Massachusetts General Hospital Cancer Center

Hitendra Patel, MD †

UC San Diego Moores Cancer Center

Katrina Pedersen, MD, MS †

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

*Leonard Saltz, MD † ‡ Þ

Memorial Sloan Kettering Cancer Center

Charles Schneider, MD †

Abramson Cancer Center

at the University of Pennsylvania

David Shibata, MD ¶

The University of Tennessee

Health Science Center

John M. Skibber, MD ¶

The University of Texas

MD Anderson Cancer Center

*Constantinos T. Sofocleous, MD, PhD ф

Memorial Sloan Kettering Cancer Center

Elena M. Stoffel, MD, MPH ¤

University of Michigan Rogel Cancer Center

Eden Stotsky-Himelfarb, BSN, RN † ¶ ¥

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

*Christopher G. Willett, MD §

Duke Cancer Institute

NCCN

Kristina Gregory, RN, MSN

Lisa Gurski, PhD

NCCN Guidelines Version 2.2021

Colon Cancer

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Table of Contents

Discussion

NCCN Colon Cancer Panel Members

Summary of the Guidelines Updates

Clinical Presentations and Primary Treatment:

• Pedunculated Polyp (Adenoma) with Invasive Cancer (COL-1)

• Sessile Polyp (Adenoma) with Invasive Cancer (COL-1)

• Colon Cancer Appropriate for Resection (COL-2)

• Suspected or Proven Metastatic Synchronous Adenocarcinoma (COL-4)

Pathologic Stage, Adjuvant Treatment (COL-3)

Surveillance (COL-8)

Recurrence and Workup (COL-9)

Metachronous Metastases (COL-9)

Principles of Imaging (COL-A)

Principles of Pathologic Review (COL-B)

Principles of Surgery (COL-C)

Systemic Therapy for Advanced or Metastatic Disease (COL-D)

Principles of Radiation and Chemoradiation Therapy (COL-E)

Principles of Risk Assessment for Stage II Disease (COL-F)

Principles of Adjuvant Therapy (COL-G)

Principles of Survivorship (COL-H)

Staging (ST-1)

The NCCN Guidelines

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

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual

clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations

or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Guidelines Version 2.2021

Colon Cancer

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Table of Contents

Discussion

UPDATES

Continued

Updates in Version 2.2021 of the NCCN Guidelines for Colon Cancer from Version 1.2021 include:

MS-1

• The discussion section was updated to reect the changes in the algorithm.

Updates in Version 1.2021 of the NCCN Guidelines for Colon Cancer from Version 4.2020 include:

COL-2

• Locally unresectable or medically inoperable

Preferred status removed from infusional 5-FU and Capecitabine

Bolus 5-FU/leucovorin removed (already noted in footnote l)

COL-3

• Adjuvant Treatment

T3, N0, M0 (MSS/pMMR and no high-risk features)

◊ Capecitabine, 5-FU/leucovorin: Timeframe added of 6 months

T3, N0, M0 at high risk for systemic recurrence or T4, N0, M0 (MSS/pMMR)

◊ Capecitabine, 5-FU/leucovorin, FOLFOX: Timeframe added of 6 months

◊ CAPEOX: Time frame added of 3 months

T1–3, N1 (low-risk stage III)

◊ FOLFOX (3–6 mo): category 1 removed for 6 mo

T4, N1–2; T Any, N2 (high-risk stage III)

◊ CAPEOX (3–6 mo): category 1 removed for 6 mo

◊ FOLFOX (6 mo): category 1 removed

• Footnote o modied with the addition of tumor budding.

• Footnote u modied: While non-inferiority of 3 mo vs. 6 mo of CAPEOX has not been proven, 3 months of CAPEOX numerically appeared

similar to 6 mo of CAPEOX for 5-year overall survival (82.1% vs. 81.2%; HR, 0.96), with considerably less toxicity. (Andre T, et al. Lancet

Oncol 2020;21:1620-1629). These results support the use of 3 mo of adjuvant CAPEOX over 6 mo of adjuvant CAPEOX in the vast majority of

patients with stage III colon cancer. In patients with colon cancer, staged as T1–3, N1 (low-risk stage III), 3 mo of CAPEOX is non-inferior to 6

mo of CAPEOX for disease-free survival; non-inferiority of 3 vs. 6 mo of FOLFOX has not been proven. In patients with colon cancer staged

as T4, N1–2 or T any, N2 (high-risk stage III), 3 mo of FOLFOX is inferior to 6 mo of FOLFOX for disease-free survival, whereas non-inferiority

of 3 vs. 6 mo of CAPEOX has not been proven. Grade 3+ neurotoxicity rates are lower for patients who receive 3 mo vs. 6 mo of treatment

(3% vs. 16% for FOLFOX; 3% vs. 9% for CAPEOX). Grothey A, et al. N Engl J Med 2018;378:1177-1188.

• Footnote removed: There are no denitive data on duration of adjuvant therapy for stage II disease.

COL-4

• Workup, last bullet modied: If potentially resectable, then multidisciplinary team evaluation, including a surgeon experienced in the

resection of hepatobiliary and

or lung metastases

NCCN Guidelines Version 2.2021

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Discussion

UPDATES

Continued

COL-5

• Adjuvant treatment timeframe modied: Up to 6 Mo Perioperative Treatment Preferred

(also applies to COL-6, COL-10, COL-11)

• Treatment

Treatment option added: Consider ([Nivolumab ± ipilimumab] or pembrolizumab [preferred]) followed by synchronous or staged colectomy

and resection of metastatic disease (dMMR/MSI-H only) (also applies to COL-6 [with removal of consider])

Footnote aa added: Data are limited and the risk of early progression may be higher than with chemotherapy. Andre T, et al. N Engl J Med

2020;383:2207-2218. (also applies to COL-6)

COL-11

• Primary Treatment

Pembrolizumab noted as preferred for dMMR/MSI-H.

Principles of Imaging

COL-A 1 of 2

• Initial Workup/Staging

Bullet 4; sub-bullet 2; diamond 2 added

◊ In selected patients considered for image-guided liver-directed therapies (ie, ablation, radioembolization).

Bullet 5 modied

◊ If liver-directed therapy or surgery is contemplated, a hepatic MRI with intravenous routine extracellular or hepatobiliary GBCA is

preferred over CT (and PET/CT)

to assess exact number and distribution of metastatic foci for local treatment planning.

• Monitoring; bullet 2 added (also applies to Surveillance; bullet 3; sub-bullet 2 on COL-A 2 of 2)

PET/CT can be considered for assessment of response and liver recurrence after image-guided liver-directed therapies (ie, ablation,

radioembolization)

COL-A 2 of 2

• References 4–8 added.

Principles of Pathologic Review

COL-B 2 of 8

• Bullet 4; Tumor budding: “grade” changed to “tier.”

COL-B 3 of 8

• Sentinel Lymph Node and Detection of Micrometastasis by Immunohistochemistry

Bullet 1; sentence 3 modied: The 8th edition of the AJCC Cancer Staging Manual and Handbook denes clumps of tumor cells ≥0.2 mm

but ≤2 mm in diameter or clusters of 10–20 tumor cells as micrometastasis and recommends that these micrometastases be considered as

standard positive lymph nodes (pN+).

COL-B 4 of 8

• KRAS, NRAS, and BRAF Mutation Testing

Bullet 2 added: BRAF V600E mutation testing via immunohistochemistry is also an option.

• Microsatellite Instability of Mismatch Repair Testing

Bullet 6 modied with the following modications: NOTE: Normal is the presence of positive protein staining (retained/intact) and abnormal

is negative or loss of staining of protein. Loss of protein expression by IHC in any one of the MMR genes guides further genetic testing

(mutation detection to the genes where the protein expression is not observed). Abnormal MLH1 IHC should be followed by tumor testing

for BRAF V600E mutation or MLH1 promoter methylation. The presence of BRAF V600E mutation or MLH1 promoter methylation is

consistent with sporadic cancer.

Updates in Version 1.2021 of the NCCN Guidelines for Colon Cancer from Version 4.2020 include:

NCCN Guidelines Version 2.2021

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UPDATES

Principles of Surgery

COL-C 2 of 3

• Liver

Bullet 5 modied: When hepatic metastatic disease is not optimally resectable based on insucient remnant liver volume, approaches

utilizing preoperative portal vein embolization, staged liver resection, or yttrium-90 radioembolization, can be considered.

Reference 15 added.

Systemic Therapy for Advanced or Metastatic Disease

COL-D 1 of 13

• Patient appropriate for intensive therapy

The following Initial Therapy options added: Nivolumab ± ipilimumab (dMMR/MSI-H only)

Pembrolizumab noted as preferred for dMMR/MSI-H (applies throughout COL-D)

• Patient not appropriate for intensive therapy

The following Initial Therapy options added: Fam-trastuzumab deruxtecan-nxki (HER2-amplied and RAS and BRAF WT)

(also added to Subsequent Therapy options on pages COL-D 2 through COL-D 6)

Infusional removed from 5-FU ± leucovorin ± bevacizumab

COL-D 2 of 13

• Subsequent Therapy

Triuridine + tipiracil modied with the addition of ± bevacizumab (also applies to COL-D 3 through COL-D 6)

COL-D 7 of 13

• Footnote o added: Some activity was seen after a previous HER2-targeted regimen. May not be indicated in patients with underlying lung

issues due to lung toxicity (2.6% report of deaths from interstitial lung disease).

• Footnote x modied with the addition of “with or without bevacizumab”

• Footnote removed from cetuximab or panitumumab

If neither previously given.

COL-D 9 of 13

• Dosing regimens added for FOLFOXIRI + cetuximab and FOLFOXIRI + panitumumab. References added.

COL-D 11 of 13

• Dosing regimens added for Triuridine + tipiracil ± bevacizumab and Fam-trastuzumab deruxtecan-nxki. References added.

Updates in Version 1.2021 of the NCCN Guidelines for Colon Cancer from Version 4.2020 include:

Continued

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Colon Cancer from Version 4.2020 include:

Principles of Radiation and Chemoradiation Therapy

COL-E 1 of 2

• Treatment Information

Bullet 1 modied: If radiation therapy is to be used, conformal external beam radiation should be routinely used and IMRT/SBRT

should

be reserved only for unique clinical situations such as reirradiation of previously treated patients with recurrent disease,

and or unique

anatomical situations where IMRT facilitates the delivery of recommended target volume doses while respecting accepted normal tissue

dose-volume constraints (eg, coverage of external iliac or inguinal lymph nodes or avoidance of small bowel).

Bullet 2 added: Consider SBRT for patients with oligometastatic disease.

Bullet 3 modied: Image-guided radiation therapy (IGRT) with kilovoltage (kV) imaging and/

or cone-beam CT imaging should be routinely

used during the course of treatment with IMRT and SBRT.

COL-E 2 of 2

• Section added for Supportive Care

Female patients should be considered for vaginal dilators and instructed on the symptoms of vaginal stenosis, if applicable.

Male patients should be counseled on sexual dysfunction and infertility risks and given information regarding sperm banking, if applicable.

Female patients should be counseled on infertility risks and given information regarding oocyte, egg, or ovarian tissue banking prior to

treatment, if applicable.

Principles of Adjuvant Therapy

COL-G 1 of 2

• Bullet 1 modied: FOLFOX is superior to 5-FU/leucovorin for patients with stage III colon cancer.Capecitabine/oxaliplatin is superior to bolus

CAPEOX or FOLFOX is superior to 5-FU/leucovorin for patients with stage III colon cancer.

• Bullet 5 modied: While non-inferiority of 3 mo vs. 6 mo of CAPEOX has not been proven, 3 mo of CAPEOX numerically appeared similar to 6

mo of CAPEOX for 5-year overall survival (82.1% vs. 81.2%; HR, 0.96), with considerably less toxicity. These results support the use of 3 mo

of adjuvant CAPEOX over 6 mo of adjuvant CAPEOX in the vast majority of patients with stage III colon cancer. In patients with colon cancer,

staged as T1–3, N1 (low-risk stage III), 3 mo of CAPEOX is non-inferior to 6 mo of CAPEOX for disease-free survival; non-inferiority of 3 vs.

6 mo of FOLFOX has not been proven. In patients with colon cancer staged as T4, N1–2 or T any, N2 (high-risk stage III), 3 mo of FOLFOX

is inferior to 6w mo of FOLFOX for disease-free survival, whereas non-inferiority of 3 vs. 6 mo of CAPEOX has not been proven. Grade 3+

neurotoxicity rates are lower for patients who receive 3 mo vs. 6 mo of treatment (3% vs. 16% for FOLFOX; 3% vs. 9% for CAPEOX).

• Bullet 6; sentence removed: There are currently no denitive data on the duration of oxaliplatin-containing regimens for adjuvant therapy in

stage II disease.

• Reference 5 added.

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Pedunculated

or sessile

polyp

(adenoma)

with invasive

cancer

COL-1

All patients with colon cancer should be counseled for family history and

considered for risk assessment. For patients with suspected Lynch syndrome,

familial adenomatous polyposis (FAP), and attenuated FAP, see the NCCN

Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.

See Principles of Imaging (COL-A).

Confirm the presence of invasive cancer (pT1). pTis has no biological potential to

metastasize.

It has not been established if molecular markers are useful in treatment

determination (predictive markers) and prognosis. College of American

Pathologists Consensus Statement 1999. Prognostic factors in colorectal cancer.

Arch Pathol Lab Med 2000;124:979-994.

See Principles of Pathologic Review (COL-B 4 of 8) - MSI or MMR Testing.

See Principles of Pathologic Review (COL-B) - Endoscopically removed

malignant polyp.

