NCCN 359

Guidelines®
Insights
Colon Cancer

CE
NCCN Guidelines® Insights
Colon Cancer, Version 2.2018
Featured Updates to the NCCN Guidelines
Al B. Benson III, MD1,*; Alan P. Venook, MD2,*; Mahmoud M. Al-Hawary, MD3; Lynette Cederquist, MD4; Yi-Jen Chen, MD, PhD5;
Kristen K. Ciombor, MD6; Stacey Cohen, MD7,*; Harry S. Cooper, MD8; Dustin Deming, MD9; Paul F. Engstrom, MD8;
Ignacio Garrido-Laguna, MD, PhD10; Jean L. Grem, MD11; Axel Grothey, MD12; Howard S. Hochster, MD13; Sarah Hoffe, MD14;
Steven Hunt, MD15; Ahmed Kamel, MD16; Natalie Kirilcuk, MD17; Smitha Krishnamurthi, MD18; Wells A. Messersmith, MD19;
Jeffrey Meyerhardt, MD, MPH20; Eric D. Miller, MD, PhD21; Mary F. Mulcahy, MD1; James D. Murphy, MD, MS4;
Steven Nurkin, MD, MS22; Leonard Saltz, MD23; Sunil Sharma, MD10; David Shibata, MD24; John M. Skibber, MD25;
Constantinos T. Sofocleous, MD, PhD23; Elena M. Stoffel, MD, MPH3; Eden Stotsky-Himelfarb, BSN, RN26;
Christopher G. Willett, MD27; Evan Wuthrick, MD21; Kristina M. Gregory, RN, MSN, OCN28,*; and Deborah A. Freedman-Cass, PhD28,*

Abstract
The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management,
perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines
Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and
adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation–positive metastatic colorectal
cancer with regimens containing vemurafenib.

J Natl Compr Canc Netw 2018;16(4):359–369

doi: 10.6004/jnccn.2018.0021

1
Robert H. Lurie Comprehensive Cancer Center of Northwest- Please Note
ern University; 2UCSF Helen Diller Family Comprehensive Can- The NCCN Clinical Practice Guidelines in Oncology
cer Center; 3University of Michigan Comprehensive Cancer (NCCN Guidelines®) are a statement of consensus of the
Center; 4UC San Diego Moores Cancer Center; 5City of Hope authors regarding their views of currently accepted ap-
Comprehensive Cancer Center; 6Vanderbilt-Ingram Cancer
proaches to treatment. The NCCN Guidelines® Insights
Center; 7Fred Hutchinson Cancer Research Center/Seattle Can-
cer Care Alliance; 8Fox Chase Cancer Center; 9University of Wis-
highlight important changes to the NCCN Guidelines®
consin Carbone Cancer Center; 10Huntsman Cancer Institute at recommendations from previous versions. Colored
the University of Utah; 11Fred & Pamela Buffett Cancer Center; markings in the algorithm show changes and the discus-
12
Mayo Clinic Cancer Center; 13Yale Cancer Center/Smilow Can- sion aims to further the understanding of these changes
cer Hospital; 14Moffitt Cancer Center; 15Siteman Cancer Center by summarizing salient portions of the NCCN Guide-
at Barnes-Jewish Hospital and Washington University School line Panel discussion, including the literature reviewed.
of Medicine; 16University of Alabama at Birmingham Com- These NCCN Guidelines Insights do not represent
prehensive Cancer Center; 17Stanford Cancer Institute; 18Case the full NCCN Guidelines; further, the National Com-
Comprehensive Cancer Center/University Hospitals Seidman
prehensive Cancer Network® (NCCN®) makes no repre-
Cancer Center and Cleveland Clinic Taussig Cancer Institute;
sentation or warranties of any kind regarding the content,
19
University of Colorado Cancer Center; 20Dana-Farber/Brigham
& Women’s Cancer Center; 21The Ohio State University Compre-
use, or application of the NCCN Guidelines and NCCN
hensive Cancer Center - James Cancer Hospital and Solove Re- Guidelines Insights and disclaims any responsibility for
search Institute; 22Roswell Park Comprehensive Cancer Center; their applications or use in any way.
23
Memorial Sloan Kettering Cancer Center; 24St. Jude Children’s
The full and most current version of these NCCN
Research Hospital/The University of Tennessee Health Science
Center; 25The University of Texas MD Anderson Cancer Center;
Guidelines are available at NCCN.org.
26
The Sidney Kimmel Comprehensive Cancer Center at Johns © National Comprehensive Cancer Network, Inc.
Hopkins; 27Duke Cancer Institute; and 28National Comprehen- 2018, All rights reserved. The NCCN Guidelines and the
sive Cancer Network. illustrations herein may not be reproduced in any form
without the express written permission of NCCN.
*Provided content development and/or authorship assistance.

©
© JNCCN—Journal
JNCCN—Journal of
of the
the National
National Comprehensive
Comprehensive Cancer
Cancer Network 
Network  | 
|  Volume
Volume 16
16 Number 4  |
Number 4  |   April
April 2018
2018
 CE
NCCN Guidelines Insights
360

Colon Cancer, Version 2.2018

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educa- All clinicians completing this activity will be issued a certificate
tional needs of physicians, nurses, and pharmacists involved in of participation. To participate in this journal CE activity: 1) re-
the management of patients with cancer. view the educational content; 2) take the posttest with a 66%
minimum passing score and complete the evaluation at https://
Accreditation Statement NCCN education.nccn.org/node/82890; and 3) view/print certificate.

Physicians: National Comprehensive Cancer Network is accred- Pharmacists: You must complete the posttest and evaluation
ited by the Accreditation Council for Continuing Medical Educa- within 30 days of the activity. Continuing pharmacy education
tion (ACCME) to provide continuing medical education for physi- credit is reported to the CPE Monitor once you have completed
cians. the posttest and evaluation and claimed your credits. Before
NCCN designates this journal-based CE activity for a maximum completing these requirements, be sure your NCCN profile has
of 1.0 AMA PRA Category 1 Credit™. Physicians should claim been updated with your NAPB e-profile ID and date of birth.
only the credit commensurate with the extent of their partici- Your credit cannot be reported without this information. If
pation in the activity. you have any questions, please e-mail education@nccn.org.

