This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions.

Abstract

This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions.

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 noted.

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

Overview

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 people will die of colon and rectal cancer combined.1 Despite these high numbers, the incidence of colon and rectal cancers per 100,000 people decreased from 60.5 in 1976 to 46.4 in 2005.2 In fact, the incidence of CRC decreased at a rate of approximately 3% per year between 2003 and 2012.1 The incidence rate for CRC reported by the CDC for 2011 is 40.0 per 100,000 persons.3 In addition, mortality from CRC decreased by almost 35% from 1990 to 2007,4 and is currently down by approximately 50% from peak mortality rates.1 These improvements in incidence of and mortality from CRC are thought to be a result of cancer prevention and earlier diagnosis through screening and better treatment modalities.

Despite the observed improvements in the overall CRC incidence rate, a retrospective cohort study of the SEER CRC registry found that the incidence of CRC in patients <50 years of age has been increasing.5 The authors estimate that the incidence rates for colon and rectal cancers will increase by 90.0% and 124.2%, respectively, for patients 20 to 34 years by 2030. The cause of this trend is currently unknown.

This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. When reviewing these guidelines, clinicians should be aware of several things. First, these guidelines adhere to the TNM staging system (Table 1 [ST-1], available in these guidelines at NCCN.org).6 Furthermore, all recommendations are classified as category 2A

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NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0036

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NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

Version 1.2017, 11-23-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0036

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NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 3; 10.6004/jnccn.2017.0036

except where noted in the text or algorithm. Although the guidelines are believed to represent the optimal treatment strategy, the panel believes that, when appropriate, patients should preferentially be included in a clinical trial over standard or accepted therapy.

Systemic Therapy for Advanced or Metastatic Disease

The current management of disseminated metastatic colon cancer involves various active drugs, either in combination or as single agents: 5-FU/leucovorin (LV), capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab, and nivolumab.748 The putative mechanisms of action of these agents are varied and include interference with DNA replication and inhibition of the activities of vascular endothelial growth factor (VEGF) and epidermal growth factors (EGFRs).4952 The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. Although the specific regimens listed in the guideline are designated according to whether they pertain to initial therapy, therapy after first progression, or therapy after second progression, it is important to clarify that these recommendations represent a continuum of care and that these lines of treatment are blurred rather than discrete.25 For example, if oxaliplatin is administered as a part of an initial treatment regimen but is discontinued after 12 weeks or earlier for escalating neurotoxicity, continuation of the remainder of the treatment regimen would still be considered initial therapy.

Principles to consider at the start of therapy include preplanned strategies for altering therapy for patients exhibiting a tumor response or disease characterized as stable or progressive, and plans for adjusting therapy for patients who experience certain toxicities. For example, decisions related to therapeutic choices after first progression of disease should be based partly on the prior therapies received (ie, exposing the patient to a range of cytotoxic agents). Furthermore, an evaluation of the efficacy and safety of these regimens for an individual patient must take into account not only the component drugs but also the doses, schedules, and methods of administration of these agents, and the potential for surgical cure and the performance status of the patient.

As initial therapy for metastatic disease in a patient appropriate for intensive therapy (ie, one with a good tolerance for this therapy for whom a high tumor response rate would be potentially beneficial), the panel recommends a choice of 5 chemotherapy regimens: FOLFOX (ie, mFOLFOX6),34,53 FOLFIRI,8 CapeOx,11,54,55 infusional 5-FU/LV or capecitabine,8,30,37,48 or FOLFOXIRI,21,40 with or without targeted agents.56

Sequencing and Timing of Therapies

Few studies have addressed the sequencing of therapies in advanced metastatic disease. Before the use of targeted agents, several studies randomized patients to different schedules.53,5759 The data from these trials suggest that there is little difference in clinical outcomes if intensive therapy is given in first line or if less intensive therapy is given first followed by more intensive combinations.

Results from a randomized study to evaluate the efficacy of FOLFIRI and FOLFOX regimens as initial therapy and to determine the effect of using sequential therapy with the alternate regimen after first progression showed neither sequence to be significantly superior with respect to progression-free survival (PFS) or median overall survival (OS).53 A combined analysis of data from 7 recent phase III clinical trials in advanced CRC provided support for a correlation between an increase in median survival and administration of all of the 3 cytotoxic agents (ie, 5-FU/LV, oxaliplatin, irinotecan) at some point in the continuum of care.60 Furthermore, OS was not found to be associated with the order in which these drugs were received.

A study of 6,286 patients from 9 trials that evaluated the benefits and risks associated with intensive first-line treatment in the setting of metastatic CRC treatment according to patient performance status showed similar therapeutic efficacy for patients with performance status of 2 or 1 or less compared with control groups, although the risks of certain gastrointestinal toxicities were significantly increased for patients with a performance status of 2.61

Overall, the panel does not consider one regimen (ie, FOLFOX, CapeOx, FOLFIRI, 5-FU/LV, capecitabine, FOLFOXIRI) to be preferable over the others as initial therapy for metastatic disease. The panel also does not indicate a preference for biologic agents used as part of initial therapy (ie, bevacizumab, cetuximab, panitumumab, none).

Maintenance Therapy

Interest in the use of a maintenance therapy approach after first-line treatment of unresectable, metastatic CRC is growing. In general, this approach involves intensive first-line therapy, followed by less intensive therapy until progression in patients with good response to initial treatment.

The CAIRO3 study was an open-label, phase III, multicenter randomized controlled trial assessing maintenance therapy with capecitabine/bevacizumab versus observation in 558 patients with metastatic CRC and with stable disease or better after first-line treatment with CapeOx/bevacizumab.62 After first progression, both groups were to receive CapeOx/bevacizumab again until second progression (PFS2). After a median follow-up of 48 months, the primary end point of PFS2 was significantly better in the maintenance arm (8.5 vs 11.7 months; hazard ratio [HR], 0.67; 95% CI, 0.56–0.81; P<.0001), with 54% of patients overall receiving CapeOx/bevacizumab the second time. Quality of life was not affected by maintenance therapy, although 23% of patients in the maintenance group developed hand-foot syndrome during the maintenance period. A nonsignificant trend toward improved OS was seen in the maintenance arm (18.1 vs 21.6 months; adjusted HR, 0.83; 95% CI, 0.68–1.01; P=.06).