Observation may be considered, with the understanding that there is significantly

greater incidence of adverse outcomes (residual disease, recurrent disease,

mortality, hematogenous metastasis, but not lymph node metastasis) than

polypoid malignant polyps. See Principles of Pathologic Review (COL-B) -

Endoscopically removed malignant polyp.

See Principles of Surgery (COL-C 1 of 3).

CLINICAL

PRESENTATION

WORKUP

FINDINGS SURGERY

• Pathology review

c,d

• Colonoscopy

• Marking of

cancerous polyp

site (at time of

colonoscopy or

within 2 weeks if

deemed necessary

by the surgeon)

• MMR/MSI testing

Single specimen,

completely removed

with favorable

histologic features

and clear margins

Fragmented

specimen or margin

cannot be assessed

or unfavorable

histologic features

Pedunculated

polyp with

invasive cancer

Sessile polyp

with invasive

cancer

Observe

Colectomy

with

en bloc removal of

regional lymph nodes

Colectomy

with

en bloc removal of

regional lymph nodes

See

Pathologic

Stage,

Adjuvant

Therapy, and

Surveillance

(COL-3)

Consider systemic therapy as per the NCCN Guidelines

for Malignant Pleural Mesothelioma (MPM-A)

Peritoneal mesothelioma or other

extrapleural mesotheliomas

• Consider pelvic MRI

• CBC, chemistry

prole, CEA

• Chest/abdominal/

pelvic CT

• PET/CT scan is not

indicated

Appendiceal adenocarcinoma

Consider systemic therapy (COL-D) as per the

NCCN Guidelines for Colon Cancer

Small bowel adenocarcinoma

See the NCCN Guidelines for Small Bowel Adenocarcinoma

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Colon cancer

appropriate

for resection

(non-

metastatic)

COL-2

All patients with colon cancer should be counseled for family history and considered for risk assessment. For patients with suspected Lynch syndrome, FAP, and

attenuated FAP, see the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.

See Principles of Imaging (COL-A).

See Principles of Pathologic Review (COL-B 4 of 8) - MSI or MMR Testing.

See Principles of Pathologic Review (COL-B) - Colon cancer appropriate for resection, pathologic stage, and lymph node evaluation.

See Principles of Surgery (COL-C 1 of 3).

For tools to aid optimal assessment and management of older adults with cancer, see the NCCN Guidelines for Older Adult Oncology.

Consider an MRI to assist with the diagnosis of rectal cancer versus colon cancer (eg, low-lying sigmoid tumor). The rectum lies below a virtual line from the sacral

promontory to the upper edge of the symphysis as determined by MRI.

See Principles of Radiation and Chemoradiation Therapy (COL-E).

Bolus 5-FU/leucovorin/RT is an option for patients not able to tolerate capecitabine or infusional 5-FU.

CLINICAL

PRESENTATION

WORKUP FINDINGS PRIMARY TREATMENT

Suspected or proven

metastatic adenocarcinoma

• Biopsy

• MMR/MSI testing

• Pathology review

• Colonoscopy

• Consider abdominal/

pelvic MRI

b,j

• CBC, chemistry prole,

CEA

• Chest/abdominal/pelvic

• Enterostomal therapist

as indicated for

preoperative marking of

site, teaching

• PET/CT scan is not

indicated

• Fertility risk discussion/

counseling in

appropriate patients

Resectable,

non-

obstructing

Resectable,

obstructing

Locally

unresectable

or medically

inoperable

See management of suspected or proven

metastatic synchronous adenocarcinoma (COL-4)

Colectomy

with en bloc removal

of regional lymph nodes

One-stage colectomy

with en bloc removal of

regional lymph nodes

Resection with diversion

Diversion

Stent (in selected cases)

Colectomy

with

en bloc removal

of regional

lymph nodes

See Pathologic

Stage, Adjuvant

Therapy, and

Surveillance (COL-3)

See Systemic Therapy (COL-D)

Infusional 5-FU + RT

k,l

Capecitabine + RT

k,l

Bulky nodal

disease

Clinical T4b

Consider neoadjuvant

FOLFOX or CAPEOX

Surgery

± IORT

Systemic

therapy

(COL-D)

Re-evaluate

for conversion

to resectable

disease

b,h

See

Adjuvant

Therapy

(COL-5)

NCCN Guidelines Version 2.2021

Colon Cancer

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

COL-3

PATHOLOGIC STAGE

ADJUVANT TREATMENT

b,u

See Principles of Imaging (COL-A).

See Principles of Pathologic Review (COL-B).

See Principles of Risk Assessment for Stage II Disease (COL-F).

High-risk factors for recurrence (exclusive of those cancers that are MSI-H):

poorly differentiated/undifferentiated histology, lymphatic/vascular invasion, bowel

obstruction, <12 lymph nodes examined, perineural invasion, localized perforation, or

close, indeterminate, positive margins, or tumor budding. In high-risk stage II patients,

there are no data that correlate risk features and selection of chemotherapy.

There are insufficient data to recommend the use of multi-gene assay panels to

determine adjuvant therapy.

See Principles of Adjuvant Therapy (COL-G).

Consider RT for T4 with penetration to a fixed structure. See Principles of Radiation

and Chemoradiation Therapy (COL-E).

A survival benefit has not been demonstrated for the addition of oxaliplatin to 5-FU/

leucovorin in stage II colon cancer. Tournigand C, et al. J Clin Oncol 2012; 30:3353-

3360.

A benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients aged 70 years

and older has not been proven.

While non-inferiority of 3 mo vs. 6 mo of CAPEOX has not been proven, 3 mo of

CAPEOX numerically appeared similar to 6 mo of CAPEOX for 5-year overall survival

(82.1% vs. 81.2%; HR, 0.96), with considerably less toxicity. (Andre T, et al. Lancet

Oncol 2020;21:1620-1629). These results support the use of 3 mo of adjuvant

CAPEOX over 6 mo of adjuvant CAPEOX in the vast majority of patients with stage

III colon cancer. In patients with colon cancer, staged as T1–3, N1 (low-risk stage

III), 3 mo of CAPEOX is non-inferior to 6 mo of CAPEOX for disease-free survival;

non-inferiority of 3 vs. 6 mo of FOLFOX has not been proven. In patients with colon

cancer staged as T4, N1–2 or T any, N2 (high-risk stage III), 3 mo of FOLFOX is

inferior to 6 mo of FOLFOX for disease-free survival, whereas non-inferiority of 3 vs.

6 mo of CAPEOX has not been proven. Grade 3+ neurotoxicity rates are lower for

patients who receive 3 mo vs. 6 mo of treatment (3% vs. 16% for FOLFOX; 3% vs.

9% for CAPEOX).

Grothey A, et al. N Engl J Med 2018;378:1177-1188.

Tis; T1, N0, M0; T2, N0, M0;

T3–4, N0, M0

(MSI-H/dMMR)

T3, N0, M0

n,o

(MSS/pMMR and

no high-risk features)

Observation

Consider capecitabine (6 mo)

or 5-FU/leucovorin (6 mo)

T3, N0, M0 at high risk for

systemic recurrence

o,p

T4, N0, M0 (MSS/pMMR)

Capecitabine (6 mo)

q,r

or 5-FU/leucovorin (6 mo)

q,r

FOLFOX (6 mo)

q,r,s,t

or CAPEOX (3 mo)

q,r,s,t

Observation

See Surveillance (COL-8)

Observation

T1–3, N1

(low-risk stage III)

Preferred:

• CAPEOX

(3 mo)

q,t

• FOLFOX (3–6 mo)

q,t

Other options include: Capecitabine (6 mo)

or 5-FU (6 mo)

T4, N1–2; T Any, N2

(high-risk stage III)

Preferred:

• CAPEOX

(3–6 mo)

q,r,t

• FOLFOX (6 mo)

q,r,t

Other options include: Capecitabine (6 mo)

q,r

or 5-FU (6 mo)

q,r

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

• Colonoscopy

• Chest/abdominal/pelvic CT

• CBC, chemistry prole

• CEA

• Determination of tumor gene status

for RAS and BRAF mutations and

HER2 amplications (individually or

as part of next-generation sequencing

[NGS panel])

v,w

• Determination of tumor MMR or MSI

status

(if not previously done)

• Biopsy, if clinically indicated

• Consider PET/CT scan (skull base

to mid-thigh) if potentially surgically

curable M1 disease in selected cases

Consider MRI of liver for liver

metastases that are potentially

resectable

• If potentially resectable, then

multidisciplinary team evaluation,

including a surgeon experienced in

the resection of hepatobiliary or lung

metastases

COL-4

See Principles of Imaging (COL-A).

See Principles of Pathologic Review (COL-B 4 of 8) - MSI or MMR Testing.

See Principles of Surgery (COL-C 2 of 3).

See Principles of Pathologic Review (COL-B 4 of 8) - KRAS, NRAS, and BRAF Mutation Testing.

If known RAS/RAF mutation, HER2 testing is not indicated. NGS panels have the ability to pick up rare and actionable mutations and fusions.

Consider colon resection only if imminent risk of obstruction, significant bleeding, perforation, or other significant tumor-related symptoms.

CLINICAL

PRESENTATION

WORKUP FINDINGS

Suspected or

proven metastatic

synchronous

adenocarcinoma

(any T, any N, M1)

Synchronous

liver only and/or

lung only

metastases

Resectable

Unresectable

(potentially

convertible

unconvertible)

Synchronous

abdominal/peritoneal

metastases

See Treatment

and Adjuvant

Therapy (COL-5)

See Treatment

and Adjuvant

Therapy (COL-6)

See Primary

Treatment (COL-7)

Synchronous

unresectable metastases

of other sites

See Systemic

Therapy (COL-D)

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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Discussion

Synchronous or staged colectomy

with liver or lung

resection (preferred) and/or local therapy

Neoadjuvant therapy (for 2–3 months) FOLFOX

(preferred) or CAPEOX (preferred) or FOLFIRI

(category 2B) or FOLFOXIRI (category 2B) followed by

synchronous or staged colectomy

and resection of

metastatic disease

Colectomy,

followed by chemotherapy (for 2–3

months) FOLFOX (preferred) or CAPEOX (preferred) or

FOLFIRI (category 2B) or FOLFOXIRI (category 2B) and

staged resection of metastatic disease

Consider ([Nivolumab ± ipilimumab] or pembrolizumab

[preferred]) (dMMR/MSI-H only)

followed by

synchronous or staged colectomyy and resection of

metastatic disease

COL-5

See Principles of Imaging (COL-A).

See Principles of Surgery (COL-C 2 of 3).

Hepatic artery infusion ± systemic 5-FU/leucovorin (category 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of

this procedure.

Resection is preferred over locally ablative procedures (eg, image-guided ablation or SBRT). However, these local techniques can be considered for liver or lung

oligometastases (COL-C and COL-E).

Data are limited and the risk of early progression may be higher than with chemotherapy. Andre T, et al. N Engl J Med 2020;383:2207-2218.

TREATMENT

Resectable

synchronous liver

and/or lung metastases only

ADJUVANT TREATMENT

(UP TO 6 MO PERIOPERATIVE TREATMENT)

(resected metastatic disease)

FOLFOX (preferred) or CAPEOX (preferred)

Capecitabine or 5-FU/leucovorin

See Surveillance (COL-8)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

• Systemic therapy

FOLFIRI or FOLFOX or

CAPEOX or FOLFOXIRI ±

bevacizumab

bb,cc

FOLFIRI or FOLFOX or

FOLFOXIRI ± panitumumab

or cetuximab

(category 2B

for FOLFOXIRI combination)

(KRAS/NRAS/BRAF WT gene

and left-sided tumors only)

v,ee

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

(dMMR/MSI-H only)

• Consider colon resection

only

if imminent risk of obstruction,

signicant bleeding, perforation,

or other signicant tumor-

related symptoms

COL-6

See Recurrence (COL-9)

See Principles of Imaging (COL-A).

See Principles of Surgery (COL-C 2 of 3).

See Principles of Pathologic Review (COL-B 4 of 8) - KRAS, NRAS, and BRAF Mutation Testing.

Data are limited and the risk of early progression may be higher than with chemotherapy. Andre T, et al. N Engl J Med 2020; 383:2207-2218.

There should be at least a 6-week interval between the last dose of bevacizumab and elective surgery and re-initiation of bevacizumab at least 6–8 weeks

postoperatively. There is an increased risk of stroke and other arterial events, especially in those aged ≥65 years. The use of bevacizumab may interfere with wound

healing.

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

There are conflicting data regarding the use of FOLFOX + cetuximab in patients who have potentially resectable liver metastases.

The panel defines the left side of the colon as splenic flexure to rectum. Evidence suggests that patients with tumors originating on the right side of the colon (hepatic

flexure through cecum) are unlikely to respond to cetuximab and panitumumab in first-line therapy for metastatic disease. Data on the response to cetuximab and

panitumumab in patients with primary tumors originating in the transverse colon (hepatic flexure to splenic flexure) are lacking.

Biologic therapy is only appropriate for continuation of favorable response from conversion therapy.

TREATMENT

Unresectable

synchronous liver

and/or lung metastases only

ADJUVANT TREATMENT

(UP TO 6

MO PERIOPERATIVE TREATMENT)

Re-evaluate for

conversion to

resectable

b,h

every

2 mo if conversion

to resectability is

a reasonable goal

Converted to

resectable

Remains

unresectable

See Systemic Therapy

(COL-D)

Synchronized

or staged

resection

of colon and

metastatic

cancer

See

Surveillance

(COL-8)

Systemic therapy ±

biologic therapy



(COL-D)

(category 2B for biologic

therapy)

Consider observation

or shortened course of

chemotherapy

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Colon resection

h,x

Diverting ostomy

Bypass of impending obstruction

Stenting

COL-7

See Principles of Surgery (COL-C 2 of 3).