Nurses: National Comprehensive Cancer Network is accredited Release date: April 10, 2018; Expiration date: April 10, 2019
as a provider of continuing nursing education by the American
Nurses Credentialing Center`s Commission on Accreditation. Learning Objectives:
NCCN designates this educational activity for a maximum of Upon completion of this activity, participants will be able to:
1.0 contact hour.
• Integrate into professional practice the updates to the
Pharmacists: National Comprehensive Cancer Network is NCCN Guidelines for Colon Cancer
accredited by the Accreditation Council for Pharmacy Edu-
cation as a provider of continuing pharmacy education. • Describe the rationale behind the decision-making
process for developing the NCCN Guidelines for Colon
NCCN designates this knowledge-based continuing education Cancer
activity for 1.0 contact hour (0.1 CEUs) of continuing education
credit. UAN: 0836-0000-18-004-H01-P

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN;
Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

Al B. Benson III, MD, Panel Chair, has disclosed that he receives grant/research support from Acerta Pharma; Bristol-Myers Squibb Company; Celgene
Corporation; Infinity Pharmaceuticals; MedImmune Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Taiho Parmaceuticals Co., Ltd.
He also receives consulting fees/honoraria from and serves as a scientific advisor for AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim GmbH;
Boston Biomedical; Bristol-Myers Squibb Company; Celgene Corporation; Eli Lilly and Company; EMO Serono; Exelixis Inc.; Genentech, Inc.; Guidant
Corporation; Halozyme, Inc.; Helsinn Therapeutics; ImmunoGen, Inc.; Lexicon Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Opsona
Therapeutics; Pfizer Inc.; Purdue Pharma LP; and Taiho Parmaceuticals Co., Ltd.
Alan P. Venook, MD, Panel Vice Chair, has disclosed that he serves as a scientific advisor for Bayer HealthCare; Bristol-Myers Squibb Company;
Genentech, Inc.; Merck & Co., Inc.; and Taiho Pharmaceuticals Co., Ltd. He also receives grant/research support from Genentech, Inc.,
and Merck & Co., Inc.
Stacey Cohen, MD, Panel Member, has disclosed that she has no relevant financial relationships.
Deborah A. Freedman-Cass, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.

This activity is supported by educational grants from AstraZeneca, Celldex Therapeutics, Celgene Corporation, Genentech, Jazz Pharmaceuticals, Inc.,
Novartis Pharmaceuticals Corporation, and Seattle Genetics, Inc. This activity is supported by independent educational grants from AbbVie, Merck &
Co., Inc. and NOVOCURE.

©©JNCCN—Journal
JNCCN—Journalofofthe
theNational
NationalComprehensive
ComprehensiveCancer
CancerNetwork 
Network | | Volume
Volume16 Number4 4 ||
16 Number   April2018
  April 2018
 CE
NCCN Guidelines Insights
361

Colon Cancer, Version 2.2018

PATHOLOGIC STAGEe ADJUVANT TREATMENTb,r

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

T3, N0, M0k (MSI-H or dMMR) Observation
Observation
T3, N0, M0k,l (MSI-L or MSS or
and no high-risk features) Consider capecitabinen or 5-FU/leucovorinn
Capecitabinen,o or 5-FU/leucovorinn,o
T3, N0, M0 at high risk for or
systemic recurrencel,m FOLFOXn,o,p,q or CAPEOXn,o,p,q
or T4, N0, M0 or
Observation

Preferred: See Surveillance (COL-8)

• CAPEOX (3 mo)n,q
T1-3, N1 or
(Low-risk stage III) • FOLFOX (3–6 mo)n,q (category 1 for 6 mo)
or
Other options include: Capecitabine (6 mo)n or 5-FU (6 mo)n
Preferred:
• CAPEOX (3–6 mo)n,o,q (category 1 for 6 mo)
T4, N1-2; T Any, N2 or
(High-risk stage III) • FOLFOX (6 mo)n,o,q (category 1)
or
Other options include: Capecitabine (6 mo)n,o or 5-FU (6 mo)n,o
bSee Principles of Imaging (COL-A). pA survival benefit has not been demonstrated for the addition of oxaliplatin to
eSee Principles of Pathologic Review (COL-B). 5-FU/leucovorin in stage II colon cancer. Tournigand C, et al. J Clin Oncol 2012;
kSee Principles of Risk Assessment for Stage II Disease (COL-F). published online ahead of print on August 20, 2012.
lHigh-risk factors for recurrence: poorly differentiated histology (exclusiveof those qA benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients age 70 and
cancers that are MSI-H), lymphatic/vascular invasion, bowel obstruction, <12 older has not been proven.
lymph nodes examined, perineural invasion, localized perforation, or close, rIn patients staged as T1-3, N1 (low-risk stage III), 3 months of CapeOX is non-
indeterminate, or positive margins. In high-risk stage II patients, there are no data inferior to 6 months of CapeOX for disease-free survival; non-inferiority of 3 vs.
that correlate risk features and selection of chemotherapy. 6 months of FOLFOX has not been proven. In patients staged as T4, N1-2 or
mThere are insufficient data to recommend the use of multi-gene assay panels to T any, N2 (high-risk stage III), 3 months of FOLFOX is inferior to 6 months of
determine adjuvant therapy. FOLFOX for disease-free survival, whereas non-inferiority of 3 vs. 6 months of
nSee Principles of Adjuvant Therapy (COL-G). CapeOX has not been proven. Grade 3+ neurotoxicity rates are lower for patients
oConsider RT for T4 with penetration to a fixed structure. who receive 3 months vs. 6 months of treatment (3% vs. 16% for FOLFOX; 3%
See Principles of Radiation Therapy (COL-E). vs. 9% for CapeOX). Shi Q, et al. J Clin Oncol 2017;35 (suppl):LBA1.