The AIO 0207 trial was an open-label, noninferiority, randomized phase III trial that randomized 472 patients whose disease did not progress on induction FOLFOX/bevacizumab or CapeOx/bevacizumab to no maintenance therapy or to maintenance therapy with fluoropyrimidine/bevacizumab or with bevacizumab alone.63 The planned protocol included reintroduction of primary therapy after first progression. The primary end point was time to failure of strategy, defined as time from randomization to second progression, death, and initiation of treatment with a new drug. After a medium follow-up of 17 months, the median time to failure of strategy was 6.4 months (95% CI, 4.8–7.6) for the no treatment group, 6.9 months (95% CI, 6.1–8.5) for the fluoropyrimidine/bevacizumab group, and 6.1 months (95% CI, 5.3–7.4) for the bevacizumab alone group. Compared with fluoropyrimidine/bevacizumab, bevacizumab alone was noninferior, whereas the absence of maintenance therapy was not. However, only approximately one-third of trial participants received the reinduction therapy, thus limiting the interpretation of results. OS was one of the secondary end points of the trial, and no relevant difference was seen between the arms.

The randomized phase III noninferiority SAKK 41/06 trial addressed the question of continuing bevacizumab alone as maintenance therapy after chemotherapy plus bevacizumab in first-line treatment.64 The primary end point of time to progression was not met (4.1 months for bevacizumab continuation vs 2.9 months for no continuation; HR, 0.74; 95% CI, 0.58–0.96), and no difference in OS was observed (25.4 vs 23.8 months; HR, 0.83; 95% CI, 0.63–1.1; P=.2). Therefore, noninferiority for treatment holidays versus bevacizumab maintenance therapy was not demonstrated.

The GERCOR DREAM trial (OPTIMOX3) was an international, open-label, phase III study that randomized patients with metastatic CRC without disease progression on bevacizumab-based therapy to maintenance therapy with bevacizumab or bevacizumab plus erlotinib.65 Intention-to-treat analysis revealed an advantage in PFS (5.4 vs 4.9 months; stratified HR, 0.81; 95% CI, 0.66–1.01; P=.06) and OS (24.9 vs 22.1 months; stratified HR, 0.79; 95% CI, 0.63–0.99; P=.04) with combination therapy. A smaller randomized trial, however, showed no difference in PFS or OS between bevacizumab and bevacizumab/erlotinib maintenance therapy in patients with KRAS wild-type tumors.66 A meta-analysis identified 3 randomized trials (682 patients) and concluded that maintenance therapy with bevacizumab/erlotinib significantly increases OS and PFS, with manageable toxicity.67

Another phase III trial investigated the role of capecitabine in the maintenance phase, after initial treatment with FOLFOX or CapeOx.68 PFS, the primary end point, was 6.4 months in the capecitabine maintenance group and 3.4 months in the group that was observed until progression (HR, 0.54; 95% CI, 0.42–0.70; P<.001). A non–statistically significant difference in the median OS was also seen (HR, 0.85; 95% CI, 0.64–1.11; P=.2247). Toxicities associated with the capecitabine maintenance therapy were acceptable.

Bevacizumab

Bevacizumab is a humanized monoclonal antibody that blocks the activity of VEGF, a factor that plays an important role in tumor angiogenesis.69 Pooled results from several randomized phase II studies have shown that the addition of bevacizumab to first-line 5-FU/LV improved OS in patients with unresectable metastatic CRC compared with those receiving these regimens without bevacizumab.7072 A combined analysis of the results of these trials showed that the addition of bevacizumab to 5-FU/LV was associated with a median survival of 17.9 versus 14.6 months for regimens consisting of 5-FU/LV or 5-FU/LV plus irinotecan without bevacizumab (P=.008).31 A study of previously untreated patients receiving bevacizumab plus irinotecan/fluorouracil/leucovorin (IFL) also provided support for the inclusion of bevacizumab in initial therapy.70 In that pivotal trial, a longer survival time was observed with the use of bevacizumab (20.3 vs 15.6 months; HR, 0.66; P<.001).

Results have also been reported from a large, head-to-head, randomized, double-blind, placebo-controlled, phase III study (NO16966) in which CapeOx (capecitabine dose, 1000 mg/m2, twice daily for 14 days) with bevacizumab or placebo was compared with FOLFOX with bevacizumab or placebo in 1,400 patients with unresectable metastatic disease.39 The addition of bevacizumab to oxaliplatin-based regimens was associated with a more modest increase of 1.4 months in PFS compared with these regimens without bevacizumab (HR, 0.83; 97.5% CI, 0.72–0.95; P=.0023), and the difference in OS, which was also a modest 1.4 months, did not reach statistical significance (HR, 0.89; 97.5% CI, 0.76–1.03; P=.077).39 Researchers have suggested that differences observed in cross-study comparisons of NO16966 with other trials might be related to differences in the discontinuation rates and durations of treatment between trials, although these hypotheses are conjectural.39 However, in this 1,400-patient randomized study, absolutely no difference in response rate was seen with and without bevacizumab, and this finding could not have been influenced by the early withdrawal rates, which would have occurred after the responses would have occurred. Results of subset analyses evaluating the benefit of adding bevacizumab to either FOLFOX or CapeOx indicated that bevacizumab was associated with improvements in PFS when added to CapeOx but not FOLFOX.39

The combination of FOLFIRI and bevacizumab in the first-line treatment of advanced CRC has been studied, although no randomized controlled trials have compared FOLFIRI with and without bevacizumab. A recent systematic review with a pooled analysis (29 prospective and retrospective studies, 3,502 patients) found that the combination gave a response rate of 51.4%, a median PFS of 10.8 months (95% CI, 8.9–12.8), and a median OS of 23.7 months (95% CI, 18.1–31.6).73 FOLFOXIRI with bevacizumab is also an accepted combination (see section on “FOLFOXIRI,” available online, in these guidelines, at NCCN.org [MS-37]), although no randomized controlled trials have compared FOLFOXIRI with and without bevacizumab.