Consider colon resection only if imminent risk of obstruction, significant bleeding, perforation, or other significant tumor-related symptoms.

Complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for select patients with limited peritoneal metastases

for whom R0 resection can be achieved.

FINDINGS PRIMARY TREATMENT

Synchronous

abdominal/

peritoneal

metastases

Nonobstructing

Obstructed

or imminent

obstruction

See Systemic Therapy

(COL-D)

See Systemic Therapy

(COL-D)

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

• History and physical every 3–6 mo for 2 y, then every 6 mo for a

total of 5 y

• CEA

every 3–6 mo for 2 y, then every 6 mo for a total of 5 y

• Chest/abdominal/pelvic CT every 6–12 mo (category 2B for

frequency <12 mo) for a total of 5 y

• Colonoscopy

in 1 y after surgery except if no preoperative

colonoscopy due to obstructing lesion, colonoscopy in 3–6 mo

If advanced adenoma, repeat in 1 y

If no advanced adenoma,

repeat in 3 y, then every 5 y

• PET/CT scan is not indicated

• See Principles of Survivorship (COL-H)

SURVEILLANCE

Colonoscopy

at 1 y after surgery

• If advanced adenoma, repeat in 1 y

• If no advanced adenoma,

repeat in 3 y, then every 5 y

See Workup and

Treatment (COL-9)

All patients with colon cancer should be counseled for family history and considered for risk assessment. For patients with suspected Lynch syndrome, FAP, and

attenuated FAP, see the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.

See Principles of Imaging (COL-A).

Villous polyp, polyp >1 cm, or high-grade dysplasia.

Kahi CJ, et al. Gastroenterology 2016;150:758-768.

If patient is a potential candidate for further intervention.

PATHOLOGIC STAGE

Stage I

Stage II, III

COL-8

• History and physical every 3–6 mo for 2 y, then every 6 mo for a

total of 5 y

• CEA

every 3–6 mo x 2 y, then every 6 mo for a total of 5 y

• Chest/abdominal/pelvic CT scan every 3–6 mo (category 2B for

frequency <6 mo) x 2 y, then every 6–12 mo for a total of 5 y

• Colonoscopy

in 1 y after surgery except if no preoperative

colonoscopy due to obstructing lesion, colonoscopy in 3–6 mo

If advanced adenoma, repeat in 1 y

If no advanced adenoma,

repeat in 3 y, then every 5 y

• See Principles of Survivorship (COL-H)

Stage IV

Serial CEA

elevation or

documented

recurrence

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Documented

metachronous

metastases

kk,ll

by CT, MRI,

and/or biopsy

COL-9

See Principles of Imaging (COL-A).

See Principles of Surgery (COL-C 2 of 3).

Determination of tumor gene status for RAS and BRAF mutations and HER2 amplifications (individually or as part of NGS panel). If known RAS/RAF mutation, HER2

testing is not indicated. Determination of tumor MMR or MSI status (if not previously done). See Principles of Pathologic Review (COL-B 4 of 8) - KRAS, NRAS, and

BRAF Mutation Testing and Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing. NGS panels have the ability to pick up rare and actionable mutations

and fusions.

Patients should be evaluated by a multidisciplinary team including surgical consultation for potentially resectable patients.

RECURRENCE WORKUP

Serial

CEA

elevation

• Physical exam

• Colonoscopy

• Chest/abdominal/

pelvic CT with

contrast

Resectable

Unresectable

(potentially

convertible

unconvertible)

Consider

PET/CT

scan

Negative

ndings

Positive

ndings

• Consider PET/CT scan

• Re-evaluate chest/

abdominal/pelvic CT

with contrast in 3 mo

See treatment

for documented

metachronous

metastases, below

Negative

ndings

Positive

ndings

Resectable

Unresectable

See Primary

Treatment (COL-10)

See Primary

Treatment (COL-11)

See treatment

for documented

metachronous

metastases, below

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

COL-10

See Principles of Imaging (COL-A).

Hepatic artery infusion ± systemic 5-FU/leucovorin (category 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of

this procedure.

Resection is preferred over locally ablative procedures (eg, image-guided ablation or SBRT). However, these local techniques can be considered for liver or lung

oligometastases (COL-C and COL-E).

RESECTABLE

METACHRONOUS

METASTASES

ADJUVANT TREATMENT

(UP TO 6 MO PERIOPERATIVE TREATMENT)PRIMARY TREATMENT

No previous

chemotherapy

Resection (preferred)

and/or local therapy

Neoadjuvant

chemotherapy (2–3 mo)

FOLFOX (preferred) or

CAPEOX (preferred) or

(Capecitabine or 5-FU/

leucovorin)

(category 2B)

FOLFOX or CAPEOX (preferred)

Capecitabine or 5-FU/leucovorin

Observation (preferred for previous

oxaliplatin-based therapy)

Systemic therapy ± biologic therapy

(COL-D) (category 2B for biologic therapy)

Resection (preferred)

and/or

Local therapy

Resection (preferred)

and/or

Local therapy

See

Surveillance

(COL-8)

Resection (preferred)

and/or local therapy

Neoadjuvant

chemotherapy (2–3 mo)

FOLFOX (preferred) or

CAPEOX (preferred) or

Capecitabine or 5-FU/

leucovorin

FOLFOX or CAPEOX

Capecitabine

5-FU/leucovorin

Observation

FOLFOX or CAPEOX

Capecitabine

5-FU/leucovorin

Observation

NCCN Guidelines Version 2.2021

Colon Cancer

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

(FOLFIRI or irinotecan) ±

(bevacizumab

[preferred]

or ziv-aibercept

or ramucirumab)

(FOLFIRI or irinotecan) ±

(cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT gene only)

([Nivolumab ± ipilimumab]

or pembrolizumab [preferred])

(dMMR/MSI-H only)

Encorafenib + (cetuximab or

panitumumab)

(BRAF V600E

mutation positive)

COL-11

See Principles of Imaging (COL-A).

See Principles of Surgery (COL-C 2 of 3).

See Principles of Pathologic Review (COL-B 4 of 8) - KRAS, NRAS, and BRAF

Mutation Testing.

Hepatic artery infusion ± systemic 5-FU/leucovorin (category 2B) is also an option

at institutions with experience in both the surgical and medical oncologic aspects

of this procedure.

Biologic therapy is only appropriate for continuation of favorable response from

conversion therapy.

For infection risk, monitoring, and prophylaxis recommendations for targeted

therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of

Cancer-Related Infections.

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Bevacizumab is the preferred anti-angiogenic agent based on toxicity and/or

cost.

UNRESECTABLE

METACHRONOUS

METASTASES

PRIMARY TREATMENT

• Previous adjuvant

FOLFOX/CAPEOX

within past 12

months

• Previous adjuvant

FOLFOX/CAPEOX

>12 months

• Previous 5-FU/LV

or capecitabine

• No previous

chemotherapy

Systemic therapy (COL-D)

Re-evaluate for

conversion to

resectable

b,h

every 2 mo if

conversion to

resectability is

a reasonable

goal

Converted to

resectable

Remains

unresectable

Resection

See

Surveillance

(COL-8)

ADJUVANT TREATMENT

(UP TO 6 MO PERIOPERATIVE

TREATMENT)

Systemic therapy

± biologic

therapy



(COL-D)

(category 2B for

biologic therapy)

Observation

Systemic therapy (COL-D)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF IMAGING

1-3

COL-A

1 OF 2

Initial Workup/Staging

• Chest, abdomen, and pelvic CT

Evaluate local extent of tumor or inltration into surrounding structures.

Assess for distant metastatic disease to lungs, thoracic and abdominal lymph nodes, liver, peritoneal cavity, and other organs.

CT should be performed with intravenous iodinated contrast and oral contrast material unless contraindicated.

Intravenous contrast is not required for the chest CT (but usually given if performed with abdominal CT scan).

If IV iodinated contrast material is contraindicated because of signicant contrast allergy, then MR examination of the abdomen and pelvis

with IV gadolinium-based contrast agent (GBCA) can be obtained instead. In patients with chronic renal failure (glomerular ltration rate

[GFR] <30 mL/min) who are not on dialysis, IV iodinated contrast material is also contraindicated, and IV GBCA can be administered in

select cases using gadofosveset trisodium, gadoxetate disodium, gadobenate dimeglumine, or gadoteridol.

If iodinated and gadolinium contrast are both contraindicated due to signicant allergy or chronic renal failure without dialysis, then

consider MR without IV contrast or consider PET/CT imaging.

• Consider an abdominal/pelvic MRI to assist with the diagnosis of rectal cancer versus colon cancer (eg, low-lying sigmoid tumor). The

rectum lies below a virtual line from the sacral promontory to the upper edge of the symphysis as determined by MRI.

• Consider MRI of liver for liver metastases if potentially resectable.

• PET/CT is not routinely indicated.

PET/CT does not supplant a contrast-enhanced diagnostic CT or MR and should only be used to evaluate an equivocal nding on a

contrast-enhanced CT or MR scan or in patients with strong contraindications to IV contrast administration.

Consider PET/CT (skull base to mid-thigh)

◊ If potentially surgically curable M1 disease in selected cases.

◊ In selected patients considered for image-guided liver-directed therapies (ie, ablation, radioembolization).

4-8

• If liver-directed therapy or surgery is contemplated, a hepatic MRI with intravenous routine extracellular or hepatobiliary GBCA is preferred

over CT to assess exact number and distribution of metastatic foci for local treatment planning.

Monitoring

• Chest, abdomen, and pelvic CT with contrast

Prior to adjuvant treatment to assess response to primary therapy or resection

During re-evaluation of conversion to resectable disease

• PET/CT can be considered for assessment of response and liver recurrence after image-guided liver-directed therapies (ie, ablation,

radioembolization)

Continued

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

PRINCIPLES OF IMAGING

1-3

COL-A

2 OF 2

Surveillance

• Stage I disease

Imaging is not routinely indicated and should only be based on symptoms and clinical concern for recurrent/metastatic disease.

• Stage II & III disease

Chest, abdomen, and pelvic CT every 6–12 months (category 2B for frequency <12 months) for a total of 5 years.

PET/CT is not indicated.

• Stage IV disease

Chest, abdomen, and pelvic CT every 3–6 months (category 2B for frequency <6 months) x 2 years, then every 6–12 months for a total of 5

years.

PET/CT can be considered for assessment of response and liver recurrence after image-guided liver-directed therapies (ie, ablation,

radioembolization)

Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective

studies including patients who have not previously undergone treatment. Radiology 2010;257:674-684.

van Kessel CS, Buckens CF, van den Bosch MA, et al. Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis. Ann Surg

Oncol 2012;19:2805-2813.

ACR Manual on Contrast Media v10.3 https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf. Accessed May 25, 2017.

Mauri G, Gennaro N, De Beni S, et al. Real-time US-

FDG-PET/CT image fusion for guidance of thermal ablation of

FDG-PET-positive liver metastases: the added

value of contrast enhancement. Cardiovasc Intervent Radiol 2019;42:60-68.

Sahin DA, Agcaoglu O, Chretien C, et al. The utility of PET/CT in the management of patients with colorectal liver metastases undergoing laparoscopic radiofrequency

thermal ablation. Ann Surg Oncol 2012;19:850-855.

Shady W, Kishore S, Gavane S, et al. Metabolic tumor volume and total lesion glycolysis on FDG-PET/CT can predict overall survival after (90)Y radioembolization of

colorectal liver metastases: a comparison with SUVmax, SUVpeak, and RECIST 1.0. Eur J Radiol 2016;85:1224-1231.

Shady W, Sotirchos VS, Do RK, et al. Surrogate imaging biomarkers of response of colorectal liver metastases after salvage radioembolization using 90Y-loaded resin

microspheres. AJR Am J Roentgenol 2016;207:661-670.

Cornelis FH, Petre EN, Vakiani E, et al. Immediate postablation

F-FDG injection and corresponding SUV are surrogate biomarkers of local tumor progression after

thermal ablation of colorectal carcinoma liver metastases. J Nucl Med 2018;59:1360-1365.

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Endoscopically Removed Malignant Polyps

• A malignant polyp is dened as one with cancer invading through the muscularis mucosa and into the submucosa (pT1). pTis is not

considered a “malignant polyp.”

• Favorable histologic features: grade 1 or 2, no angiolymphatic invasion, and negative margin of resection. There is no consensus as to the

denition of what constitutes a positive margin of resection. A positive margin has been dened as: 1) tumor <1 mm from the transected

margin; 2) tumor <2 mm from the transected margin; and 3) tumor cells present within the diathermy of the transected margin.

1-4

• Unfavorable histologic features: grade 3 or 4, angiolymphatic invasion, or a “positive margin.” See the positive margin denition above. In

several studies, tumor budding has been shown to be an adverse histologic feature associated with adverse outcome and may preclude

polypectomy as an adequate treatment of endoscopically removed malignant polyps.

• There is controversy as to whether malignant colorectal polyps with a sessile conguration can be successfully treated by endoscopic

removal. The literature seems to indicate that endoscopically removed sessile malignant polyps have a signicantly greater incidence of

adverse outcomes (residual disease, recurrent disease, mortality, and hematogenous metastasis, but not lymph node metastasis) than do

pedunculated malignant polyps. However, when one closely looks at the data, conguration by itself is not a signicant variable for adverse

outcome, and endoscopically removed malignant sessile polyps with grade I or II histology, negative margins, and no lymphovascular

invasion can be successfully treated with endoscopic polypectomy.

3-7

Colon Cancer Appropriate for Resection

• Histologic conrmation of primary colonic malignant neoplasm.