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any
form without the express written permission of NCCN®.
COL-3

Overview
NCCN Categories of Evidence and Consensus
Colorectal cancer (CRC) is the fourth most fre-
Category 1: Based upon high-level evidence, there
quently diagnosed cancer and the second leading
is uniform NCCN consensus that the intervention cause of cancer death in the United States. In 2018,
is appropriate. an estimated 97,220 new cases of colon cancer and
approximately 43,030 cases of rectal cancer will
Category 2A: Based upon lower-level evidence, there
is uniform NCCN consensus that the intervention is
be diagnosed. During the same year, an estimated
appropriate. 50,630 people will die of colon and rectal cancers
combined.1 The incidence of CRC has been declin-
Category 2B: Based upon lower-level evidence, there
ing; incidence per 100,000 people decreased from
is NCCN consensus that the intervention is appro-
priate.
60.5 in 1976 to 46.4 in 2005, and to 40.7 in 2009–
2013.2,3 In fact, the incidence of CRC decreased at
Category 3: Based upon any level of evidence, there a rate of approximately 3% per year between 2003–
is major NCCN disagreement that the intervention
2012.4 In addition, mortality from CRC decreased
is appropriate.
by almost 35% from 1990–2007,5 and is currently
All recommendations are category 2A unless otherwise reduced by 51% from peak mortality rates—from
noted. 28.6 per 100,000 in 1976 to 14.1 in 2014.3 These im-
Clinical trials: NCCN believes that the best management provements in incidence of and mortality from CRC
for any patient with cancer is in a clinical trial. Participa- are thought to be a result of shifting patterns of CRC
tion in clinical trials is especially encouraged. risk factors, cancer prevention and earlier diagnosis
through screening, and better treatment modalities.6

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
362

Colon Cancer, Version 2.2018

UNRESECTABLE PRIMARY TREATMENT ADJUVANT TREATMENTb

METACHRONOUS (6 MO PERIOPERATIVE
METASTASES TREATMENT PREFERRED)
(FOLFIRI or irinotecan) ±
(bevacizumab [preferred]
or ziv-aflibercept
or ramucirumab)ff
or Systemic therapy
(FOLFIRI or irinotecan) ± ± biologic
• Previous adjuvant (cetuximab or panitumumab) therapy (COL-D) See
FOLFOX/CAPEOX (KRAS/NRAS WT gene only)e,gg Converted to
Re-evaluate for resectable Resectiont (category 2B for Surveillance
within past 12 or biologic therapy) (COL-8)
conversion to
months (Nivolumab or pembrolizumab) or
resectableb,g
(dMMR/MSI-H only) Observation
every 2 mo if
or
conversion to
(Irinotecan + [cetuximab or
resectability is
panitumumab] + vemurafenib
a reasonable
[BRAF V600E mutation
goal Remains Systemic therapy
positive])gg
unresectable (COL-D)

• Previous adjuvant
FOLFOX/CAPEOX
>12 months Systemic therapy
• Previous 5-FU/LV (COL-D)
or capecitabine
• No previous
chemotherapy

bSee Principles of Imaging (COL-A).

eSee Principles of Pathologic Review (COL-B 4 of 5) - KRAS, NRAS, and BRAF Mutation Testing.
gSee Principles of Surgery (COL-C 2 of 3).
tHepatic 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.
ffBevacizumab is the preferred anti-angiogenic agent based on toxicity and/or cost.
ggBRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor.

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any
form without the express written permission of NCCN®.
COL-11

Despite the observed improvements in the over- Risk Stratification and Adjuvant Treatment for
all CRC incidence rate, its incidence in patients Stage III Colon Cancer
aged <50 years has been increasing.3,7 In 2017, ap- Nonmetastatic colon cancer is generally treated with
proximately 7,550 cases of CRC were diagnosed in curative intent by colectomy and, in some cases, ad-
this population.3 In a retrospective cohort study of juvant chemotherapy.10 Population and institutional
the SEER CRC registry, it was estimated that the studies have shown that adjuvant therapy may con-
incidence rates for colon and rectal cancers in pa- fer a survival advantage in some patients with resect-
tients aged 20 to 34 years will increase by 90.0% and ed colon cancer (eg, those with stage III or high-risk
124.2%, respectively, by 2030.7 The cause of this stage II disease).11–14 Furthermore, randomized con-
trend is currently unknown. trolled trials have shown that the addition of oxali-
platin to these adjuvant regimens benefits some pa-
tients.15–19 However, adjuvant treatment, especially
2018 Updates to the NCCN Guidelines with regimens containing oxaliplatin, is associated
for Colon Cancer with considerable toxicity (notably chemotherapy-
During the meeting to update the guidelines for induced peripheral neuropathy),16,20 and not all pa-
2018, the panel discussed many issues. Most notable tients derive benefit. Consideration of disease stage
were the results of the IDEA collaboration and their and pathologic features, microsatellite instability
impact on adjuvant treatment in patients with stage (MSI) status, possible efficacy and toxicity profiles
III colon cancer,8 and results of the SWOG S1406 associated with treatment choice, and patient age,
trial and their impact on treatment of patients with comorbidities, and preferences aid in decision-mak-
BRAF-mutant metastases.9 ing regarding the use of adjuvant therapy for patients

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
363

Colon Cancer, Version 2.2018

PRINCIPLES OF PATHOLOGIC REVIEW

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.
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.43,44,45 BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF
inhibitor.46-48
• Testing for KRAS, NRAS, and BRAF mutations should be performed only in laboratories that are certified under the clinical laboratory
improvement amendments of 1988 (CLIA-88) as qualified to perform high-complexity clinical laboratory (molecular pathology) testing. No
specific methodology is recommended (eg, sequencing, hybridization).
• The testing can be performed on formalin-fixed paraffin-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.49

Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing

• Universal MMR* or MSI* testing is recommended in all patients with a personal history of colon or rectal 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.
• Stage II MSI-H patients may have a good prognosis and do not benefit from 5-FU adjuvant therapy.50
• MMR or MSI testing should be performed only in CLIA-approved laboratories.
• Testing for MSI may be accomplished with a validated NGS panel, especially in patients with metastatic disease who require genotyping of
RAS and BRAF.