A prospective observational cohort study (ARIES) included 1,550 patients who received first-line therapy with bevacizumab with chemotherapy for metastatic CRC and 482 patients treated with bevacizumab in second-line therapy.74 Median OS was 23.2 months (95% CI, 21.2–24.8) for the first-line cohort and 17.8 months (95% CI, 16.5–20.7) in the second-line group. A similar cohort study (ETNA) of first-line bevacizumab use with irinotecan-based therapy reported a median OS of 25.3 months (95% CI, 23.3–27.0).75

Several meta-analyses have shown a benefit for the use of bevacizumab in first-line therapy for metastatic CRC.7684 A meta-analysis of 6 randomized clinical trials (3,060 patients) that assessed the efficacy of bevacizumab in first-line treatment of metastatic CRC found that bevacizumab gave a PFS (HR, 0.72; 95% CI, 0.66–0.78; P<.00001) and OS (HR, 0.84; 95% CI, 0.77–0.91; P<.00001) advantage.85 However, subgroup analyses showed that the advantage was limited to irinotecan-based regimens. In addition, a recent analysis of the SEER-Medicare database found that bevacizumab added a modest improvement to OS of patients with stage IV colorectal cancer diagnosed between 2002 and 2007 (HR, 0.85; 95% CI, 0.78–0.93).86 The survival advantage was not evident when bevacizumab was combined with oxaliplatin-based chemotherapy, but was evident in irinotecan-based regimens. Limitations of this analysis have been discussed,87,88 but, overall, the addition of bevacizumab to first-line chemotherapy appears to offer a modest clinical benefit.

No data directly address whether bevacizumab should be used with chemotherapy in the perioperative treatment of resectable metastatic disease. Recent data regarding the lack of efficacy of bevacizumab in the adjuvant setting in stage II and III colon cancer89,90 have prompted some to reconsider the role of bevacizumab in the adjuvant setting of resectable colorectal metastases. However, the panel does not recommend the use of bevacizumab in the perioperative stage IV setting.

A recent meta-analysis of randomized controlled trials showed that the addition of bevacizumab to chemotherapy is associated with a higher incidence of treatment-related mortality than chemotherapy alone (relative risk [RR], 1.33; 95% CI, 1.02–1.73; P=.04), with hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal perforation (7.1%) being the most common causes of fatality.91 Venous thromboembolisms, on the other hand, were not increased in patients receiving bevacizumab with chemotherapy versus those receiving chemotherapy alone.92 Another meta-analysis showed that bevacizumab was associated with a significantly higher risk of hypertension and gastrointestinal hemorrhage and perforation, although the overall risk for hemorrhage and perforation is low.93 The risk of stroke and other arterial events is increased in patients receiving bevacizumab, especially in those aged ≥65 years. Gastrointestinal perforation is a rare but important side effect of bevacizumab therapy in patients with CRC.94,95 Extensive prior intra-abdominal surgery, such as peritoneal stripping, may predispose patients to gastrointestinal perforation. A small cohort of patients with advanced ovarian cancer had an unacceptably high rate of gastrointestinal perforation when treated with bevacizumab.96 This result illustrated that peritoneal debulking surgery may be a risk factor for gastrointestinal perforation, whereas the presence of an intact primary tumor does not seem to increase the risk for gastrointestinal perforation. The FDA recently approved a safety label warning of the risk for necrotizing fasciitis, sometimes fatal and usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation after bevacizumab use.69

Use of bevacizumab may interfere with wound healing.69,94,95 A retrospective evaluation of data from 2 randomized trials of 1,132 patients undergoing chemotherapy with or without bevacizumab as initial therapy for metastatic CRC indicated that the incidence of wound healing complications was increased for the group of patients undergoing a major surgical procedure while receiving a bevacizumab-containing regimen compared with the group receiving chemotherapy alone while undergoing major surgery (13% vs 3.4%, respectively; P=.28).95 However, when chemotherapy plus bevacizumab or chemotherapy alone was administered before surgery, with a delay between bevacizumab administration and surgery of at least 6 weeks, the incidence of wound healing complications in either group of patients was low (1.3% vs 0.5%; P=.63). Similarly, results of a single-center, nonrandomized phase II trial of patients with potentially resectable liver metastases showed no increase in bleeding or wound complications when the bevacizumab component of CapeOx plus bevacizumab therapy was stopped 5 weeks before surgery (ie, bevacizumab excluded from the sixth cycle of therapy).97 In addition, no significant differences in bleeding, wound, or hepatic complications were seen in a retrospective trial evaluating the effects of preoperative bevacizumab stopped at ≤8 weeks versus at >8 weeks before resection of liver colorectal metastases in patients receiving oxaliplatin- or irinotecan-containing regimens.98 The panel recommends an interval of at least 6 weeks (which corresponds to 2 half-lives of the drug69) between the last dose of bevacizumab and any elective surgery.

Preclinical studies suggested that cessation of anti-VEGF therapy might be associated with accelerated recurrence, more aggressive tumors on recurrence, and increased mortality. A recent retrospective meta-analysis of 5 placebo-controlled, randomized phase III trials including 4,205 patients with metastatic colorectal, breast, renal, or pancreatic cancer found no difference in time to disease progression and mortality with discontinuation of bevacizumab versus discontinuation of placebo.99 Although this meta-analysis has been criticized,100,101 the results are supported by recent results from the NSABP Protocol C-08 trial.89 This trial included patients with stage II and III CRC, and no differences in recurrence, mortality, or mortality 2 years after recurrence were seen between patients receiving bevacizumab versus those in the control arm. These results suggest that no “rebound effect” is associated with bevacizumab use.

Cetuximab and Panitumumab

Cetuximab and panitumumab are monoclonal antibodies directed against EGFR that inhibit its down-stream signaling pathways. Panitumumab is a fully human monoclonal antibody, whereas cetuximab is a chimeric monoclonal antibody.102,103 Cetuximab and panitumumab have been studied in combination with FOLFIRI and FOLFOX as initial therapy options for treatment of metastatic CRC. Recent meta-analyses of randomized controlled trials have concluded that EGFR inhibitors provide a clear clinical benefit in the treatment in patients with RAS wild-type metastatic CRC.104,105 Individual trials and the role of KRAS, NRAS, and BRAF are discussed herein.