Pathologic Stage

• The following parameters should be reported:

Grade of the cancer

Depth of penetration (T)

Number of lymph nodes evaluated and number positive (N)

Status of proximal, distal, radial, and mesenteric margins

8-9

See Staging (ST-1)

Lymphovascular invasion

10,11

Perineural invasion (PNI)

12-14

Tumor deposits

15-18

COL-B

1 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW

References

See Pathologic Stage (continued) on COL-B (2 of 8)

See Lymph Node Evaluation on COL-B (3 of 8)

See KRAS, NRAS, and BRAF Mutation Testing on COL-B (4 of 8)

HER2-Testing and NTRK Fusions on COL-B (5 of 8)

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

Pathologic Stage (continued)

• Radial (circumferential) margin evaluation - The serosal surface (peritoneal) does not constitute a surgical margin. In colon cancer the

circumferential (radial) margin represents the adventitial soft tissue closest to the deepest penetration of tumor, and is created surgically

by blunt or sharp dissection of the retroperitoneal aspect. The radial margins should be assessed in all colonic segments with non-

peritonealized surfaces. The circumferential resection margin corresponds to any aspect of the colon that is not covered by a serosal layer

of mesothelial cells, and must be dissected from the retroperitoneum to remove the viscus. On pathologic examination it is dicult to

appreciate the demarcation between a peritonealized surface and non-peritonealized surface. Therefore, the surgeon is encouraged to mark

the area of non-peritonealized surface with a clip or suture. The mesenteric resection margin is the only relevant circumferential margin in

segments completely encased by the peritoneum.

10-11

• PNI - The presence of PNI is associated with a signicantly worse prognosis. In multivariate analysis, PNI has been shown to be an

independent prognostic factor for cancer-specic, overall, and disease-free survival. For stage II carcinoma, those with PNI have a

signicantly worse 5-year disease-free survival compared to those without PNI (29% vs. 82% [P = .0005]).

12-14

• Tumor deposits - Irregular discrete tumor deposits in pericolic or perirectal fat away from the leading edge of the tumor and showing no

evidence of residual lymph node tissue, but within the lymphatic drainage of the primary carcinoma, are considered peritumoral deposits or

satellite nodules and are not counted as lymph nodes replaced by tumor. Most examples are due to lymphovascular invasion or, more rarely,

PNI. Because these tumor deposits are associated with reduced disease-free and overall survival, their number should be recorded in the

surgical pathology report. This poorer outcome has also been noted in patients with stage III carcinoma.

15-18

• Tumor budding - In recent years, tumor budding has been identied as a new prognostic factor in colon cancer. Recently, there was an

international consensus conference on tumor budding reporting.

A tumor bud is dened as a single cell or a cluster of ≤4 cells detected by

hematoxylin and eosin (H&E) at the advancing edge of the invasive carcinoma. The total number of buds should be reported from a selected

hot spot measuring 0.785 mm (20x ocular in most microscopes/via a conversion factor). Budding is separated into three tiers: low tier (0–4

buds), intermediate tier (5–9 buds), and high tier (10 or more buds). Two recent studies

20,21

using this scoring system have shown tumor

budding to be an independent prognostic factor for stage II colon cancer. An ASCO guideline for stage II colon cancer designates tumor

budding as an adverse (high-risk) factor.

Several studies have shown that high-tier tumor budding in pT1 colorectal carcinomas, including

malignant polyps, is associated with an increased risk of lymph node metastasis; however, methodologies for assessing tumor budding and

tier were not uniform.

23-27

COL-B

2 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW

References

See Endoscopically Removed Malignant Polyps and Colon Cancer Appropriate for Resection on COL-B (1 of 8)

See Lymph Node Evaluation on COL-B (3 of 8)

See KRAS, NRAS, and BRAF Mutation Testing on COL-B (4 of 8)

HER2 Testing and NTRK Fusions on COL-B (5 of 8)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Lymph Node Evaluation

• The AJCC and College of American Pathologists recommend examination of a minimum of 12 lymph nodes to accurately stage colon

cancers.

8,9,28

The literature lacks consensus as to what is the minimal number of lymph nodes to accurately identify stage II

cancer. The minimal number of nodes has been reported as >7, >9, >13, >20, and >30.

29-37

The number of lymph nodes retrieved can vary

with age of the patient, gender, tumor grade, and tumor site.

For stage II (pN0) colon cancer, if fewer than 12 lymph nodes are initially

identied, it is recommended that the pathologist go back to the specimen and resubmit more tissue of potential lymph nodes. If 12 lymph

nodes are still not identied, a comment in the report should indicate that an extensive search for lymph nodes was undertaken. The

pathologist should attempt to retrieve as many lymph nodes as possible. It has been shown that the number of negative lymph nodes is an

independent prognostic factor for patients with stage IIIB and IIIC colon cancer.

Sentinel Lymph Node and Detection of Micrometastasis by Immunohistochemistry

• Examination of the lymph nodes (sentinel or routine) by intense histologic and/or immunohistochemical investigation helps to detect the

presence of metastatic disease. The detection of single cells by immunohistochemistry (IHC) or by multiple H&E levels and/or clumps of

tumor cells <0.2 mm are considered isolated tumor cells (pN0). The 8th edition of the AJCC Cancer Staging Manual and Handbook

denes

clumps of tumor cells ≥0.2 mm but ≤2 mm in diameter or clusters of 10–20 tumor cells as micrometastasis and recommends that these

micrometastases be considered as standard positive lymph nodes (pN+).

• At the present time the use of sentinel lymph nodes and detection of isolated tumor cells by IHC alone should be considered investigational,

and results should be used with caution in clinical management decisions.

40-49

Some studies have shown that the detection of IHC

cytokeratin-positive cells in stage II (N0) colon cancer (dened by H&E) has a worse prognosis, while others have failed to show this survival

dierence. In some of these studies, what are presently dened as isolated tumor cells were considered to be micrometastases.

45-50

A recent

meta-analysis

demonstrated that micrometastases (≥0.2 mm) are a signicant poor prognostic factor. However, another recent multicenter

prospective study of stage I or II disease (via H&E) had a 10% decrease in survival for IHC-detected isolated tumor cells, (<0.2 mm) but only

in those with pT3–pT4 disease.

COL-B

3 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW

References

See Endoscopically Removed Malignant Polyps and Colon Cancer Appropriate for Resection on COL-B (1 of 8)

See Pathologic Stage on COL-B (2 of 8)

See KRAS, NRAS, and BRAF Mutation Testing on COL-B (4 of 8)

HER2 Testing and NTRK Fusions on COL-B (5 of 8)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

KRAS, NRAS, and BRAF Mutation Testing

• All patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF mutations

individually or as part of an NGS panel. Patients with any known KRAS mutation (exon 2, 3, 4) or NRAS mutation (exon 2, 3, 4) should not

be treated with either cetuximab or panitumumab.

53-55

BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely

unless given with a BRAF inhibitor.

56-58

• BRAF V600E mutation testing via immunohistochemistry is also an option.

• Testing for KRAS, NRAS, and BRAF mutations should be performed only in laboratories that are certied under the clinical laboratory

improvement amendments of 1988 (CLIA-88) as qualied to perform high-complexity clinical laboratory (molecular pathology) testing. No

specic methodology is recommended (eg, sequencing, hybridization).

• The testing can be performed on formalin-xed paran-embedded tissue. The testing can be performed on the primary colorectal cancers

and/or the metastasis, as literature has shown that the KRAS, NRAS, and BRAF mutations are similar in both specimen types.

Microsatellite Instability or Mismatch Repair Testing

• Universal mismatch repair (MMR)

or microsatellite instability (MSI)

testing is recommended in all newly diagnosed patients with colon

cancer. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.

• The presence of a BRAF V600E mutation in the setting of MLH1 absence would preclude the diagnosis of Lynch syndrome (LS) in the

vast majority of cases. However, approximately 1% of cancers with BRAF V600E mutations (and loss of MLH-1) are LS. Caution should be

exercised in excluding cases with a strong family history from germline screening in the case of BRAF V600E mutations.

• Stage II MSI high (MSI-H) patients may have a good prognosis and do not benet from 5-FU adjuvant therapy.

• MMR or MSI testing should be performed only in CLIA-approved laboratories.

• Testing for MSI may be accomplished by polymerase chain reaction (PCR) or a validated NGS panel, the latter especially in patients with

metastatic disease who require genotyping of RAS and BRAF.

• IHC refers to staining tumor tissue for protein expression of the four MMR genes known to be mutated in LS (MLH1, MSH2, MSH6, and

PMS2). A normal IHC test implies that all four MMR proteins are normally expressed (retained). Loss (absence) of expression of one or more

of the four DNA MMR proteins is often reported as abnormal or positive IHC. When IHC is reported as positive, caution should be taken to

ensure that positive refers to absence of mismatch expression and not presence of expression. NOTE: Normal is the presence of positive

protein staining (retained/intact) and abnormal is negative or loss of staining of protein. Loss of protein expression by IHC in any one of the

MMR genes guides further genetic testing (mutation detection to the genes where the protein expression is not observed). Abnormal MLH1

IHC should be followed by tumor testing for BRAF V600E mutation or MLH1 promoter methylation. The presence of BRAF V600E mutation

or MLH1 promoter methylation is consistent with sporadic cancer. However, caution should be exercised in excluding cases from germline

screening on the basis of BRAF V600E mutations in the setting of a strong family history.

COL-B

4 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW

IHC for MMR and DNA analysis for MSI are different assays and measure different biological effects caused by deficient MMR function.

References

See Endoscopically Removed Malignant Polyps and Colon Cancer Appropriate for Resection on COL-B (1 of 8)

See Pathologic Stage on COL-B (2 of 8)

HER2 Testing and NTRK Fusions on COL-B (5 of 8)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF PATHOLOGIC REVIEW

COL-B

5 OF 8

HER2 Testing

• Diagnostic testing is via immunohistochemistry, uorescence in situ hybridization (FISH), or NGS.

• Positive by immunohistochemistry is dened as: 3+ staining in more than 50% of tumor cells. 3+ staining is dened as an intense membrane

staining that can be circumferential, basolateral, or lateral. Those that have a HER2 score of 2+ should be reexed to FISH testing.

62-64

HER2 amplication by FISH is considered positive when the HER2:CEP17 ratio is ≥2 in more than 50% of the cells.

62-64

NGS is another

methodology for testing for HER2 amplication.

• Anti-HER2 therapy is only indicated in HER2-amplied tumors that are also RAS and BRAF wild type.

NTRK Fusions

• NTRK fusions are extremely rare in colorectal carcinomas.

The overall incidence is approximately 0.35% in a cohort of 2314 colorectal

carcinomas, with NTRK fusions conned to those tumors that are pan-wild type KRAS, NRAS, and BRAF. In one study of 8 colorectal

cancers harboring NTRK fusions, 7 were found in the small subset that were dMMR (MLH-1)/MSI-H.

These data support limiting the

subpopulation of colorectal cancers that should be tested for NTRK fusions to those with wild type KRAS, NRAS, BRAF, and arguably to

those that are MMR decient (dMMR)/MSI-H.

• NTRK inhibitors have been shown to have activity ONLY in those cases with NTRK fusions, and NOT with NTRK point mutations.

• Methodologies for detecting NTRK fusions are IHC,

FISH, DNA-based NGS, and RNA-based NGS.

66,69

In one study, DNA-based sequencing

showed an overall sensitivity and specicity of 81.1% and 99.9%, respectively, for detection of NTRK fusions when compared to RNA-based

sequencing and immunohistochemistry showed an overall sensitivity of 87.9% and specicity of 81.1%. Since approximately 1 in 5 tumors

identied as having an NTRK fusion by IHC will be a false positive, tumors that test positive by IHC should be conrmed by RNA NGS.

That same study commented that RNA-based sequencing appears to be the optimal way to approach NTRK fusions, because the splicing

out of introns simplies the technical requirements of adequate coverage and because detection of RNA-level fusions provides direct

evidence of functional transcription.

However, selection of the appropriate assay for NTRK fusion detection depends on tumor type and

genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether

comprehensive genomic testing is needed concurrently.

References

See Endoscopically Removed Malignant Polyps and Colon Cancer Appropriate for Resection on COL-B (1 of 8)

See Pathologic Stage (continued) on COL-B (2 of 8)

See Lymph Node Evaluation on COL-B (3 of 8)

See KRAS, NRAS, and BRAF Mutation Testing on COL-B (4 of 8)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

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Cooper HS, Deppisch LM, Gourley WK, et al. Endoscopically removed

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Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in

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Morson BC, Whiteway JE, Jones EA, et al. Histopathology and prognosis

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Compton CC and Greene FL. The staging of colorectal cancer: 2004 and beyond.

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Compton CC, Fielding LP, Burgardt LJ, et al. Prognostic factors in colorectal

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Ueno H, Mochizuki H, Hashiguchi Y, et al. Extramural cancer deposits without

nodal structure in colorectal cancer: optimal categorization for prognostic

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Lo DS, Pollett A, Siu LL, et al. Prognostic significance of mesenteric tumor

nodules in patients with stage III colorectal cancer. Cancer 2008;112:50-54.

Puppa G, Maisonneuve P, Sonzogni A, et al. Pathological assessment of

pericolonic tumor deposits in advanced colonic carcinoma: relevance to

prognosis and tumor staging. Mod Pathol 2007;20:843-855.

Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding

in colorectal cancer based on the International Tumor Budding Consensus

Conference (ITBCC) 2016. Mod Pathol 2017;30:1299-1311.

Lee VWK, Chan KF. Tumor budding and poorly-differentiated cluster in

prognostication in Stage II colon cancer. Pathol Res Pract 2018;214:402-407.

Romiti A, Roberto M, Marchetti P, et al. Study of histopathologic parameters to

define the prognosis of stage II colon cancer. Int J Colorectal Dis 2019;34:905-

913.