See Endoscopically Removed Malignant Polyps and Colon Cancer Appropriate for Resection on COL-B 1 of 5
See Pathologic Stage on COL-B 2 of 5
See Lymph Node Evaluation on COL-B 3 of 5

*IHC for MMR and DNA analysis for MSI are different assays measuring the same biological effect. See references on COL-B 5 of 5
(available at NCCN.org)

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any COL-B
form without the express written permission of NCCN®.
4 OF 5

with colon cancer.21–25 Better risk stratification could of grades 2 and 3/4 diarrhea were also lower with the
improve adjuvant treatment selection to help pa- shorter duration of therapy (P<.0001 for FOLFOX;
tients avoid unnecessary toxicities without compro- P=.01 for CapeOX). The primary end point of 3-year
mising outcomes. disease-free survival (DFS) did not meet the pre-
The IDEA collaboration investigated whether specified cutoff for noninferiority, despite the small
a shortened duration of adjuvant therapy would be absolute difference of 0.9% (74.6% for 3 months vs
a feasible way to avoid or lessen toxicities associ- 75.5% for 6 months; hazard ratio [HR], 1.07; 95%
ated with oxaliplatin-containing adjuvant therapy CI, 1.00–1.15), which is of questionable clinical sig-
in some patients with locoregional colon cancer,
nificance. Notable differences in 3-year DFS were
without impairing oncologic outcomes. IDEA in-
seen between FOLFOX and CapeOX and between
cluded >12,000 patients in an international effort
patients with T1–3N1 (low-risk) versus T4 or N2
that pooled data from 6 concurrently conducted ran-
(high-risk) disease. Specifically, in the T1–3N1 sub-
domized phase III trials to assess the noninferiority
of 3 months compared with 6 months of adjuvant set, DFS with 3 months of CapeOX was noninferior
FOLFOX or CapeOX in patients with stage III colon to that with 6 months of CapeOX (HR, 0.85; 95%
cancer.8 Median follow-up was 39 months. Impor- CI, 0.71–1.01), whereas noninferiority could not be
tantly, grade ≥3 neurotoxicity rates were lower in the proven for 3 versus 6 months of FOLFOX (HR, 1.10;
3 months’ versus 6 months’ treatment arms (3% vs 95% CI, 0.96–1.26). In the T4 or N2 subset, DFS
16% for FOLFOX; 3% vs 9% for CapeOX; P<.0001), with 3 months of FOLFOX was inferior to that of
as were grade 2 neurotoxicity rates (14% vs 32% for 6 months with FOLFOX (HR, 1.20; 95% CI, 1.07–
FOLFOX; 12% vs 36% for CapeOX; P<.0001). Rates 1.35), whereas noninferiority could not be proven

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
364

Colon Cancer, Version 2.2018

CONTINUUM OF CARE - SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE1

SUBSEQUENT THERAPY2
Irinotecan6 + (cetuximab or Regorafenib12
FOLFIRI6 or irinotecan6 panitumumab)*3,4,11 or
or (KRAS/NRAS WT only) Trifluridine + tipiracil12
FOLFIRI6 + (bevacizumab9 [preferred] or or
ziv-aflibercept9,10 or ramucirumab9,10) Regorafenib12
or or
Irinotecan6 + (bevacizumab9 [preferred] or Trifluridine + tipiracil12
ziv-aflibercept9,10 or ramucirumab9,10) or
(Nivolumab or pembrolizumab)* Regorafenib**12
(dMMR/MSI-H only) or
or Trifluridine + tipiracil**12
Previous
oxaliplatin- or
FOLFIRI6 + (cetuximab or See Subsequent therapy Best supportive care
based therapy panitumumab)*3,4,11 (KRAS/NRAS WT only)
without or
irinotecan Irinotecan6 + (cetuximab or Regorafenib12
panitumumab)*3,4,11 (KRAS/NRAS WT only) or
or Trifluridine + tipiracil12
Irinotecan6 + (cetuximab or panitumumab)*3 or
+ vemurafenib (BRAF V600E mutation (Nivolumab or pembrolizumab)*
positive) (dMMR/MSI-H only)
or
See Subsequent therapy
(Nivolumab or pembrolizumab)*
(dMMR/MSI-H only) See Subsequent therapy

*if neither previously given

**if not previously given See footnotes COL-D 6 of 10
(available at NCCN.org)

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any COL-D
form without the express written permission of NCCN®.
2 OF 10

for 3 versus 6 months of CapeOX (HR, 1.02; 95% the CapeOX and FOLFOX arms (percent reaching
CI, 0.89–1.17). planned last cycle was 90% for 3-month FOLFOX,
The panel discussed several details of the trial 86% for 3-month CapeOX, 71% for 6-month FOLF-
and how they believed the results should be translat- OX, and 65% for 6-month CapeOX), and therefore
ed into guideline recommendations. First, the pan- compliance is unlikely to account for the differences
el discussed what might account for the unexpect- between the regimens. Importantly, the panel noted
ed differences seen in DFS between FOLFOX and that no significant differences have been seen be-
CapeOX. Oxaliplatin doses are different between tween CapeOX and FOLFOX in randomized adju-
the regimens (85 mg/m² every 2 weeks for mFOLF- vant or metastatic studies.26,27 Therefore, the panel
OX6; 130 mg/m² every 3 weeks for CapeOX), which discussed the possibility that selection bias may ac-
might partially account for the observed difference count for the difference in DFS seen between FOLF-
in outcomes. Although total oxaliplatin exposure OX and CapeOX in IDEA. The use of FOLFOX
is similar, more oxaliplatin is received in the first 4 versus CapeOX was by physician’s choice, not by
weeks with CapeOX (260 mg/m2) compared with randomization; choice of regimen was used as a strat-
FOLFOX (170 mg/m2). Also, the panel noted that ification factor for randomization to 3 or 6 months of
capecitabine may result in more continuous fluoro- treatment duration. The proportion of patients treat-
uracil exposure than 5-FU/leucovorin. One panel ed with CapeOX varied from 0% to 75% between
member noted that some sites used FOLFOX4; how- trial sites.8 In the US/Canadian study that used only
ever, panel consensus was that this difference would mFOLFOX6, in fact, 3 months of FOLFOX achieved
only account for differences in toxicity, not in ef- noninferiority to 6 months of FOLFOX, with an HR
ficacy. Treatment compliance was similar between for DFS of 1.10. However, in the French trial,8 most