Administration of either cetuximab or panitumumab has been associated with severe infusion reactions, including anaphylaxis, in 3% and 1% of patients, respectively.102,103 Based on case reports and a small trial, administration of panitumumab seems to be feasible for patients experiencing severe infusion reactions to cetuximab.106108 Skin toxicity is a side effect of both of these agents and is not considered part of the infusion reactions. The incidence and severity of skin reactions with cetuximab and panitumumab seem to be very similar. Furthermore, the presence and severity of skin rash in patients receiving either of these drugs have been shown to predict increased response and survival.44,109113 An NCCN task force addressed the management of dermatologic and other toxicities associated with anti-EGFR inhibitors.114 Cetuximab and panitumumab have also been associated with a risk for venous thromboembolic and other serious adverse events.115,116

Based on the results of the PACCE and CAIRO2 trials, the panel strongly advises against the concurrent use of bevacizumab with either cetuximab or panitumumab (see “Bevacizumab,” page 380).41,117 Several trials that assessed EGFR inhibitors in combination with various chemotherapy agents are discussed herein.

The Role of Primary Tumor Sidedness: A growing body of data has shown that the location of the primary tumor can be both prognostic and predictive of response to EGFR inhibitors in metastatic CRC.118125 For example, outcomes of 75 patients with metastatic CRC treated with cetuximab, panitumumab, or cetuximab/irinotecan in first-line or subsequent lines of therapy at 3 Italian centers were analyzed based on sidedness of the primary tumor.119 No responses were seen in the patients with right-sided primary tumors, compared with a response rate of 41% in those with left-sided primaries (P=.003). The median PFS was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (HR, 3.97; 95% CI, 2.09–7.53; P<.0001).

The strongest evidence for the predictive value of primary tumor sidedness and response to EGFR inhibitors is in the first-line treatment of patients in the phase III CALGB/SWOG 80405 trial.125,126 The study showed that patients with all RAS wild-type, right-sided primary tumors (cecum to hepatic flexure) had longer OS if treated with bevacizumab than if treated with cetuximab in the first line (HR, 1.36; 95% CI, 0.93–1.99; P=.10), whereas patients with all RAS wild-type, left-sided primary tumors (splenic flexure to rectum) had longer OS if treated with cetuximab than with bevacizumab (HR, 0.77; 95% CI, 0.59–0.99; P=.04).126 OS was prolonged with cetuximab versus bevacizumab in the left-sided primary group (39.3 vs 32.6 months) but shortened in the right-sided primary group (13.6 vs 29.2 months).

These and other data suggest that cetuximab and panitumumab confer little if any benefit to patients with metastatic CRC if the primary tumor originated on the right side.118,119,121,122 The panel believes that primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes across the colon and that the ongoing analysis of tumor specimens from the study will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy,118,119,122 but the panel awaits more definitive studies. Until such data are available, all patients with RAS wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given.

The Role of KRAS, NRAS, and BRAF Status: The receptor for EGFR has been reported to be over-expressed in 49% to 82% of colorectal tumors.127130 EGFR testing of colorectal tumor cells has no proven predictive value in determining likelihood of response to either cetuximab or panitumumab. Data from the BOND study indicated that the intensity of immunohistochemical staining of EGFR in colorectal tumor cells did not correlate with the response rate to cetuximab.14 A similar conclusion was drawn with respect to panitumumab.131 Therefore, routine EGFR testing is not recommended, and no patient should be considered for or excluded from cetuximab or panitumumab therapy based on EGFR test results.

Cetuximab and panitumumab are monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways, but EGFR status as assessed using immunohistochemistry is not predictive of treatment efficacy.14,132 Furthermore, cetuximab and panitumumab are only effective in approximately 10% to 20% of patients with CRC.14,45,132 The RAS/RAF/MAPK pathway is downstream of EGFR; mutations in components of this pathway are being studied in search of predictive markers for efficacy of these therapies.

A sizable body of literature has shown that tumors with a mutation in codon 12 or 13 of exon 2 of the KRAS gene are essentially insensitive to cetuximab or panitumumab therapy (see “KRAS Exon 2 Mutations,” this page).7,44,110,133138 More recent evidence shows mutations in KRAS outside of exon 2 and mutations in NRAS are also predictive for a lack of benefit to cetuximab and panitumumab (see “NRAS and Other KRAS Mutations,” page 384).105,139

The panel therefore strongly recommends KRAS/NRAS genotyping of tumor tissue (either primary tumor or metastasis) in all patients with metastatic CRC. Patients with known KRAS or NRAS mutations should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified. It is implied throughout the guidelines that NCCN recommendations involving cetuximab or panitumumab relate only to patients with disease characterized by KRAS/NRAS wild-type genes. ASCO released a provisional clinical opinion update on extended RAS testing in patients with metastatic CRC that is consistent with the NCCN panel's recommendations.140

The panel strongly recommends genotyping of tumor tissue (either primary tumor or metastasis) in all patients with metastatic CRC for RAS (KRAS exon 2 and non-exon 2; NRAS) and BRAF at diagnosis of stage IV disease. The recommendation for KRAS/NRAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of KRAS/NRAS status is appropriate to plan for the treatment continuum, so that the information may be obtained in a non–time-sensitive manner and the patient and provider can discuss the implications of a KRAS/NRAS mutation, if present, while other treatment options still exist. Note that because anti-EGFR agents have no role in the management of stage I, II, or III disease, KRAS/NRAS genotyping of CRC at these earlier stages is not recommended.

KRAS mutations are early events in CRC formation, and therefore a very tight correlation exists between mutation status in the primary tumor and the metastases.141143 For this reason, KRAS/NRAS genotyping can be performed on archived specimens of either the primary tumor or a metastasis. Fresh biopsies should not be obtained solely for the purpose of KRAS/NRAS genotyping unless an archived specimen from either the primary tumor or a metastasis is unavailable.