Costas-Chavarri A, Nandakumar G, Temin S, et al. Treatment of patients with

early-stage colorectal cancer: ASCO Resource-Stratified Guideline. J Glob

Oncol 2019;5:1-19.

Koelzer VH, Zlobec I, Lugli A. Tumor budding in colrectal cancer – ready for

diagnostic practice? Hum Pathol 2016;47:4-19.

Bosch SL, Teerenstra S, de Wilt JH, et al. Predicting lymph node metastasis in

pT1 colorectal cancer: a systematic review of risk factors providing rationale for

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Brown IS, Bettington ML, Bettington A, et al. Adverse histological features in

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2016;69:292-299.

Backes Y, Elias SG, Groen JN, et al. Histologic factors associated with

need for surgery in patients with pedunculated T1 colorectal carcinomas.

Gastroenterology 2018;154:1647-1659.

Pai RK, Chen YW, Jakubowski MA, et al. Colorectal carcinomas with

submucosal invasion (pT1): analysis of histopathological and molecular factors

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6 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW -- REFERENCES

Continued

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

COL-B

7 OF 8

PRINCIPLES OF PATHOLOGIC REVIEW -- REFERENCES

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Sarli L, Bader G, Lusco D, et al. Number of lymph nodes examined and

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Saha S, Van AG, Beutler T, et al. Sentinal lymph mapping techniques in

colorectal cancer. Sem Oncol 2004;31:374-81.

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sentinal node mapping in early colorectal carcinoma. Detection of missed

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Wiese DA, Sha S, Badin J, et al. Pathological evaluation of sentinel lymph

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Bertagnolli M, Miedema B, Redstone M, et al. Sentinal node staging of

resectable colon cancer. Results of a multicenter study. Ann Surg 2004;240:624-

630.

Noura S, Yamamoto H, Ohnishi T, et al. Comparative detection of lymph

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4241.

Yasuda K, Adachi Y, Shiraishi N, et al. Pattern of lymph node micrometastasis

and prognosis of patients with colorectal cancer. Ann Surg Oncol 2001;8:300-

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Continued

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF PATHOLOGIC REVIEW -- REFERENCES

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NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Colectomy

• Lymphadenectomy

Lymph nodes at the origin of feeding vessel(s) should be identied for pathologic exam.

Clinically positive lymph nodes outside the eld of resection that are considered suspicious should be biopsied or removed, if possible.

Positive nodes left behind indicate an incomplete (R2) resection.

A minimum of 12 lymph nodes need to be examined to establish N stage.

• Minimally invasive approaches may be considered based on the following criteria:

The surgeon has experience performing laparoscopically assisted colorectal operations.

3,4

Minimally invasive approaches are generally not indicated for locally advanced cancer or acute bowel obstruction or perforation from

cancer.

Thorough abdominal exploration is required.

Consider preoperative marking of lesion(s).

• Management of patients with carrier status of known or clinically suspected LS.

Consider more extensive colectomy for patients with a strong family history of colon cancer or young age (<50 y).

See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal

• Resection needs to be complete to be considered curative.

COL-C

1 OF 3

PRINCIPLES OF SURGERY

See Criteria for Resectability of Metastases and

Locoregional Therapies Within Surgery on COL-C (2 of 3)

References

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Liver

• Hepatic resection is the treatment of choice for resectable liver

metastases from colorectal cancer.

• Complete resection must be feasible based on anatomic grounds

and the extent of disease; maintenance of adequate hepatic function

is required.

• The primary tumor must have been resected for cure (R0). There

should be no unresectable extrahepatic sites of disease.

8-11

Having

a plan for a debulking resection (less than an R0 resection) is not

recommended.

• Patients with resectable metastatic disease and a primary tumor

in place should have both sites resected with curative intent.

These can be resected in one operation or as a staged approach,

depending on the complexity of the hepatectomy or colectomy,

comorbid diseases, surgical exposure, and surgeon expertise.

• When hepatic metastatic disease is not optimally resectable

based on insucient remnant liver volume, approaches utilizing

preoperative portal vein embolization,

staged liver resection,

yttrium-90 radioembolization

can be considered.

• Ablative techniques may be considered alone or in conjunction

with resection. All original sites of disease need to be amenable to

ablation or resection.

• Arterially directed catheter therapy, and in particular yttrium-90

microsphere selective internal radiation, is an option in highly

selected patients with chemotherapy-resistant/-refractory disease

and with predominant hepatic metastases.

• Conformal external beam radiation therapy may be considered

in highly selected cases or in the setting of a clinical trial and

should not be used indiscriminately in patients who are potentially

surgically resectable.

• Re-resection can be considered in selected patients.

Lung

• Complete resection based on the anatomic location and extent of

disease with maintenance of adequate function is required.

17-20

• The primary tumor must have been resected for cure (R0).

• Resectable extrapulmonary metastases do not preclude

resection.

21-24

• Re-resection can be considered in selected patients.

• Ablative techniques may be considered alone or in conjunction with

resection for resectable disease. All original sites of disease need to

be amenable to ablation or resection.

• Ablative techniques can also be considered when unresectable and

amenable to complete ablation.

• Patients with resectable synchronous metastases can be resected

synchronously or using a staged approach.

• Conformal external beam radiation therapy may be considered

in highly selected cases or in the setting of a clinical trial and

should not be used indiscriminately in patients who are potentially

surgically resectable.

Evaluation for Conversion to Resectable or Ablatable Disease

• Re-evaluation for resection and ablation should be considered in

otherwise unresectable patients after 2 months of preoperative

chemotherapy and every 2 months thereafter.

26-29

• Disease with a higher likelihood of being converted to resectable

are those with initially convertible disease distributed within limited

sites.

• When considering whether disease has been converted to

resectable, all original sites need to be amenable to resection.

• Preoperative chemotherapy regimens with high response rates

should be considered for patients with potentially convertible

disease.

COL-C

2 OF 3

PRINCIPLES OF SURGERY

CRITERIA FOR RESECTABILITY OF METASTASES AND LOCOREGIONAL THERAPIES WITHIN SURGERY

References

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

LeVoyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with

increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-

0089. J Clin Oncol 2003;21:2912-2919.

The Clinical Outcomes of Surgical therapy Study Group. A comparison of laparoscopically

assisted and open colectomy for colon cancer. N Engl J Med 2004;350:2050-2059.

Wishner JD, Baker JW, Jr., Hoffman GC, et al. Laparoscopic-assisted colectomy. The

learning curve. Surg Endosc 1995;9:1179-1183.

Nelson H, Weeks JC, Wieand HS. Proposed phase III trial comparing laparoscopic-

assisted colectomy versus open colectomy for colon cancer. J Natl Cancer Inst Monogr

1995:51-56.

Ota DM, Nelson H, Weeks JC. Controversies regarding laparoscopic colectomy for

malignant diseases. Curr Opin Gen Surg 1994:208-213.

Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic

resection, radiofrequency ablation, and combined resection/ablation for colorectal liver

metastases. Ann Surg 2004;239:818-825; discussion 825-7.

Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic

colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1261-8.

Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin

Oncol 1997;15:938-946.

Nordlinger B, Quilichini MA, Parc R, Hannoun L, Delva E, Huguet C. Surgical resection of

liver metastases from colo-rectal cancers. Int Surg 1987;72:70-72.

Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting

recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001

consecutive cases. Ann Surg 1999;230:309-318; discussion 318-321.

Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver

resection for hepatic colorectal metastases. Ann Surg 2002 Jun;235(6):759-66.

Reddy SK, Pawlik TM, Zorzi D, et al. Simultaneous resections of colorectal cancer

and synchronous liver metastases: a multi-institutional analysis. Ann Surg Oncol 2007

Dec;14(12):3481-91.

Covey AM, Brown KT, Jarnagin WR, et al. Combined portal vein embolization and

neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal

metastases. Ann Surg 2008 Mar;247(3):451-5.

Adam R, Miller R, Pitombo M, et al. Two-stage hepatectomy approach for initially

unresectable colorectal hepatic metastases. Surg Oncol Clin N Am 2007 Jul;16(3):525-

36, viii.

Teo JY, Allen JC, Jr, Ng DC, et al. A systematic review of contralateral liver lobe

hypertrophy after unilobar selective internal radiation therapy with Y90. HPB (Oxford)

2016;18:7-12.

Adam R, Bismuth H, Castaing D, et al. Repeat hepatectomy for colorectal liver

metastases. Ann Surg 1997;225:51-62.

McAfee MK, Allen MS, Trastek VF, Ilstrup DM, Deschamps C, Pairolero PC. Colorectal

lung metastases: results of surgical excision. Ann Thorac Surg 1992;53:780-785;

discussion 785-786.

Regnard JF, Grunenwald D, Spaggiari L, et al. Surgical treatment of hepatic and

pulmonary metastases from colorectal cancers. Ann Thorac Surg 1998;66:214-218;

discussion 218-219.

Inoue M, Kotake Y, Nakagawa K, Fujiwara K, Fukuhara K, Yasumitsu T. Surgery for

pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2000;70:380-383.

Sakamoto T, Tsubota N, Iwanaga K, Yuki T, Matsuoka H, Yoshimura M. Pulmonary

resection for metastases from colorectal cancer. Chest 2001;119:1069-1072.

Rena O, Casadio C, Viano F, et al. Pulmonary resection for metastases from colorectal

cancer: factors influencing prognosis. Twenty-year experience. Eur J Cardiothorac Surg

2002;21:906-912.

Irshad K, Ahmad F, Morin JE, Mulder DS. Pulmonary metastases from colorectal cancer:

25 years of experience. Can J Surg 2001;44:217-221.

Ambiru S, Miyazaki M, Ito H, et al. Resection of hepatic and pulmonary metastases in

patients with colorectal carcinoma. Cancer 1998;82:274-278.

Yano T, Hara N, Ichinose Y, Yokoyama H, Miura T, Ohta M. Results of pulmonary

resection of metastatic colorectal cancer and its application. J Thorac Cardiovasc Surg

1993;106:875-879.

Hendriks JM, Romijn S, Van Putte B, et al. Long-term results of surgical resection of lung

metastases. Acta Chir Belg 2001;101:267-272.

Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after

neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8:347-353.

Rivoire M, De Cian F, Meeus P, Negrier S, Sebban H, Kaemmerlen P. Combination of

neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of

unresectable liver metastases from colorectal carcinoma. Cancer 2002;95:2283-2292.

Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis

and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J

Clin Oncol 2006 May 1;24(13):2065-72.

Pawlik TM, Olino K, Gleisner AL, et al. Preoperative chemotherapy for colorectal liver

metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg

2007 Jul;11(7):860-8.

Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases

after chemotherapy: does it mean cure? J Clin Oncol 2006 Aug 20;24(24):3939-45.

Bartlett DL, Berlin J, Lauwers GY, et al. Chemotherapy and regional therapy of hepatic

colorectal metastases: expert consensus statement. Ann Surg Oncol. 2006;13:1284-92.

COL-C

3 OF 3

PRINCIPLES OF SURGERY – REFERENCES

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b

INITIAL THERAPY

Patient

appropriate

for intensive

therapy

FOLFOX ± bevacizumab

CAPEOX

± bevacizumab

FOLFOX + (cetuximab or panitumumab)

e,f

(KRAS/NRAS/BRAF WT and left-sided tumors only)

FOLFIRI

± bevacizumab

FOLFIRI

+ (cetuximab or panitumumab)

e,f

(KRAS/NRAS/BRAF WT and left-sided tumors only)

FOLFOXIRI

g,h

± bevacizumab

([Nivolumab ± ipilimumab] or pembrolizumab

[preferred]*)

i,j,k,l

(dMMR/MSI-H only)

Patient not

appropriate

for intensive

therapy

Improvement in

functional status

No improvement in

functional status

Consider initial

therapy as above

If previous

uoropyrimidine,

see COL-D (5 of 13)

Best

supportive care

See NCCN

Guidelines for

Palliative Care

5-FU ± leucovorin ± bevacizumab

Capecitabine ± bevacizumab

(Cetuximab or panitumumab)

e,f

(category 2B) (KRAS/NRAS/BRAF WT and

left-sided tumors only)

(Nivolumab or pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

Nivolumab + ipilimumab

i,j,k,l

(dMMR/MSI-H only)

(category 2B)

(Trastuzumab

+ [pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-nxki

(HER2-

amplied and RAS and BRAF WT)

See COL-D (2 of 13)Progression

Progression See COL-D (4 of 13)

Progression See COL-D (3 of 13)

COL-D

1 OF 13

See footnotes on COL-D (7 of 13)

Progression

Progression See COL-D (5 of 13)

Patients should be followed closely for 10 weeks to assess for response.