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
365

Colon Cancer, Version 2.2018

patients (90%) received FOLFOX, and the HR for United States, routinely reduce the starting dose of
DFS between 3 and 6 months of FOLFOX was the capecitabine, but the panel strongly believes that
worst of all trial sites at 1.27. Though the reasons the starting dose used in IDEA8 (1,000 mg/m2 twice
for the different outcomes based on regimen choice daily) should be used because it is the only validat-
are not completely clear, the panel agreed that the ed dose. The panel also discussed that, in practice,
data are convincing and that the difference cannot oxaliplatin is dropped from FOLFOX and CapeOX
be ignored. after 6 to 10 doses to reduce the risk of severe neu-
Another point that the NCCN Panel discussed rotoxicity. Therefore, it may be reasonable to com-
was whether DFS data formed a sufficient basis for plete 3 months of CapeOX for patients with high-
guideline recommendations. The panel was unified risk stage III colon cancer and then drop oxaliplatin
in its opinion that, although DFS effects have been
and continue capecitabine. However, the panel was
shown to be larger than overall survival (OS) effects
divided on whether to recommend this approach.
in other trials, the almost complete elimination of
Because of the methodologies and results of
oxaliplatin toxicity with a shorter treatment dura-
IDEA, some of the findings are open to interpreta-
tion justified changes to the guidelines at this time.
The data were sufficient to warrant division of tion. However, it will be difficult to generate data
stage III colon cancer into a low-risk (T1–3N1) and that are any more definitive than those from the
a high-risk group (T4N1–2 or TanyN2; see COL-3, IDEA analysis. Therefore, the NCCN Guidelines
page 361. For the low-risk group, the recommended list FOLFOX and CapeOX as equally preferred op-
duration of adjuvant therapy is 3 months if CapeOX tions without strongly recommending one over the
is chosen, because noninferiority for DFS was proven other. Efficacy is similar, FOLFOX is less expensive
in IDEA and patients should be spared the increased for US patients, and CapeOX is more convenient
toxicity, cost, and inconvenience of longer therapy. for most patients (especially 3 months of CapeOX
If FOLFOX is chosen for these patients, then 3 to vs 6 months of FOLFOX). Both regimens are pre-
6 months of FOLFOX is recommended. The panel ferred over the other options for adjuvant treatment
believes the shorter duration can be considered to of patients with stage III colon cancer—6 months of
reduce toxicity, cost, and inconvenience, but nonin- either capecitabine or 5-FU/leucovorin—which are
feriority could not be proven for 3 versus 6 months generally only recommended for patients with stage
of FOLFOX in this subset. For patients with high- III colon cancer if they cannot tolerate oxaliplatin.
risk stage III colon cancer, 3 to 6 months of adju- Despite the large number of patients in IDEA,
vant therapy is recommended if CapeOX is chosen; the results were not as definitive as the panel would
noninferiority of the shorter duration was not prov- require for these new recommendations to be listed
en in this subset of patients, but the panel believes as category 1. Therefore, these shorter durations are
the shorter duration can be considered to minimize included in the guidelines as category 2A recom-
toxicity, cost, and inconvenience. Furthermore, DFS
mendations. The 6-month durations of FOLFOX or
with 3 months of therapy was noninferior to DFS
CapeOX for patients with stage III colon cancer re-
with 6 months for the entire cohort (TanyN1–2)
main as category 1 recommendations based on older
who received CapeOX (HR, 0.95; 95% CI, 0.85–
trials.15–19
1.06).8 Finally, FOLFOX, if chosen, should be given
for a full 6 months in the high-risk group because Finally, the panel also briefly discussed the lim-
3 months was shown to be inferior to 6 months for ited data from IDEA on stage II colon cancer or stage
DFS. With these updated and nuanced recommen- II/III rectal cancer. Only one site included patients
dations, careful discussion and review of the avail- with rectal cancer, none of whom had preoperative
able data between the patient and clinician are im- chemotherapy, and only 2 sites included patients
portant to guide the choice of approach. with stage II colon cancer, one of which included
The panel then discussed some concerns about mostly those with high-risk stage II. Overall, the
the dosing of capecitabine in CapeOX, which they panel believed there are not enough data from IDEA
believe is critical if the decision is to give 3 months to draw any conclusions for patients with rectal or
of CapeOX. Many oncologists, especially in the stage II colon cancer.

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
366

Colon Cancer, Version 2.2018

Treatment of RAS Wild-Type/BRAF BRAF and EGFR inhibition may improve antitumor
Mutation–Positive Metastatic CRC activity.44,45
In the 2017 version of the NCCN Guidelines, pa- The combination of vemurafenib, cetuximab,
tients with unresectable, advanced, or metastatic and irinotecan was thus tested in patients with
CRC (mCRC) were managed with a continuum of BRAF V600E–mutated mCRC in the recent phase
care that included 20 first-line systemic treatment II SWOG S1406 trial. In this trial, 99 patients with
options, 33 second-line options, and 13 options for BRAF-mutant, RAS wild-type tumors who received
subsequent therapies in up to 7 lines of treatment.28,29 1 or 2 prior regimens were randomized to irinote-
A growing list of factors are considered when choos- can and cetuximab with or without vemurafenib.9
ing therapies for each patient, including the goals The NCCN Panel reviewed updated results of this
of treatment, type and timing of prior therapy, dif- trial that were presented at the 2017 ASCO annual
ferent efficacy and toxicity profiles of the regimens, meeting. The primary end point of median progres-
KRAS and NRAS mutational tumor status, and pa- sion-free survival (PFS) was improved in the vemu-
tient comorbidities and preferences. MSI status and rafenib arm (4.3 vs 2.0 months; HR, 0.48; 95% CI,
location of the primary tumor were recently added 0.31–0.75; P=.001). Response was also improved,
as additional considerations.30–34 Although survival with response rates (only partial responses [PRs]
for patients with advanced CRC has improved dra- were seen) of 4% vs 16% (P=.08) and disease con-
matically over the past decades, the most recently trol rates (partial responses + stable disease) of 22%
reported 5-year survival rate for patients with stage vs 67% (P=.001). Grade 3/4 adverse events (AEs)
IV CRC was only 14%.1,35 Moreover, patients with that were higher in the vemurafenib arm included
BRAF-mutated mCRC have a particularly poor neutropenia (33% vs 7%), anemia (13% vs 0%), and
prognosis. BRAF V600E mutations are present in nausea (20% vs 2%). Crossover was allowed for the
approximately 8% of mCRC cases and are associ- cetuximab/irinotecan group, and 48% of those pa-
ated with a more aggressive biology, shorter OS, and tients received vemurafenib at time of progression.
decreased response to chemotherapy compared with Of those who crossed over, the partial response rate
BRAF wild-type tumors.36 Thus, additional treat- was 17% and the stable disease rate was 55%, for a
ment options are still needed in mCRC, especially disease control rate of 72%. The HR for the second-
for the BRAF mutation–positive subset of patients. ary end point of OS, which would be attenuated by
BRAF is downstream of EGFR and RAS in the the crossover, was 0.73 (95% CI, 0.45–1.17; P=.19).
MAPK signaling pathway. The BRAF V600E mu- After the panel reviewed these data, one mem-
tation results in constitutive MAPK signaling that ber pointed out that results of the safety lead-in
encourages cellular proliferation.37 Vemurafenib se- phase of the BEACON CRC trial (ClinicalTrials.
lectively inhibits the V600E-mutated form of the gov Identifier: NCT02928224) were to be present-
BRAF kinase, thereby reducing aberrant MAPK sig- ed at the ESMO 2017 Congress. This international
naling.38 It has an FDA indication for treatment of phase III trial is comparing (1) encorafenib with ce-
patients with BRAF V600E–mutated, unresectable, tuximab plus or minus binimetinib versus (2) inves-
or metastatic melanoma.39 However, vemurafenib tigator choice of irinotecan/cetuximab or FOLFIRI/
monotherapy has shown limited activity in mCRC.40 cetuximab in patients with BRAF V600E–mutant
Preclinical data suggest that BRAF V600E inhibi- mCRC whose disease has progressed on 1 or 2 prior
tion alone is ineffective because feedback activation metastatic regimens. Encorafenib is another inhibi-
of EGFR occurs.41,42 Therefore, blockage of EGFR tor of mutant BRAF, and binimetinib inhibits MEK,
and BRAF V600E together has been speculated to be which is downstream from BRAF in the MAPK
more effective than BRAF V600E inhibition alone. pathway.37,46 The combination of these 2 drugs has
In fact, preclinical studies show a synergistic effect been shown to improve PFS in BRAF-mutant mela-
of such dual inhibition.41,42 However, vemurafenib noma compared with encorafenib monotherapy.47
in combination with cetuximab- or panitumumab- Although the BEACON CRC data had not been
based therapy has been ineffective in early clinical presented at the time of panel discussion, several
trials.43 Results from preclinical and early clinical panel members were aware that the results would be
studies suggest that the addition of irinotecan to better than those seen in SWOG S1406. In fact, the