The panel recommends that KRAS, NRAS, and BRAF gene testing be performed only in laboratories that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88) as qualified to perform highly complex molecular pathology testing.144 No specific testing methodology is recommended.145

KRAS Exon 2 Mutations: Approximately 40% of colorectal cancers are characterized by mutations in codons 12 and 13 in exon 2 of the coding region of the KRAS gene.7,146 A sizable body of literature has shown that these KRAS exon 2 mutations are predictive of lack of response to cetuximab or panitumumab therapy,7,44,110,133138,147 and FDA labels for cetuximab and panitumumab specifically state that these agents are not recommended for the treatment of CRC characterized by these mutations.102,103 Results are mixed regarding the prognostic value of KRAS mutations. In the Alliance N0147 trial, patients with KRAS exon 2 mutations experienced a shorter disease-free survival than patients without such mutations.148 At this time, however, the test is not recommended for prognostic reasons.

A retrospective study from De Roock et al149 raised the possibility that codon 13 mutations (G13D) in KRAS may not be absolutely predictive of nonresponse. Another retrospective study showed similar results.138 However, more recent retrospective analysis of 3 randomized controlled phase III trials concluded that patients with KRAS G13D mutations were unlikely to respond to panitumumab.150 Results from a prospective phase II single-arm trial assessed the benefit of cetuximab monotherapy in 12 patients with refractory metastatic CRC whose tumors contained KRAS G13D mutations.151 The primary end point of 4-month progression-free rate was not met (25%), and no responses were seen. Preliminary results of the phase II AGITG ICECREAM trial also failed to see a benefit of cetuximab monotherapy in patients with KRAS G13D mutations.152 However, partial responses were reported after treatment with irinotecan plus cetuximab in 9% of this irinotecan-refractory population. The panel believes that patients with any known KRAS mutation, including G13D, should not be treated with cetuximab or panitumumab.

NRAS and Other KRAS Mutations: In the AGITG MAX study, 10% of patients with wild-type KRAS exon 2 had mutations in KRAS exons 3 or 4 or in NRAS exons 2, 3, and 4.153 In the PRIME trial, 17% of 641 patients without KRAS exon 2 mutations were found to have mutations in exons 3 and 4 of KRAS or mutations in exons 2, 3, and 4 of NRAS. A predefined retrospective subset analysis of data from PRIME revealed that PFS (HR, 1.31; 95% CI, 1.07–1.60; P=.008) and OS (HR, 1.21; 95% CI, 1.01–1.45; P=.04) were decreased in patients with any KRAS or NRAS mutation who received panitumumab plus FOLFOX compared with those who received FOLFOX alone.139 These results show that panitumumab does not benefit patients with KRAS or NRAS mutations and may even have a detrimental effect in these patients.

Updated analysis of the FIRE-3 trial (discussed in “Cetuximab or Panitumumab Versus Bevacizumab in First-Line,” page 387) was recently published.154 When all RAS (KRAS/NRAS) mutations were considered, PFS was significantly worse in patients with RAS-mutant tumors receiving FOLFIRI plus cetuximab than in patients with RAS-mutant tumors receiving FOLFIRI plus bevacizumab (6.1 vs 12.2 months; P=.004). On the other hand, patients with KRAS/NRAS wild-type tumors showed no difference in PFS between the regimens (10.4 vs 10.2 months; P=.54). This result indicates that cetuximab likely has a detrimental effect in patients with KRAS or NRAS mutations.

The FDA indication for panitumumab was recently updated to state that panitumumab is not indicated for the treatment of patients with KRAS or NRAS mutation–positive disease in combination with oxaliplatin-based chemotherapy.103 The NCCN Colon Cancer Panel believes that non–exon 2 KRAS mutation status and NRAS mutation status should be determined at diagnosis of stage IV disease. Patients with any known KRAS mutation (exon 2 or non-exon 2) or NRAS mutation should not be treated with either cetuximab or panitumumab.

BRAF V600E Mutations: Although mutations of KRAS/NRAS indicate a lack of response to EGFR inhibitors, many tumors containing wild-type KRAS/NRAS still do not respond to these therapies. Therefore, studies have addressed factors downstream of KRAS/NRAS as possible additional biomarkers predictive of response to cetuximab or panitumumab. Approximately 5% to 9% of CRCs are characterized by a specific mutation in the BRAF gene (V600E).155,156 BRAF mutations are, for all practical purposes, limited to tumors that do not have KRAS exon 2 mutations.155,157 Activation of the protein product of the nonmutated BRAF gene occurs down-stream of the activated KRAS protein in the EGFR pathway; the mutated BRAF protein product is believed to be constitutively active,158160 thereby putatively bypassing inhibition of EGFR by cetuximab or panitumumab.

Limited data from unplanned retrospective subset analyses of patients with metastatic CRC treated in the first-line setting suggest that, although a BRAF V600E mutation confers a poor prognosis regardless of treatment, patients with disease characterized by this mutation may receive some benefit from the addition of cetuximab to front-line therapy.156,161 A planned subset analysis of the PRIME trial also found that mutations in BRAF indicated a poor prognosis but were not predictive of benefit to panitumumab added to FOLFOX in first-line treatment of metastatic CRC.139 On the other hand, results from the randomized phase III Medical Research Council (MRC) COIN trial suggest that cetuximab may have no effect or even a detrimental one in patients with BRAF-mutated tumors treated with CapeOx or FOLFOX in the first-line setting.157

In subsequent lines of therapy, retrospective evidence suggests that mutated BRAF is a marker of resistance to anti-EGFR therapy in the non–first-line setting of metastatic disease.162164 A retrospective study of 773 primary tumor samples from patients with chemotherapy-refractory disease showed that BRAF mutations conferred a significantly lower response rate to cetuximab (2/24; 8.3%) compared with tumors with wild-type BRAF (124/326; 38.0%; P=.0012).165 Furthermore, data from the multicenter randomized controlled PICCOLO trial are consistent with this conclusion, with a suggestion of harm seen for the addition of panitumumab to irinotecan in the non–first-line setting in the small subset of patients with BRAF mutations.166

A meta-analysis published in 2015 identified 9 phase III trials and 1 phase II trial that compared cetuximab or panitumumab with standard therapy or best supportive care, including 463 patients with metastatic colorectal tumors with BRAF mutations (first-line, second-line, or refractory settings).167 The addition of an EGFR inhibitor did not improve PFS (HR, 0.88; 95% CI, 0.67–1.14; P=.33), OS (HR, 0.91; 95% CI, 0.62–1.34; P=.63), or overall response rate (RR, 1.31; 95% CI, 0.83–2.08, P=.25) compared with control arms. Similarly, another meta-analysis identified 7 randomized controlled trials and found that cetuximab and panitumumab did not improve PFS (HR, 0.86; 95% CI, 0.61–1.21) or OS (HR, 0.97; 95% CI, 0.67–1.41) in patients with BRAF mutations.168