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

SUBSEQUENT THERAPY

c,r,s

oxaliplatin-

based therapy

without

irinotecan

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b,q

FOLFIRI

or irinotecan

FOLFIRI

+ (bevacizumab

d,t

[preferred]

ziv-aibercept

t,u

or ramucirumab

t,u

)

Irinotecan

+ (bevacizumab

d,t

[preferred]

ziv-aibercept

t,u

or ramucirumab

t,u

)

FOLFIRI

+ (cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Irinotecan

+ (cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Encorafenib + (cetuximab or panitumumab)

(BRAF V600E mutation positive)

([Nivolumab ± ipilimumab] or pembrolizumab

[preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-nxki

(HER2-

amplied and RAS and BRAF WT)

Irinotecan

+ (cetuximab or

panitumumab)

(KRAS/NRAS/BRAF WT only)

Regorafenib

Triuridine + tipiracil ± bevacizumab

d,x

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or

lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab

or lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

Regorafenib

x,y

Triuridine + tipiracil

bevacizumab

d,x

Best supportive care

See NCCN Guidelines

for Palliative Care

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

See Subsequent Therapy

COL-D

2 OF 13

See footnotes on COL-D (7 of 13)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

SUBSEQUENT THERAPY

c,r,s

irinotecan-

based therapy

without

oxaliplatin

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b,q

FOLFOX or CAPEOX

FOLFOX + bevacizumab

CAPEOX + bevacizumab

FOLFOX +

(cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Irinotecan

(cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Encorafenib +

(cetuximab or panitumumab)

(BRAF V600E mutation positive)

([Nivolumab ± ipilimumab] or pembrolizumab

[preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-nxki

(HER2-amplied and RAS and BRAF WT)

Irinotecan

+ (cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Regorafenib

Triuridine + tipiracil ± bevacizumab

d,x

([Nivolumab ± ipilimumab] or pembrolizumab

[preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-nxki

(HER2-amplied and RAS and BRAF WT)

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

See Subsequent Therapy

Regorafenib

x,y

Triuridine

+ tipiracil

bevacizumab

d,x

Best supportive

care

See NCCN

Guidelines for

Palliative Care

Regorafenib

Triuridine

+ tipiracil ±

bevacizumab

d,x

COL-D

3 OF 13

FOLFOX or CAPEOX

([Nivolumab ± ipilimumab]

or pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab

or lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

See footnotes on COL-D (7 of 13)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Irinotecan

+ (cetuximab or panitumumab)

(KRAS/NRAS/BRAF WT only)

Encorafenib + (cetuximab or panitumumab)

(BRAF V600E mutation positive)

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

([Nivolumab ± ipilimumab] or pembrolizumab

[preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-nxki

(HER2-

amplied and RAS and BRAF WT)

Regorafenib

x,y

Triuridine + tipiracil

± bevacizumab

d,x

Best supportive care

See NCCN Guidelines

for Palliative Care

SUBSEQUENT THERAPY

c,r,s

treatment

with

oxaliplatin

and

irinotecan

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b,q

See Subsequent Therapy

Regorafenib

Triuridine + tipiracil ± bevacizumab

d,x

([Nivolumab ± ipilimumab]

or pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or

lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

See Subsequent Therapy

COL-D

4 OF 13

See footnotes on COL-D (7 of 13)

Regorafenib

x,y

Triuridine + tipiracil

± bevacizumab

d,x

Best supportive care

See NCCN Guidelines

for Palliative Care

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

SUBSEQUENT THERAPY

c,r,s

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b,q

FOLFOX or CAPEOX

(FOLFOX or CAPEOX)

+ bevacizumab

FOLFIRI

or irinotecan

(FOLFIRI or irinotecan)

(bevacizumab

d,t

[preferred]

or ziv-aibercept

t,u

or ramucirumab

t,u

)

Irinotecan

+ oxaliplatin

± bevacizumab

Encorafenib + (cetuximab or

panitumumab)

(BRAF V600E mutation positive)

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or

lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

Irinotecan

+ (cetuximab

or panitumumab)

(KRAS/NRAS/BRAF WT

only)

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

([Nivolumab ± ipilimumab]

or pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or

lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied and RAS and

BRAF WT)

See Subsequent Therapy

FOLFOX or CAPEOX

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

[pertuzumab or lapatinib])

or fam-trastuzumab deruxtecan-

nxki

(HER2-amplied and RAS

and BRAF WT)

Regorafenib

x,y

Triuridine

+ tipiracil

bevacizumab

d,x

Best supportive

care

See NCCN

Guidelines for

Palliative Care

Regorafenib

Triuridine

+ tipiracil ±

bevacizumab

d,x

therapy

without

irinotecan or

oxaliplatin

See Subsequent Therapy

COL-D

5 OF 13

See next page

See footnotes on COL-D (7 of 13)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

SUBSEQUENT THERAPY

c,r,s

following therapy without

irinotecan or oxaliplatin

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

a,b,q

FOLFOX or CAPEOX

(FOLFOX or CAPEOX)

+ bevacizumab

Irinotecan

+ (cetuximab

or panitumumab)

(KRAS/NRAS/BRAF WT only)

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab

or lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

Regorafenib

x,y

Triuridine + tipiracil

± bevacizumab

d,x

Best supportive care

See NCCN Guidelines

for Palliative Care

Regorafenib

Triuridine + tipiracil

± bevacizumab

d,x

Irinotecan

± (cetuximab

or panitumumab)

(KRAS/NRAS/BRAF WT only)

Encorafenib + (cetuximab

or panitumumab)

(BRAF V600E mutation positive)

([Nivolumab ± ipilimumab] or

pembrolizumab [preferred])

i,j,k,l

(dMMR/MSI-H only)

(Trastuzumab

+ [pertuzumab or

lapatinib])

or fam-trastuzumab

deruxtecan-nxki

(HER2-amplied

and RAS and BRAF WT)

See Subsequent Therapy

COL-D

6 OF 13

See footnotes on COL-D (7 of 13)

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

For chemotherapy references, see Chemotherapy Regimens and References (COL-D [8 of 13]).

For infection risk, monitoring, and prophylaxis recommendations for targeted therapies, see INF-A in the NCCN Guidelines for Prevention and Treatment of Cancer-

Related Infections.

Chest/abdominal/pelvic CT with contrast or chest CT and abdominal/pelvic MRI with contrast to monitor progress of therapy. PET/CT should not be used. See

Principles of Imaging (COL-A).

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

See Principles of Pathologic Review (COL-B 4 of 8).

The panel defines the left side of the colon as splenic flexure to rectum. Evidence suggests that patients with tumors originating on the right side of the colon (hepatic

flexure through cecum) are unlikely to respond to cetuximab and panitumumab in first-line therapy for metastatic disease. Data on the response to cetuximab and

panitumumab in patients with primary tumors originating in the transverse colon (hepatic flexure to splenic flexure) are lacking.

Irinotecan should be used with caution in patients with Gilbert syndrome or elevated serum bilirubin. There is a commercially available test for UGT1A1. Guidelines for

use in clinical practice have not been established.

FOLFOXIRI should be strongly considered for patients with excellent performance status.

These therapies are FDA approved for colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. However, a number

of patients in the clinical trials had not received all three prior systemic therapies. Thirty-seven percent of patients received nivolumab monotherapy and 24% received

ipilimumab/nivolumab combination therapy in first- or second-line, and 28% and 31% of patients had not received all three indicated prior therapies before treatment

with nivolumab or ipilimumab/nivolumab, respectively.

See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

If disease response, consider discontinuing checkpoint inhibitor after 2 years of treatment.

If no previous treatment with a checkpoint inhibitor.

An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

If no previous treatment with HER2 inhibitor.

Some activity was seen after a previous HER2-targeted regimen. May not be indicated in patients with underlying lung issues due to lung toxicity (2.6% report of

deaths from interstitial lung disease).

The use of single-agent capecitabine after progression on a fluoropyrimidine-containing regimen has been shown to be ineffective; therefore, this is not recommended.

Arterially directed catheter therapy, and in particular yttrium-90 microsphere selective internal radiation, is an option in highly selected patients with chemotherapy-

resistant/-refractory disease and with predominant hepatic metastases. See Principles of Surgery (COL-C).

Larotrectinib or entrectinib are treatment options for patients with metastatic colorectal cancer that is NTRK gene fusion positive.

If patients had therapy stopped for reasons other than progression (eg, cumulative toxicity, elective treatment break, patient preference), rechallenge is an option at

time of progression.

Bevacizumab is the preferred anti-angiogenic agent based on toxicity and/or cost.

There are no data to suggest activity of FOLFIRI-ziv-aflibercept or FOLFIRI-ramucirumab in a patient who has progressed on FOLFIRI-bevacizumab, or vice versa.

Ziv-aflibercept and ramucirumab have only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients.

Cetuximab or panitumumab are recommended in combination with irinotecan-based therapy or as single-agent therapy for patients who cannot tolerate irinotecan.

In the second-line setting for BRAF V600E mutation positive tumors, there is phase 3 evidence for better efficacy with targeted therapies over FOLFIRI.

Regorafenib or trifluridine + tipiracil with or without bevacizumab are treatment options for patients who have progressed through all available regimens.

If not previously given.

COL-D

7 OF 13

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -- FOOTNOTES

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

mFOLFOX 6

1,2,3

Oxaliplatin 85 mg/m

IV day 1

Leucovorin 400 mg/m

IV day 1

5-FU 400 mg/m

IV bolus on day 1, followed by 1200 mg/m

/day x 2

days (total 2400 mg/m

over 46–48 hours) IV continuous infusion

Repeat every 2 weeks

mFOLFOX 7

Oxaliplatin 85 mg/m

IV day 1

Leucovorin 400 mg/m

IV day 1

5-FU 1200 mg/m

/day x 2 days (total 2400 mg/m

over 46–48 hours)

IV continuous infusion

Repeat every 2 weeks

FOLFOX + bevacizumab

5,d,cc

Bevacizumab 5 mg/kg IV, day 1

Repeat every 2 weeks

FOLFOX + panitumumab

(KRAS/NRAS/BRAF WT only)

Panitumumab 6 mg/kg IV over 60 minutes, day 1

Repeat every 2 weeks

FOLFOX + cetuximab

(KRAS/NRAS/BRAF WT only)

Cetuximab 400 mg/m

IV over 2 hours rst infusion,

followed by 250 mg/m

IV over 60 minutes weekly

or Cetuximab 500 mg/m

IV over 2 hours, day 1, every 2 weeks

CAPEOX

Oxaliplatin 130 mg/m

IV day 1

Capecitabine 1000

mg/m

twice daily PO for 14 days

Repeat every 3 weeks

CAPEOX + bevacizumab

8,d,cc

Oxaliplatin 130 mg/m

IV day 1

Capecitabine 1000

mg/m

PO twice daily for 14 days

Bevacizumab 7.5 mg/kg IV day 1

Repeat every 3 weeks

FOLFIRI

9,10

Irinotecan 180 mg/m

IV over 30–90 minutes, day 1

Leucovorin

400 mg/m

IV infusion to match duration of irinotecan

infusion, day 1

5-FU 400 mg/m

IV bolus day 1, followed by 1200 mg/m

/day x 2 days

(total 2400 mg/m

over 46–48 hours) continuous infusion

Repeat every 2 weeks

FOLFIRI + bevacizumab

11,d,cc

Bevacizumab 5 mg/kg IV, day 1

Repeat every 2 weeks

COL-D

8 OF 13

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1 mg/m

/min. Leucovorin infusion should match infusion time of

oxaliplatin. Cercek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1 mg/m

/min. J Oncol Pract 2016;12:e548-553.

Leucovorin 400 mg/m

is the equivalent of levoleucovorin 200 mg/m

The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m

twice daily for 14 days,

repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other

fluoropyrimidines) than European patients, and may require a lower dose of capecitabine.

Bevacizumab may be safely given at a rate of 0.5 mg/kg/min (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes).

Continued

References

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - CHEMOTHERAPY REGIMENS

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

COL-D

9 OF 13

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1 mg/m

/min. Leucovorin infusion should match infusion time of

oxaliplatin. Cercek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1 mg/m

/min. J Oncol Pract 2016;12:e548-553.

Leucovorin 400 mg/m

is the equivalent of levoleucovorin 200 mg/m

Bevacizumab may be safely given at a rate of 0.5 mg/kg/min (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes).

FOLFIRI + cetuximab (KRAS/NRAS/BRAF WT only)

Cetuximab 400 mg/m

IV over 2 hours rst infusion,

followed by 250 mg/m

IV over 60 minutes weekly

or Cetuximab 500 mg/m

IV over 2 hours, day 1, every 2 weeks

FOLFIRI

+ panitumumab

(KRAS/NRAS/BRAF WT only)

Panitumumab 6 mg/kg IV over 60 minutes, day 1

Repeat every 2 weeks

FOLFIRI + ziv-aibercept

Ziv-aibercept 4 mg/kg IV over 60 minutes, day 1

Repeat every 2 weeks

FOLFIRI + ramucirumab

Ramucirumab 8 mg/kg over 60 minutes, day 1

Repeat every 2 weeks

FOLFOXIRI

Irinotecan 165 mg/m

IV day 1, oxaliplatin 85 mg/m

IV day 1,

Leucovorin 400

mg/m

day 1, uorouracil 1200 mg/m

/day x 2 days

(total 2400 mg/m

over 48 hours) continuous infusion starting on day 1.

Repeat every 2 weeks

The dose used in European studies was 3200 mg/m

. U.S. patients

have been shown to have poorer tolerance for 5-FU. The dose listed

above is recommended for U.S. patients.

FOLFOXIRI

+ bevacizumab

18,d,cc

Bevacizumab 5 mg/kg IV, day 1

Repeat every 2 weeks

FOLFOXIRI + cetuximab

(KRAS/NRAS/BRAF WT only)

Cetuximab 400 mg/m

IV over 2 hours rst infusion,

followed by 250 mg/m

IV over 60 minutes weekly

or Cetuximab 500 mg/m

IV over 2 hours, day 1

Repeat every 2 weeks

FOLFOXIRI + panitumumab

(KRAS/NRAS/BRAF WT only)

Panitumumab 6 mg/kg IV over 60 minutes, day 1

Repeat every 2 weeks

IROX

Oxaliplatin 85 mg/m

IV,

followed by irinotecan 200 mg/m

over 30–90 minutes every 3 weeks

IROX + bevacizumab

d,cc

Bevacizumab 7.5 mg/kg IV on day 1

Repeat every 3 weeks

Bolus or infusional 5-FU/leucovorin

Roswell Park regimen

Leucovorin 500 mg/m

IV over 2 hours, days 1, 8, 15, 22, 29, and 36

5-FU 500 mg/m

IV bolus 1 hour after start of leucovorin,

days 1, 8, 15, 22, 29, and 36

Repeat every 8 weeks

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - CHEMOTHERAPY REGIMENS

Continued

References

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

COL-D

10 OF 13

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m

twice daily for 14 days,

repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other

fluoropyrimidines) than European patients, and may require a lower dose of capecitabine.