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
367

Colon Cancer, Version 2.2018

now-presented data show that the triplet regimen believe that dabrafenib and vemurafenib are inter-
(encorafenib/cetuximab/binimetinib) was fairly well changeable. Dabrafenib was studied in patients with
tolerated in 30 patients, with dose-limiting toxici- BRAF V600E–mutant mCRC in a case report and
ties in 5 patients (cetuximab infusion reaction, n=2; a few early clinical trials.51–54 The largest was a sin-
grade 2 retinopathy, n=2; grade 2 decreased ejection gle-arm trial that included 43 patients with BRAF
fraction, n=1). Of the 30 patients, 19 (63%) expe- V600E–mutant mCRC who received dabrafenib
rienced a grade 3 or 4 AE, including fatigue (grade with trametinib.51 Trametinib is another MEK in-
3 in 4 patients), urinary tract infection (grade 3 in hibitor with an FDA indication in BRAF-mutated
3 patients), increased aspartate aminotransferase melanoma and non–small cell lung cancer in com-
(grade 3 in 2 patients; grade 4 in 1 patient), and in- bination with dabrafenib.55 The complete response
creased blood creatine phosphokinase (grade 3 in rate was 2% (1 patient), partial response rate was
3 patients). The most common AEs of any grade 9% (4 patients), and stable disease rate was 56%
were diarrhea (77%), dermatitis acneiform (67%), (24 patients). Grade 3 AEs occurred in 58% of pa-
nausea (63%), and fatigue (63%).48,49 In 29 patients tients, with nausea, pyrexia, and fatigue being the
with BRAF V600E–mutated mCRC, the overall re- most common events of any grade. Four patients
sponse rate (3 complete responses + 11 partial re- (9%) discontinued treatment because of AEs. To the
sponses) was 48%. All remaining patients had stable best of the panel’s knowledge, however, dabrafenib
disease, for a disease control rate of 100%. The pre- has not been studied in combination with irinote-
liminary estimated median PFS was 8 months. One can or an EGFR inhibitor, and therefore no safety
panel member reasoned that vemurafenib/cetux- data for the proposed combination exist. Therefore,
imab/irinotecan should not be added based on the
the panel declined to add dabrafenib/(cetuximab or
SWOG S1406 results, but rather the panel should
panitumumab)/irinotecan to the continuum of care
wait for BEACON CRC results and FDA approval
for patients with BRAF-mutant mCRC. The panel
of encorafenib and binimetinib. Although the panel
noted that trametinib/dabrafenib/panitumumab is
members eagerly await more mature data from BEA-
currently being studied in an open-label phase I/II
CON CRC and forthcoming FDA approvals, the
trial of patients with BRAF V600E–mutated mCRC
vast majority of the panel felt that the data from
(ClinicalTrials.gov identifier: NCT01750918).
SWOG S1406 were strong enough to warrant the
Overall, the panel is gratified by the addition
addition of vemurafenib/cetuximab/irinotecan for
patients with BRAF V600E–mutated mCRC at this of new treatment options for patients with BRAF-
time. They believed that this subset of patients is in mutated mCRC that has progressed on 1 or 2 previ-
great need of additional treatment options and saw ous metastatic regimens (see COL-11 and COL-D 2
no justification for waiting for better regimens. of 10, pages 362 and 364, respectively, as examples).
The panel then discussed whether to recommend They are hopeful that ongoing trials will lead to
vemurafenib/panitumumab/irinotecan for these pa- even better options for this difficult-to-treat subset
tients by extrapolation from the SWOG S1406 data. of patients. With the addition of vemurafenib/(ce-
In general, the panel believes that panitumumab tuximab or panitumumab)/irinotecan to the mCRC
and cetuximab are interchangeable, and some clin- continuum of care, the BRAF status of the tumor is
ic formularies may only list one or the other agent. now another factor that must be considered when
Furthermore, panel members pointed out that some choosing therapies for patients with mCRC. BRAF
patients may experience a severe reaction to cetux- status can be determined using any methodology, in-
imab. Safety of vemurafenib/panitumumab/irinote- cluding next-generation sequencing, which can be
can has been shown in a case report of a patient with used to simultaneously test for MSI and mutations
BRAF-mutant cholangiocarcinoma.50 Therefore, the in RAS (COL-B 4 of 5, page 363). The panel fur-
panel voted to add this regimen as an additional op- ther notes that BRAF and RAS mutations are mu-
tion for patients with BRAF V600E–mutant mCRC. tually exclusive. Therefore, although the guidelines
Next, the panel discussed whether dabrafenib only indicate that the new regimens are for “BRAF
could be substituted for vemurafenib by extrapola- V600E mutation–positive” disease, these patients’
tion of SWOG S1406 data. However, they do not tumors contain wild-type RAS.