Despite uncertainty over its role as a predictive marker, it is clear that mutations in BRAF are a strong prognostic marker.146,156,157,169174 A prospective analysis of tissues from patients with stage II and III colon cancer enrolled in the PETACC-3 trial showed that the BRAF mutation is prognostic for OS in patients with microsatellite instability–low (MSI-L) or microsatellite stable (MSS) tumors (HR, 2.2; 95% CI, 1.4–3.4; P=.0003).146 Moreover, an updated analysis of the CRYSTAL trial showed that patients with metastatic colorectal tumors carrying a BRAF mutation have a worse prognosis than those with the wild-type gene.156 Additionally, BRAF mutation status predicted OS in the AGITG MAX trial, with an HR of 0.49 (95% CI, 0.33–0.73; P=.001).170 The OS for patients with BRAF mutations in the COIN trial was 8.8 months, whereas those with KRAS exon 2 mutations and wild-type KRAS exon 2 tumors had OS times of 14.4 and 20.1 months, respectively.157 Results from a recent systematic review and meta-analysis of 21 studies, including 9,885 patients, suggest that BRAF mutation may accompany specific high-risk clinicopathologic characteristics.175 In particular, an association was observed between BRAF mutation and proximal tumor location (odds ratio [OR], 5.22; 95% CI, 3.80–7.17; P<.001), T4 tumors (OR, 1.76; 95% CI, 1.16–2.66; P=.007), and poor differentiation (OR, 3.82; 95% CI, 2.71–5.36; P<.001).

Overall, the panel believes that evidence increasingly suggests that BRAF V600E mutation makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely. The panel recommends BRAF genotyping of tumor tissue (either primary tumor or metastasis176) at diagnosis of stage IV disease. Testing for the BRAF V600E mutation can be performed on formalin-fixed paraffin-embedded tissues and is usually performed by polymerase chain reaction (PCR) amplification and direct DNA sequence analysis. Allele-specific PCR is another acceptable method for detecting this mutation.

HER2 Overexpression: HER2 is a member of the same family of signaling kinase receptors as EGFR and has been successfully targeted in breast cancer in both the advanced and adjuvant settings. HER2 is rarely overexpressed in CRC (approximately 3% overall), but the prevalence is higher in RAS/BRAF wild-type tumors (reported at 5%–14%).177,178 Specific molecular diagnostic methods have been proposed for HER2 testing in CRC,179 and various therapeutic approaches are being tested in patients with tumors that have HER2 overexpression (eg, trastuzumab plus lapatinib, trastuzumab plus pertuzumab).177,180 These approaches are currently considered investigational, and enrollment in a clinical trial is encouraged.

Evidence does not support a prognostic role of HER2 overexpression.181 However, initial results indicate HER2 overexpression may be predictive of resistance to EGFR-targeting monoclonal antibodies.178,182 For example, in a cohort of 97 patients with RAS/BRAF wild-type metastatic CRC, median PFS on first-line therapy without an EGFR inhibitor was similar regardless of HER2 status.178 However, in second-line therapy with an EGFR inhibitor, the PFS was significantly shorter in those with HER2 amplification compared with those without (2.9 vs 8.1 months; HR, 5.0; P<.0001). Larger confirmatory studies are needed, and the panel does not recommend HER2 testing for prognostication or treatment planning at this time.

Cetuximab With FOLFIRI: Use of cetuximab as initial therapy for metastatic disease was investigated in the CRYSTAL trial, in which patients were randomly assigned to receive FOLFIRI with or without cetuximab.44 Retrospective analyses of the subset of patients with known KRAS exon 2 tumor status showed a statistically significant improvement in median PFS with the addition of cetuximab in the wild-type (9.9 vs 8.7 months; HR, 0.68; 95% CI, 0.50–0.94; P=.02).44 The statistically significant benefit in PFS for patients with KRAS exon 2 wild-type tumors receiving cetuximab was confirmed in a recent publication of an updated analysis of the CRYSTAL data.156 This recent study included a retrospective analysis of OS in the KRAS exon 2 wild-type population and found an improvement with the addition of cetuximab (23.5 vs 20.0 months; P=.009). Importantly, the addition of cetuximab did not affect the quality of life of participants in the CRYSTAL trial.183 As has been seen with other trials, when DNA samples from the CRYSTAL trial were reanalyzed for additional KRAS and NRAS mutations, patients with RAS wild-type tumors derived a clear OS benefit (HR, 0.69; 95% CI, 0.54–0.88), whereas those with any RAS mutation did not (HR, 1.05; 95% CI, 0.86–1.28).184

Panitumumab With FOLFIRI: FOLFIRI with panitumumab is listed as an option for first-line therapy in metastatic CRC based on extrapolation from data in second-line treatment.36,166,185,186

Cetuximab With FOLFOX: Three trials have assessed the combination of FOLFOX and cetuximab in first-line treatment of metastatic CRC. In a retrospective evaluation of the subset of patients with known tumor KRAS exon 2 status enrolled in the randomized phase II OPUS trial, addition of cetuximab to FOLFOX was associated with an increased objective response rate (61% vs 37%; OR, 2.54; P=.011) and a very slightly lower risk of disease progression (7.7 vs 7.2 months [a 15-day difference]; HR, 0.57; 95% CI, 0.36–0.91; P=.016) compared with FOLFOX alone in the subset of patients with KRAS exon 2 wild-type tumors.134 Although data supporting the statistically significant benefits in objective response rate and PFS for patients with tumors characterized by KRAS wild-type exon 2 were upheld in an update of this study, no median OS benefit was observed for the addition of cetuximab to chemotherapy (22.8 months in the cetuximab arm vs 18.5 months in the arm undergoing chemotherapy alone; HR, 0.85; P=.39).187