Bevacizumab may be safely given at a rate of 0.5 mg/kg/min (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes).

Simplied biweekly infusional 5-FU/LV (sLV5FU2)

Leucovorin

400 mg/m

IV over 2 hours on day 1,

followed by 5-FU bolus 400 mg/m

followed by 1200 mg/m

/day x 2

days (total 2400 mg/m

over 46–48 hours) continuous infusion

Repeat every 2 weeks

Weekly

Leucovorin 20 mg/m

IV over 2 hours on day 1, 5-FU 500 mg/m

bolus injection 1 hour after the start of leucovorin. Repeat weekly.

5-FU 2600 mg/m

by 24-hour infusion plus leucovorin 500 mg/m

Repeat every week

Bolus or infusional 5-FU + bevacizumab

d,cc

Bevacizumab 5 mg/kg IV on Day 1

Repeat every 2 weeks

Capecitabine

23,bb

Capecitabine 850–1250 mg/m

PO twice daily for 14 days

Repeat every 3 weeks

Capecitabine + bevacizumab

24,d,cc

Bevacizumab 7.5 mg/kg IV, day 1

Repeat every 3 weeks

Irinotecan

Irinotecan 125 mg/m

IV over 30–90 minutes, days 1 and 8

Repeat every 3 weeks

25,26

or Irinotecan 180 mg/m

IV over 30–90 minutes, day 1

Repeat every 2 weeks

or Irinotecan 300–350 mg/m

IV over 30–90 minutes, day 1

Repeat every 3 weeks

Irinotecan + cetuximab (KRAS/NRAS/BRAF WT only)

Cetuximab 400 mg/m

rst infusion,followed by 250 mg/m

weekly

or Cetuximab 500 mg/m

IV over 2 hours, day 1, every 2 weeks

Irinotecan + panitumumab

14,28

(KRAS/NRAS/BRAF WT only)

Panitumumab 6 mg/kg IV over 60 minutes every 2 weeks

Irinotecan + bevacizumab

29,d,cc

Irinotecan 180 mg/m

IV, day 1

Bevacizumab 5 mg/kg IV, day 1

Repeat every 2 weeks

Irinotecan 300–350 mg/m

IV, day 1

Bevacizumab 7.5 mg/kg IV, day 1

Repeat every 3 weeks

Irinotecan + ramucirumab

Ramucirumab 8 mg/kg IV over 60 minutes every 2 weeks

Irinotecan + ziv-aibercept

Irinotecan 180 mg/m

IV, day 1

Ziv-aibercept 4 mg/kg IV, day 1

Repeat every 2 weeks

Cetuximab (KRAS/NRAS/BRAF WT only)

Cetuximab 400 mg/m

rst infusion, followed by 250 mg/m

weekly

or Cetuximab 500 mg/m

IV over 2 hours, day 1, every 2 weeks

Panitumumab

(KRAS/NRAS/BRAF WT only)

Panitumumab 6 mg/kg IV over 60 minutes every 2 weeks

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - CHEMOTHERAPY REGIMENS

Continued

References

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

COL-D

11 OF 13

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - CHEMOTHERAPY REGIMENS

Regorafenib

Regorafenib 160 mg PO daily on days 1–21

First cycle: Regorafenib 80 mg PO daily on days 1–7, followed by

120 mg PO daily on days 8–14, followed by 160 mg PO daily on days

15–21

Subsequent cycles: Regorafenib 160 mg PO daily on days 1–21

Repeat every 28 days

Triuridine + tipiracil ± bevacizumab

d, 33,34

Triuridine + tipiracil 35 mg/m

up to a maximum dose of 80 mg per

dose (based on the triuridine component)

PO twice daily days 1–5 and 8–12

Bevacizumab 5 mg/kg on days 1 and 15

Repeat every 28 days

Pembrolizumab

(dMMR/MSI-H only)

Pembrolizumab 2 mg/kg IV every 3 weeks

or Pembrolizumab 200 mg IV every 3 weeks

or Pembrolizumab 400 mg IV every 6 weeks

Nivolumab

(dMMR/MSI-H only)

Nivolumab 3 mg/kg every 2 weeks

or Nivolumab 240 mg IV every 2 weeks

or Nivolumab 480 mg IV every 4 weeks

Nivolumab + ipilimumab

(dMMR/MSI-H only)

Nivolumab 3 mg/kg (30-minute IV infusion) and ipilimumab 1 mg/kg

(30-minute IV infusion) once every 3 weeks for four doses, followed

by Nivolumab 3 mg/kg IV or nivolumab 240 mg IV every 2 weeks or

Nivolumab 480 mg IV every 4 weeks

Trastuzumab

+ pertuzumab

(HER2-amplied and RAS and BRAF WT)

Trastuzumab 8 mg/kg IV loading dose on day 1 of cycle 1,

followed by 6 mg/kg IV every 21 days

Pertuzumab 840 mg IV loading dose on day 1 of cycle 1,

followed by 420 mg IV every 21 days

Trastuzumab

+ lapatinib

(HER2-amplied and RAS and BRAF WT)

Trastuzumab 4 mg/kg IV loading dose on day 1 of cycle 1,

followed by 2 mg/kg IV weekly

Lapatinib 1000 mg PO daily

Fam-trastuzumab deruxtecan-nxki

Fam-trastuzumab deruxtecan-nxki 6.4 mg/kg IV on Day 1

Repeat every 21 days

Encorafenib + cetuximab

41-43

(BRAF V600E mutation positive)

Encorafenib 300 mg PO daily

Cetuximab 400 mg/m

followed by 250 mg/m

weekly

Encorafenib + panitumumab

41-43

(BRAF V600E mutation positive)

Encorafenib 300 mg PO daily

Panitumumab 6 mg/kg IV every 14 days

Larotrectinib

(NTRK gene fusion positive)

100 mg PO twice daily

Entrectinib

(NTRK gene fusion positive)

600 mg PO once daily

References

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

deGramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or

without oxaliplatin as first-line treatment in advanced rectal cancer. J Clin Oncol

2000;18:2938-2947.

Cheeseman SL, Joel SP, Chester JD, et al. A ‘modified de Gramont’ regimen of

fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer

2002;87:393-399.

Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose

intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion

regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol

2000;11:1477-1483.

Hochster HS, Grothey A, Hart L, et al. Improved time to treatment failure with an

intermittent oxaliplatin strategy: results of CONcePT. Ann Oncol 2014;25:1172-1178.

Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in

combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with

metastatic colorectal cancer: a multicenter phase II study. BMC Cancer 2007;7:91.

Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab

with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4

alone as first-line treatment in patients with previously untreated metastatic colorectal

cancer: the PRIME study. J Clin Oncol 2010;28:4697-4705.

Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined

with cetuximab or bevacizumab on overall survival in patients with KRAS wild-

type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA

2017;317:2392-2401.

Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-

based chemotherapy as first-line therapy in metastatic colorectal cancer: a

randomized phase III study. J Clin Oncol 2008;26:2013-2019.

Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to

bimonthly, high-dose leucovorin and bolus and continous-infusion 5-fluorouracil

(FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer 1999;35(9):1343-

Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan

plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic

colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007;25:4779-4786.

Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus

FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic

colorectal cancer (FIRE-3): a randomized, open-label, phase 3 trial. Lancet Oncol

2014;15:1065-1075.

Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab

plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med

2004;351:337-345.

Martín-Martorell P, Roselló S, Rodríguez-Braun E, et al. Biweekly cetuximab and

irinotecan in advanced colorectal cancer patients progressing after at least one

previous line of chemotherapy: results of a phase II single institution trial. Br J

Cancer 2008;99:455-458.

Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of

panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared

with FOLFIRI alone as second-line treatment in patients with metastatic colorectal

cancer. J Clin Oncol 2010;28:4706-4713.

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil,

leucovorin, and irinotecan improves survival in a phase III randomized trial in

patients with metastatic colorectal cancer previously treated with an oxaliplatin-

based regimen. J Clin Oncol 2012;30:3499-3506.

Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in

combination with second-line FOLFIRI in patients with metastatic colorectal

carcinoma that progressed during or after first-line therapy with bevacizumab,

oxaliplatin, and a fluoropyrimidine (RAISE): a randomized, double-blind, multicentre,

phase 3 study. Lancet Oncol 2015;16:499-508.

Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil,

leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional

fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for

metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol

2007;25(13):1670-1676.

Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus

FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic

colorectal cancer: updated overall survival and molecular subgroup analyses of the

open-label, phase 3 TRIBE study. Lancet Oncol 2015;16:1306-1315.

Cremolini C, Antoniotti C, Lonardi S, et al. Activity and safety of cetuximab plus

modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab

for RAS and BRAF wild-type metastatic colorectal cancer: A randomized phase 2

clinical trial. JAMA Oncol 2018;4:529-536.

Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared

with irinotecan alone as second-line treatment after single agent fluoropyrimidine

therapy for metastatic colorectal carcinoma. J Clin Oncol 2008;26:4544-4550.

Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated

fluorouracil as postoperative adjuvant therapy for primary colon cancer: results

from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol

1993;11:1879-1887.

Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose

leucovorin combined with fluorouracil in advanced colorectal cancer: results of a

randomized multicenter trial. J Clin Oncol 1996;14:2274-2279.

COL-D

12 OF 13

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - REFERENCES

Continued

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

COL-D

13 OF 13

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE - REFERENCES

Van Custem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with

intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer:

results of a large phase III study. J Clin Oncol 2001;19:4097-4106.

Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine

versus capecitabine alone in elderly patients with previously untreated metastatic

colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol

2013;14:1077-1085.

Cunningham D, Pyrhonen S, James R, et al. Randomised trial of irinotecan plus

supportive care versus supportive care alone after fluorouracil failure for patients

with metastatic colorectal cancer. The Lancet 1998;352:1413-1418.

Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan

dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol

2003;21:807-814.

Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose

escalation in metastatic colorectal cancer according to the grade of early skin

reactions: The Randomized EVEREST Study. J Clin Oncol 2012;30:2861-2868.

Andre T, Blons H, Mabro M, et al. Panitumumab combined with irinotecan for

patients with KRAS wild-type metastatic colorectal cancer refractory to standard

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Ann Oncol 2013;24:412-419.

Yildiz R, Buyukberber S, Uner A, et al. Bevacizumab plus irinotecan-based therapy

in metastatic colorectal cancer patients previously treated with oxaliplatin-based

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Van Custem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab

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chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-

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Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair

deficiency. N Engl J Med 2015;372:2509-2520.

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plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high

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Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab

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study of trastuzumab deruxtecan in patients with HER2-expressing metastatic

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cetuximab triplet therapy for patients with BRAF V600E-mutant metastatic colorectal

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BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019;381:1632-1643.

Kopetz S, Grothey A, Van Cutsem E. et al. Encorafenib plus cetuximab with or

without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-

of-life results from a randomized, three-arm, phase III study versus the choice of

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Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-

positive cancers in adults and children. N Engl J Med 2018;378:731-739.

Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or

metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase

1-2 trials. Lancet Oncol 2020;21:271-282.

NCCN Guidelines Version 2.2021

Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

General Principles

• Neoadjuvant radiation therapy with concurrent uoropyrimidine-based chemotherapy may be considered for initially unresectable or

medically inoperable non-metastatic T4 colon cancer to aid resectability.

Infusional 5-FU + RT

5-FU 225 mg/m

IV over 24 hours 5 or 7 days/week during RT

Capecitabine + RT

2,3

Capecitabine 825 mg/m

PO twice daily 5 days/week during RT

Bolus 5-FU/leucovorin + RT

1,a

5-FU 400 mg/m

IV bolus + leucovorin 20 mg/m

IV bolus for 4 days during week 1 and 5 of RT

• In patients with a limited number of liver or lung metastases, ablative radiotherapy to the metastatic site can be considered in highly

selected cases or in the setting of a clinical trial. Radiotherapy should not be used in the place of surgical resection. Radiotherapy should be

delivered in a highly conformal manner. The techniques can include 3-D conformal radiation therapy, intensity-modulated radiation therapy

(IMRT), or stereotactic body radiation therapy (SBRT).

Treatment Information

• If radiation therapy is to be used, conformal external beam radiation should be routinely used and IMRT should be reserved only for unique

clinical situations such as reirradiation of previously treated patients with recurrent disease and unique anatomical situations where

IMRT facilitates the delivery of recommended target volume doses while respecting accepted normal tissue dose-volume constraints (eg,

coverage of external iliac or inguinal lymph nodes or avoidance of small bowel).

• Consider SBRT for patients with oligometastatic disease.

• Image-guided radiation therapy (IGRT) with kilovoltage (kV) imaging or cone-beam CT imaging should be routinely used during the course of

treatment with IMRT and SBRT.

• Arterially directed catheter therapy, and in particular yttrium-90 microsphere-selective internal radiation, is an option in highly selected

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

• Intraoperative radiation therapy (IORT), if available, may be considered for patients with T4 or recurrent cancers as an additional boost.

• Target Volumes

Radiation therapy elds should include the tumor bed, which should be dened by preoperative radiologic imaging and/or surgical clips.

Radiation doses should be: 45–50 Gy in 25–28 fractions.

◊ Consider boost for close or positive margins after evaluating the cumulative dose to adjacent organs at risk.

◊ Small bowel dose should be limited to 45 Gy.

◊ Large bowel, stomach, and liver are critical structures that should be evaluated on the dose-volume histogram (DVH).

◊ Fluoropyrimidine-based chemotherapy should be delivered concurrently with radiation.