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
368

Colon Cancer, Version 2.2018

Conclusions mCRC, data from the SWOG S1406 trial has led to
Personalizing treatment allows patients to maximize new treatment options specifically for patients with
benefits while minimizing harms, thus providing op- BRAF V600E–mutated tumors. These patients have
timal survival and quality of life. In stage III colon derived little benefit from EGFR-targeted agents in
cancer, data from the IDEA trial have led to more the past and have had poor prognoses. The addi-
refined risk stratification that allows some patients to
tion of an inhibitor of the specific BRAF mutation
opt for a shorter duration of adjuvant therapy. Thus,
they can be spared the associated toxicity, cost, provides additional treatment options that include
and inconvenience of longer adjuvant treatment EGFR inhibitors and gives these patients a chance
without jeopardizing their oncologic outcomes. In for delayed disease progression.

References 18. 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
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin safety analysis in 1,864 patients. J Clin Oncol 2007;25:102–109.
2018;68:7–30. 19. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with
2. Cheng L, Eng C, Nieman LZ, et al. Trends in colorectal cancer incidence weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy
by anatomic site and disease stage in the United States from 1976 to 2005. for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol
Am J Clin Oncol 2011;34:573–580. 2007;25:2198–2204.
3. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. 20. Andre T, Boni C, Navarro M, et al. Improved overall survival with
CA Cancer J Clin 2017;67:177–193. oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or
4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–3116.
2016;66:7–30. 21. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a
5. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy
of eliminating socioeconomic and racial disparities on premature cancer in colon cancer. J Clin Oncol 2010;28:3219–3226.
deaths. CA Cancer J Clin 2011;61:212–236. 22. Kim JE, Hong YS, Kim HJ, et al. Defective mismatch repair status was not
6. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the associated with DFS and OS in stage II colon cancer treated with adjuvant
status of cancer, 1975-2006, featuring colorectal cancer trends and impact chemotherapy. Ann Surg Oncol 2015;22(Suppl 3):S630–637.
of interventions (risk factors, screening, and treatment) to reduce future 23. McCleary NJ, Meyerhardt JA, Green E, et al. Impact of age on the efficacy
rates. Cancer 2010;116:544–573. of newer adjuvant therapies in patients with stage II/III colon cancer:
7. Bailey CE, Hu CY, You YN, et al. Increasing disparities in the age-related findings from the ACCENT database. J Clin Oncol 2013;31:2600–2606.
incidences of colon and rectal cancers in the United States, 1975-2010. 24. Yothers G, O’Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant
JAMA Surg 2015;150:17–22. therapy for colon cancer: updated results of NSABP C-07 trial, including
8. Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six survival and subset analyses. J Clin Oncol 2011;29:3768–3774.
phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based 25. Tournigand C, Andre T, Bonnetain F, et al. Adjuvant therapy with
therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): fluorouracil and oxaliplatin in stage II and elderly patients (between ages
the IDEA (International Duration Evaluation of Adjuvant chemotherapy) 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter
collaboration [abstract]. J Clin Oncol 2017;35(Suppl):Abstract LBA1. International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the
9. Kopetz S, McDonough SL, Lenz HJ, et al. Randomized trial of irinotecan Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 2012;30:3353–
and cetuximab with or without vemurafenib in BRAF-mutant 3360.
metastatic colorectal cancer (SWOG S1406) [abstract]. J Clin Oncol 26. Pectasides D, Karavasilis V, Papaxoinis G, et al. Randomized phase III
2017;35(Suppl):Abstract 3505. clinical trial comparing the combination of capecitabine and oxaliplatin
10. Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Guidelines for (CAPOX) with the combination of 5-fluorouracil, leucovorin and
Colon Cancer. Version 2.2018. Accessed March 17, 2018. To view the oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with
most recent version of these guidelines, visit NCCN.org. operated high-risk stage II or stage III colorectal cancer. BMC Cancer
11. Boland GM, Chang GJ, Haynes AB, et al. Association between adherence 2015;15:384.
to National Comprehensive Cancer Network treatment guidelines and 27. Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of
improved survival in patients with colon cancer. Cancer 2013;119:1593– capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus
1601. oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin
12. Booth CM, Nanji S, Wei X, et al. Use and effectiveness of adjuvant Oncol 2008;26:2006–2012.
chemotherapy for stage III colon cancer: a population-based study. J Natl 28. Benson AB III, Venook AP, Cederquist L, et al. NCCN Guidelines for
Compr Canc Netw 2016;14:47–56. Colon Cancer. Version 2.2017. Accessed June 26, 2017. To view the most
13. Casadaban L, Rauscher G, Aklilu M, et al. Adjuvant chemotherapy is recent version of these guidelines, visit NCCN.org.
associated with improved survival in patients with stage II colon cancer. 29. Benson AB III, Venook AP, Cederquist L, et al. NCCN Guidelines for
Cancer 2016;122:3277–3287. Rectal Cancer. Version 3.2017. Accessed July 21, 2017. To view the most
14. Hines RB, Barrett A, Twumasi-Ankrah P, et al. Predictors of guideline recent version of these guidelines, visit NCCN.org.
treatment nonadherence and the impact on survival in patients with 30. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-
colorectal cancer. J Natl Compr Canc Netw 2015;13:51–60. repair deficiency. N Engl J Med 2015;372:2509–2520.
15. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, 31. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit
and leucovorin as adjuvant treatment for colon cancer. N Engl J Med with nivolumab plus ipilimumab in DNA mismatch repair-deficient/
2004;350:2343–2351. microsatellite instability-high metastatic colorectal cancer. J Clin Oncol
16. Andre T, de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, 2018;36:773–779.
leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year 32. Moretto R, Cremolini C, Rossini D, et al. Location of primary tumor and
survival and outcomes according to BRAF mutation and mismatch repair benefit from anti-epidermal growth factor receptor monoclonal antibodies
status of the MOSAIC study. J Clin Oncol 2015;33:4176–4187. in patients with RAS and BRAF wild-type metastatic colorectal cancer.
17. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin Oncologist 2016;21:988–994.
compared with fluorouracil and folinic acid as adjuvant therapy for stage 33. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive
III colon cancer. J Clin Oncol 2011;29:1465–1471. relevance of primary tumor location in patients with RAS wild-type