Furthermore, in the recent randomized phase III MRC COIN trial, no benefit in OS (17.9 vs 17.0 months; P=.067) or PFS (8.6 months in both groups; P=.60) was seen with the addition of cetuximab to FOLFOX or CapeOx as first-line treatment of patients with locally advanced or metastatic CRC and wild-type KRAS exon 2.157 Exploratory analyses of the COIN trial, however, suggest that there may be a benefit to the addition of cetuximab in patients who received FOLFOX instead of CapeOx.157 Similarly, a recent pooled analysis of the COIN and OPUS studies found that a benefit was suggested in response rate and PFS with the addition of cetuximab to FOLFOX in patients with KRAS exon 2 wild-type tumors, although there was no OS benefit.188

Notably, more recent trials examining the efficacity of the addition of cetuximab to oxaliplatin-containing regimens in the first-line treatment of patients with advanced or metastatic CRC and wild-type KRAS exon 2 have not shown any benefit. The addition of cetuximab to the Nordic FLOX regimen showed no OR or PFS benefit in this population of patients in the randomized phase III NORDIC VII study of the Nordic Colorectal Cancer Biomodulation Group.189

However, results from the recent randomized phase III CALGB/SWOG 80405 trial of >3,000 patients (discussed in “Cetuximab or Panitumumab Versus Bevacizumab in First-Line,” page 387) showed that the combination of FOLFOX with cetuximab can be effective in the first-line treatment of metastatic CRC.190 The panel thus added a recommendation for the use of cetuximab with FOLFOX as initial therapy for patients with advanced or metastatic disease to the 2015 version of these guidelines.

The New EPOC trial, which was stopped early because it met protocol-defined futility criteria, found a lack of benefit to cetuximab with chemotherapy in the perioperative metastatic setting (>85% received FOLFOX or CapeOx; patients with prior oxaliplatin received FOLFIRI).191 In fact, with fewer than half of expected events observed, PFS was significantly reduced in the cetuximab arm (14.8 vs 24.2 months; HR, 1.50; 95% CI, 1.00–2.25; P<.048). The panel thus cautions that cetuximab in the perioperative setting may harm patients. The panel therefore does not recommend the use of FOLFOX plus cetuximab in patients with resectable disease and should be used with caution in those with unresectable disease that could potentially be converted to a resectable status.

Panitumumab With FOLFOX: Panitumumab in combination with either FOLFOX20,139 or FOLFIRI33 has also been studied in the first-line treatment of patients with metastatic CRC. Results from the large, open-label, randomized PRIME trial comparing panitumumab plus FOLFOX versus FOLFOX alone in patients with KRAS/NRAS wild-type advanced CRC showed a statistically significant improvement in PFS (HR, 0.72; 95% CI, 0.58–0.90; P=.004) and OS (HR, 0.77; 95% CI, 0.64–0.94; P=.009) with the addition of panitumumab.139 Therefore, the combination of FOLFOX and panitumumab remains an option as initial therapy for patients with advanced or metastatic disease. Importantly, the addition of panitumumab had a detrimental impact on PFS for patients with tumors characterized by mutated KRAS/NRAS in the PRIME trial (discussed further in “NRAS and Other KRAS Mutations,” page 384).139

Cetuximab or Panitumumab Versus Bevacizumab in First-Line

The randomized, open-label, multicenter FIRE-3 trial from the German AIO group compared the efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in first-line, KRAS exon 2 wild-type, metastatic disease.154 This trial did not meet its primary end point of investigator-read objective response rate in the 592 randomized patients (62.0% vs 58.0%; P=.18). PFS was nearly identical between the arms of the study, but a statistically significant improvement in OS was reported in the cetuximab arm (28.7 vs 25.0 months; HR, 0.77; 95% CI, 0.62–0.96; P=.017). The panel has several criticisms of the trial, including the lack of third-party review and low rates of second-line therapy.192,193 Although the rate of adverse events was similar between the arms, more skin toxicity was observed in those receiving cetuximab.

Results of the phase III CALGB/SWOG 80405 trial, comparing FOLFOX/FOLFIRI with cetuximab or bevacizumab, were recently reported.190 In this study, patients with wild-type KRAS exon 2 received either FOLFOX (73%) or FOLFIRI (27%) and were randomized to receive cetuximab or bevacizumab. The primary end point of OS was equivalent between the arms: 29.0 months (95% CI, 25.7–31.2 months) in the bevacizumab arm versus 29.9 months (95% CI, 27.6–31.2 months) in the cetuximab arm (HR, 0.92; 95% CI, 0.78–1.09; P=.34).

Results were also published for the randomized multicenter phase II PEAK trial, which compared FOLFOX/panitumumab with FOLFOX/bevacizumab in first-line treatment of patients with wild-type KRAS exon 2.194 In the subset of 170 participants with wild-type KRAS/NRAS based on extended tumor analysis, PFS was better in the panitumumab arm (13.0 vs 9.5 months; HR, 0.65; 95% CI, 0.44–0.96; P=.03), and a trend toward improved OS was seen (41.3 vs 28.9 months; HR, 0.63; 95% CI, 0.39–1.02; P=.06). Although these data are intriguing, definitive conclusions are hindered by the small sample size and limitations of subset analyses.195

Economic analyses suggest that bevacizumab may be more cost-effective than EGFR inhibitors in first-line therapy for metastatic CRC.196,197

At this time, the panel considers the addition of cetuximab, panitumumab, or bevacizumab to chemotherapy as equivalent choices in the first-line, RAS wild-type, metastatic setting.

Therapy After Progression

Decisions regarding therapy after progression of metastatic disease depend on previous therapies. The panel recommends against the use of mitomycin, alfa-interferon, taxanes, methotrexate, pemetrexed, sunitinib, sorafenib, erlotinib, or gemcitabine, either as single agents or in combination, as therapy in patients exhibiting disease progression after treatment with standard therapies. These agents have not been shown to be effective in this setting. Furthermore, no objective responses were observed when single-agent capecitabine was administered in a phase II study of patients with CRC resistant to 5-FU.198

The recommended therapy options after first progression for patients who have received prior 5-FU/LV-based or capecitabine-based therapy are dependent on the initial treatment regimen and are outlined in the guidelines.