If IORT is not available, additional 10–20 Gy external beam radiation therapy and/or brachytherapy could be considered to a limited volume.

• Consider radiation treatment for T4 with penetration to a xed structure after surgery.

COL-E

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PRINCIPLES OF RADIATION AND CHEMORADIATION THERAPY

Continued

Bolus 5-FU/leucovorin/RT is an option for patients not able to tolerate capecitabine or infusional 5-FU.

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Colon Cancer

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Martenson JA Jr, Willett CG, Sargent DJ, et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical

adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004;15:3277-3283.

O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from

National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 2014;32:1927-1934.

Hofheinz R, Wenz FK, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomized, multicentre, non-

inferiority, phase 3 trial. Lancet Oncol 2012;13:579-588.

COL-E

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PRINCIPLES OF RADIATION AND CHEMORADIATION THERAPY

Supportive Care

• Female patients should be considered for vaginal dilators and instructed on the symptoms of vaginal stenosis, if applicable.

• Male patients should be counseled on sexual dysfunction and infertility risks and given information regarding sperm banking, if applicable.

• Female patients should be counseled on infertility risks and given information regarding oocyte, egg, or ovarian tissue banking prior to

treatment, if applicable.

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Colon Cancer

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

• Patient/physician discussion regarding the potential risks of therapy compared to potential benets, including prognosis. This should

include discussion of evidence supporting treatment, assumptions of benet from indirect evidence, morbidity associated with treatment,

high-risk characteristics, and patient preferences.

• When determining if adjuvant therapy should be administered, the following should be taken into consideration:

Number of lymph nodes analyzed after surgery (<12)

Poor prognostic features (eg, poorly dierentiated histology [exclusive of those that are MSI-H]; lymphatic/vascular invasion; bowel

obstruction; PNI; localized perforation; close, indeterminate, or positive margins)

Assessment of other comorbidities and anticipated life expectancy.

• The benet of adjuvant chemotherapy does not improve survival by more than 5%.

• MSI or MMR testing (see COL-B 4 of 8)

COL-F

PRINCIPLES OF RISK ASSESSMENT FOR STAGE II DISEASE

1,2,3

Benson III AB, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin

Oncol 2004;16:3408-3419.

Figueredo A, Charette ML, Maroun J, et al. Adjuvant therapy for stage II colon cancer: a systematic review from the cancer care ontario program in evidence-based

care’s gastrointestinal cancer disease site group. J Clin Oncol 2004;16:3395-3407.

Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin

Oncol 2004;22:1797-1806.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

• CAPEOX or FOLFOX is superior to 5-FU/leucovorin for patients with stage III colon cancer.

1,2

• Capecitabine appears to be equivalent to bolus 5-FU/leucovorin in patients with stage III colon cancer.

• A survival benet has not been demonstrated for the addition of oxaliplatin to 5-FU/leucovorin in stage II colon cancer.

FOLFOX is

reasonable for stage II patients with multiple high-risk factors and is not indicated for good- or average-risk patients with stage II colon

cancer.

• A benet for the addition of oxaliplatin to 5-FU/leucovorin in patients aged 70 years and older has not been proven.

• While non-inferiority of 3 months vs. 6 months of CAPEOX has not been proven, 3 months of CAPEOX numerically appeared similar to 6

months of CAPEOX for 5-year overall survival (82.1% vs. 81.2%; HR, 0.96), with considerably less toxicity.

These results support the use of

3 months of adjuvant CAPEOX over 6 months of adjuvant CAPEOX in the vast majority of patients with stage III colon cancer. In patients with

colon cancer, staged as T1–3, N1 (low-risk stage III), 3 months of CAPEOX is non-inferior to 6 months of CAPEOX for disease-free survival;

non-inferiority of 3 vs. 6 months of FOLFOX has not been proven. In patients with colon cancer staged as T4, N1–2 or T any, N2 (high-risk

stage III), 3 months of FOLFOX is inferior to 6 months of FOLFOX for disease-free survival, whereas non-inferiority of 3 vs. 6 months of

CAPEOX has not been proven. Grade 3+ neurotoxicity rates are lower for patients who receive 3 months vs. 6 months of treatment (3% vs.

16% for FOLFOX; 3% vs. 9% for CAPEOX) (Grothey A, et al. N Engl J Med 2018;378:1177-1188).

• A pooled analysis of high-risk stage II patients in the IDEA collaboration did not show non-inferiority of 3 months compared to 6 months of

adjuvant treatment. Similar to stage III, the duration of therapy was associated with a small (and not statistically signicant) dierence in

DFS between 3 and 6 months of CAPEOX. There were signicantly less grade 3–5 toxicities with 3 months versus 6 months.

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PRINCIPLES OF ADJUVANT THERAPY

See Principles of Adjuvant Therapy - Chemotherapy

Regimens and References on COL-G (2 of 2)

Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-51.

Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the

MOSAIC trail. J Clin Oncol 2009;27:3109-3116.

Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352(26):2696-2704.

Tournigand C, Andre T, Bonnetain F, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon

cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin

Oncol 2012;30:3353-3360.

André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a

prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol 2020;21:1620-1629.

Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 2018;378:1177-1188.

Iveson T, Sobrero AF, Yoshino T, et al. Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6

months {m} for patients (pts) with high-risk stage II colorectal cancer (CC) [abstract]. J Clin Oncol 2019;37:3501-3501.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

mFOLFOX 6

Oxaliplatin 85 mg/m

IV, day 1

Leucovorin 400 mg/m

IV, day 1

5-FU 400 mg/m

IV bolus on day 1, followed by 1200 mg/m

/day x 2

days (total 2400 mg/m

over 46–48 hours) continuous infusion.

Repeat every 2 weeks.

1,2,3

Capecitabine

Capecitabine 1000–1250

mg/m

PO twice daily for 14 days every 3

weeks x 24 weeks.

CAPEOX

Oxaliplatin 130 mg/m

day 1

Capecitabine 1000

mg/m

PO twice daily for 14 days every 3 weeks x

24 weeks.

5-FU/leucovorin

• Leucovorin 500 mg/m

given as a 2-hour infusion and repeated

weekly x 6. 5-FU 500 mg/m

given bolus 1 hour after the start of

leucovorin and repeated 6 x weekly. Every 8 weeks for 4 cycles.

• Simplied biweekly infusional 5-FU/LV (sLV5FU2)

Leucovorin 400

mg/m

IV day 1, followed by 5-FU bolus 400 mg/m

followed by 1200 mg/m

/day x 2 days (total 2400 mg/m

over 46–48

hours) continuous infusion. Repeat every 2 weeks.

COL-G

2 OF 2

PRINCIPLES OF ADJUVANT THERAPY - CHEMOTHERAPY REGIMENS AND REFERENCES

Footnotes

Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1 mg/m

/min. Leucovorin infusion should match infusion time of

oxaliplatin. Cercek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1 mg/m

/min. J Oncol Pract 2016;12:e548-553.

Leucovorin 400 mg/m

is the equivalent of levoleucovorin 200 mg/m

The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m

twice daily for 14 days,

repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other

fluoropyrimidines) than European patients, and may require a lower dose of capecitabine.

References

Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351.

Cheeseman SL, Joel SP, Chester JD, et al. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer

2002;87:393-399.

Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion

regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol 2000;11:1477-1483.

Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704.

Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis

in 1,864 patients. J Clin Oncol 2007;25:102-109. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as

adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-1471.

Haller DG, Catalano PJ, Macdonald JS Mayer RJ. Phase III study of fluorouracil, leucovorin and levamisole in high risk stage II and III colon cancer: final report of

Intergroup 0089. J Clin Oncol 2005:23:8671-8678.

Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continous-infusion 5-fluorouracil

(FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer 1999;35(9):1343-1347.

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Colon Cancer

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

Colorectal Cancer Surveillance

• See COL-8

• Long-term surveillance should be carefully managed with routine

good medical care and monitoring, including cancer screening,

routine health care, and preventive care.

• Routine CEA monitoring and routine CT scanning are not

recommended beyond 5 years.

Survivorship Care Planning

The oncologist and primary care provider should have dened roles

in the surveillance period, with roles communicated to patient.

• Develop survivorship care plan that includes:

Overall summary of treatment, including all surgeries, radiation

treatments, and chemotherapy received.

Description of possible expected time to resolution of acute

toxicities, long-term eects of treatment, and possible late

sequelae of treatment.

Surveillance recommendations.

Delineate appropriate timing of transfer of care with specic

responsibilities identied for primary care physician and

oncologist.

Health behavior recommendations.

Management of Late/Long-Term Sequelae of Disease or Treatment

2-6

• For issues related to distress, pain, neuropathy, fatigue, or sexual

dysfunction, see NCCN Guidelines for Survivorship.

• For chronic diarrhea or incontinence

Consider anti-diarrheal agents, bulk-forming agents, diet

manipulation, pelvic oor rehabilitation, and protective

undergarments.

• Management of an ostomy

Consider participation in an ostomy support group or coordination

of care with a health care provider specializing in ostomy care (ie,

ostomy nurse)

Screen for distress around body changes (See NCCN Guidelines

for Distress Management) and precautions around involvement

with physical activity (see page SPA-C in the NCCN Guidelines for

Survivorship).

• For oxaliplatin-induced neuropathy

Consider duloxetine for painful neuropathy only, not eective for

numbness, tingling, or cold sensitivity.

Consider non-pharmacologic therapies such as heat or

acupuncture.

Pregabalin or gabapentin are not recommended.

Counseling Regarding Healthy Lifestyle and Wellness

See NCCN Guidelines for Survivorship

• Undergo all age- and gender-appropriate cancer and preventive

health screenings as per national guidelines.

• 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). Activity

recommendations may require modication based on treatment

sequelae (ie, ostomy, neuropathy).

• Consume a healthy diet with emphasis on plant sources. Diet

recommendations may be modied based on severity of bowel

dysfunction.

• Consider daily aspirin 325 mg for secondary prevention.

• Eliminate or limit alcohol consumption, no more than 1 drink/day for

women, and 2 drinks/day for men.

• Receive smoking cessation counseling as appropriate.

Additional health monitoring and immunizations 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.

COL-H

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PRINCIPLES OF SURVIVORSHIP – Colorectal Long-term Follow-up Care

References

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Colon Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

COL-H

2 OF 2

PRINCIPLES OF SURVIVORSHIP – References

Hewitt M, Greenfield S, Stovall E. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, D.C.:The National Academies Press;2006.

Schneider EC, Malin JL, Kahn KL, et al. Surviving colorectal cancer. Cancer 2007;110:2075-82.

Sprangers MAG, Taal BG, Aaronson NK, et al. Quality of life in colorectal cancer: stoma vs. nonstoma patients. Dis Colon Rectum 1995;38:361-369.

Gami B, Harrington K, Blake P, et al. How patients manage gastrointestinal symptoms after pelvic radiotherapy. Aliment Pharmacol Ther 2003;18:987-994.

DeSnoo L, Faithfull S. A qualitative study of anterior resection syndrome: the experiences of cancer survivors who have undergone resection surgery. Eur J Cancer

2006;15:244-251.

McGough C, Baldwin C, Frost C, Andreyev HJN. Role of nutritional intervention in patients treated with radiotherapy for pelvic malignancy. Br J Cancer 2004;90:2278-

2287.

Lavoie Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral

neuropathy. JAMA 2013;309:1359-1367.

Kushi LH, Byers T, Doyle C, et al and The American Cancer Society 2006 Nutrition and Physical Activity Guidelines Advisory Committee. American Cancer Society

Guidelines on Nutrition and Physical Activity for Cancer Prevention: Reducing the Risk of Cancer With Healthy Food Choices and Physical Activity CA Cancer J Clin

2006;56:254-281.

ST-1

American Joint Committee on Cancer (AJCC) TNM Staging Classication for Colon Cancer 8th ed., 2017

Table 1. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ: intramucosal carcinoma (involvement of lamina

propria with no extension through muscularis mucosae)

T1 Tumor invades the submucosa (through the muscularis mucosa

but not into the muscularis propria)

T2 Tumor invades the muscularis propria

T3 Tumor invades through the muscularis propria into pericolorectal

tissues

T4 Tumor invades* the visceral peritoneum or invades or adheres** to

adjacent organ or structure

T4a Tumor invades* through the visceral peritoneum (including gross

perforation of the bowel through tumor and continuous invasion of

tumor through areas of inammation to the surface of the visceral

peritoneum)

T4b Tumor directly invades* or adheres** to adjacent organs or

structures

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 One to three regional lymph nodes are positive (tumor in lymph

nodes measuring ≥0.2 mm), or any number of tumor deposits are

present and all identiable lymph nodes are negative

N1a One regional lymph node is positive

N1b Two or three regional lymph nodes are positive

N1c No regional lymph nodes are positive, but there are tumor

deposits in the subserosa, mesentery, or nonperitonealized

pericolic, or perirectal/mesorectal tissues

N2 Four or more regional lymph nodes are positive

N2a Four to six regional lymph nodes are positive

N2b Seven or more regional lymph nodes are positive

M Distant Metastasis

M0 No distant metastasis by imaging, etc.; no evidence of tumor

in distant sites or organs. (This category is not assigned by

pathologists)

M1 Metastasis to one or more distant sites or organs or peritoneal

metastasis is identied

M1a Metastasis to one site or organ is identied without peritoneal

metastasis

M1b Metastasis to two or more sites or organs is identied without

peritoneal metastasis

M1c Metastasis to the peritoneal surface is identied alone or with

other site or organ metastases

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.

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

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.

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Discussion

ST-2

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

Stage IVA Any T Any N M1a

Stage IVB Any T Any N M1b

Stage IVC Any T Any N M1c

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.

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Discussion

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Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus 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.

CAT-1

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.