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018
 CE
NCCN Guidelines Insights
369

Colon Cancer, Version 2.2018

metastatic colorectal cancer: retrospective analyses of the CRYSTAL and metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov
FIRE-3 trials [published online October 10, 2016]. JAMA Oncol, doi: 2016;6:1352–1365.
10.1001/jamaoncol.2016.3797 46. Sullivan R, LoRusso P, Boerner S, Dummer R. Achievements and
34. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) challenges of molecular targeted therapy in melanoma. Am Soc Clin
tumor location on overall survival (OS) and progression free survival Oncol Educ Book 2015:177–186.
(PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis
of all RAS wt patients on CALGB/SWOG 80405 (Alliance) [abstract]. J 47. Dummer R, Ascierto PA, Gogas H, et al. Results of COLUMBUS part
Clin Oncol 2016;34(Suppl):Abstract 3504. 2: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus
ENCO in BRAF-mutant melanoma [abstract]. Ann Oncol 2017;28(Suppl
35. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA
Cancer J Clin 2014;64:104–117. 5):Abstract 1215O.
36. Morris V, Overman MJ, Jiang ZQ, et al. Progression-free survival remains 48. Huijberts S, Schellens JH, Elez E, et al. BEACON CRC: safety lead-in
poor over sequential lines of systemic therapy in patients with BRAF- (SLI) for the combination of binimetinib (BINI), encorafenib (ENCO),
mutated colorectal cancer. Clin Colorectal Cancer 2014;13:164–171. and cetuximab (CTX) in patients (Pts) with BRAF-V600E metastatic
37. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic colorectal cancer (mCRC) [abstract]. Ann Oncol 2017;28(Suppl
development against cancer. J Clin Oncol 2005;23:6771–6790. 5):Abstract 517P.
38. Sharma A, Shah SR, Illum H, Dowell J. Vemurafenib: targeted inhibition 49. Cutsem EV, Cuyle PJ, Huijberts S, et al. BEACON CRC study safety
of mutated BRAF for treatment of advanced melanoma and its potential in lead-in (SLI) in patients with BRAFV600E metastatic colorectal
other malignancies. Drugs 2012;72:2207–2222. cancer (mCRC): efficacy and tumor markers [abstract]. J Clin Oncol
39. Zelboraf [package insert]. South San Francisco, CA: Genentech USA, 2018;36(Suppl):Abstract 627.
Inc.; 2017. 50. Silkin SV, Startsev SS, Krasnova ME, et al. Complete clinical response of
40. Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in BRAF-mutated cholangiocarcinoma to vemurafenib, panitumumab, and
patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol irinotecan. J Gastrointest Cancer 2016;47:502–505.
2015;33:4032–4038. 51. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and
41. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant
BRAF(V600E) inhibition through feedback activation of EGFR. Nature colorectal cancer. J Clin Oncol 2015;33:4023–4031.
2012;483:100–103.
52. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with
42. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of melanoma, untreated brain metastases, and other solid tumours: a phase 1
MAPK signaling contributes to insensitivity of BRAF mutant colorectal dose-escalation trial. Lancet 2012;379:1893–1901.
cancers to RAF inhibition with vemurafenib. Cancer Discov 2012;2:227–
235. 53. Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436
targeted inhibition of mutant BRAF in cancer patients does not impair
43. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations
in patients with advanced colorectal cancer receiving cetuximab and overall immune competency. Clin Cancer Res 2012;18:2326–2335.
panitumumab: a meta-analysis. Eur J Cancer 2015;51:587–594. 54. Williams CB, McMahon C, Ali SM, et al. A metastatic colon
44. Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF adenocarcinoma harboring BRAF V600E has a durable major response
inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal to dabrafenib/trametinib and chemotherapy. Onco Targets Ther
cancer. Cancer Res 2012;72:779–789. 2015;8:3561–3564.
45. Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib 55. Mekinist [package insert]. East Hanover, NJ: Novartis Pharmaceuticals
in combination with irinotecan and cetuximab in patients with Corporation; 2017.

Instructions for Completion choice questions. Credit cannot be obtained for tests complet-
To participate in this journal CE activity: 1) review the learning ed on paper. You must be a registered user on NCCN.org. If you
objectives and author disclosures; 2) study the education con- are not registered on NCCN.org, click on “New Member? Sign
tent; 3) take the posttest with a 66% minimum passing score up here” link on the left hand side of the Web site to register.
and complete the evaluation at http://education.nccn.org/ Only one answer is correct for each question. Once you suc-
node/82890; and 4) view/print certificate. After reading the cessfully answer all posttest questions you will be able to view
article, you should be able to answer the following multiple- and/or print your certificate. Software requirements: Internet

Posttest Questions d. 3 months of FOLFOX was

proven to be noninferior to 6
months of FOLFOX in patients
1. True or False: Patients with stage III colon cancer are now
with TanyN2 or T4N1–2 colon
divided into high- and low-risk subsets in the 2018 version of cancer
the NCCN Guidelines for Colon Cancer, with different adju- e. None of the above
vant treatment recommendations for the 2 groups.

3. Which of the following regimens are included in the 2018

2. In the IDEA collaboration, which of the following was version of the NCCN Guidelines for Colon Cancer for pa-
proven to be noninferior for 3-year disease-free survival? tients with metastatic disease whose tumors contain BRAF
a. 3 months of CapeOX was proven to be noninferior to 6 V600E mutations?
months of CapeOX in patients with T1–3N1 colon cancer a. Dabrafenib/(cetuximab or panitumumab)/irinotecan
b. 3 months of FOLFOX was proven to be noninferior to 6 b. Dabrafenib/(cetuximab or panitumumab)/trametinib
months of FOLFOX in patients with T1–3N1 colon cancer c. Vemurafenib/(cetuximab or panitumumab)/irinotecan
c. 3
 months of CapeOX was proven to be noninferior to 6 d. Encorafenib/(cetuximab or panitumumab)/
months of CapeOX in patients with TanyN2 or T4N1–2 binimetinib
colon cancer e. All of the above

© JNCCN—Journal of the National Comprehensive Cancer Network  |  Volume 16 Number 4  |  April 2018