Single-agent irinotecan administered after first progression has been shown to significantly improve OS relative to best supportive care15 or infusional 5-FU/LV.199 In the study of Rougier et al,199 median PFS was 4.2 months for irinotecan versus 2.9 months for 5-FU (P=.030), whereas Cunningham et al15 reported a survival rate at 1 year of 36.2% in the group receiving irinotecan versus 13.8% in the supportive care group (P=.0001). Furthermore, no significant differences in OS were observed in the Intergroup N9841 trial when FOLFOX was compared with irinotecan monotherapy after first progression of metastatic CRC.200

A meta-analysis of randomized trials found that the addition of a targeted agent after first-line treatment improves outcomes but also increases toxicity.201 Another meta-analysis showed an OS and PFS benefit to continuing an antiangiogenic agent after progression on an antiangiogenic agent in first-line treatment.202 Data relating to specific biologic therapies are discussed below.

Cetuximab and Panitumumab in the Non–First-Line Setting: For patients with wild-type KRAS/NRAS CRC who experienced progression on therapies not containing an EGFR inhibitor, cetuximab or panitumumab plus irinotecan, cetuximab or panitumumab plus FOLFIRI, or single-agent cetuximab or panitumumab136 is recommended. For patients with wild-type KRAS/NRAS CRC progressing on therapies that did contain an EGFR inhibitor, administration of an EGFR inhibitor is not recommended in subsequent lines of therapy. No data support switching to either cetuximab or panitumumab after failure of the other drug, and the panel recommends against this practice.

Panitumumab has been studied as a single agent in the setting of metastatic CRC for patients with disease progression on oxaliplatin/irinotecan-based chemotherapy.45 In a retrospective analysis of the subset of patients in this trial with known KRAS exon 2 tumor status, the benefit of panitumumab versus best supportive care was shown to be enhanced in patients with KRAS exon 2 wild-type tumors.7 PFS was 12.3 versus 7.3 weeks in favor of the panitumumab arm. Response rates to panitumumab were 17% versus 0% in the wild-type and mutant arms, respectively.7

Panitumumab has also been studied in combination therapy in the setting of progressing metastatic CRC. Among patients with KRAS exon 2 wild-type tumors enrolled in the large study 181 comparing FOLFIRI alone versus FOLFIRI plus panitumumab as second-line therapy for metastatic CRC, addition of the biologic agent was associated with improvement in median PFS (5.9 vs 3.9 months; HR, 0.73; 95% CI, 0.59–0.90; P=.004), although differences in OS between the arms did not reach statistical significance.36 These results were confirmed in the final results of study 181.186 Furthermore, reanalysis of samples from the trial showed that the benefit of the combination was limited to participants with no RAS mutations.203 In addition, secondary analysis from the STEPP trial showed that panitumumab in combination with irinotecan-based chemotherapy in second-line therapy has an acceptable toxicity profile.185 The randomized multicenter PICCOLO trial, which assessed the safety and efficacy of irinotecan/panitumumab, did not meet its primary end point of improved OS in patients with wild-type KRAS/NRAS tumors.166

Cetuximab has been studied both as a single agent14,109,132,136 and in combination with irinotecan14 in patients experiencing disease progression on initial therapy not containing cetuximab or panitumumab for metastatic disease. Results of a large phase III study comparing irinotecan with or without cetuximab did not show a difference in OS, but showed significant improvement in response rate and median PFS with irinotecan and cetuximab compared with irinotecan alone.204 Importantly, KRAS status was not determined in this study and toxicity was higher in the cetuximab-containing arm (eg, rash, diarrhea, electrolyte imbalances).204

In a retrospective analysis of the subset of patients with known KRAS exon 2 tumor status receiving cetuximab monotherapy as second-line therapy,109 the benefit of cetuximab versus best supportive care was shown to be enhanced in patients with KRAS exon 2 wild-type tumors.136 For those patients, median PFS was 3.7 versus 1.9 months (HR, 0.40; 95% CI, 0.30–0.54; P<.001) and median OS was 9.5 versus 4.8 months (HR, 0.55; 95% CI, 0.41–0.74; P<.001), in favor of the cetuximab arm.136

The recently published randomized, multicenter, open-label, noninferiority phase III ASPECCT trial compared single-agent cetuximab with single-agent panitumumab in the chemotherapy-refractory metastatic setting.205 The primary noninferiority OS end point was reached, with a median OS of 10.4 months (95% CI, 9.4–11.6) with panitumumab and 10.0 months (95% CI, 9.3–11.0) with cetuximab (HR, 0.97; 95% CI, 0.84–1.11). The incidence of adverse events was similar between the groups.

Bevacizumab in the Non–First-Line Setting: In the ML18147 (TML) trial, patients with metastatic CRC that progressed on regimens containing bevacizumab received second-line therapy consisting of a different chemotherapy regimen with or without bevacizumab.206 This study met its primary end point, with patients continuing on bevacizumab having a modest improvement in OS (11.2 vs 9.8 months; HR, 0.81; 95% CI, 0.69–0.94; P=.0062). Subgroup analyses from this trial found that these treatment effects were independent of KRAS exon 2 status.207

Similar results were reported from the GONO group's phase III randomized BEBYP trial, in which the PFS of patients who continued on bevacizumab plus a different chemotherapy regimen after progression on bevacizumab was 6.8 versus 5.0 months in the control arm (HR, 0.70; 95% CI, 0.52–0.95; P=.001).208 An improvement in OS was also seen in the bevacizumab arm (HR, 0.77; 95% CI, 0.56–1.06; P=.04). The EAGLE trial randomized 387 patients with disease progression after oxaliplatin-based therapy with bevacizumab to second-line therapy with FOLFIRI plus either 5 or 10 mg/kg of bevacizumab.209 No difference was seen in PFS or time to treatment failure between the arms, indicating that 5 mg/kg of bevacizumab is an appropriate dose in second-line treatment of metastatic CRC.

The continuation of bevacizumab after progression on bevacizumab was also studied in a community oncology setting through a retrospective analysis of 573 patients from US Oncology's iKnowMed electronic medical record system.210 Bevacizumab beyond progression was associated with a longer OS (HR, 0.76; 95% CI, 0.61–0.95) and a longer postprogression OS (HR, 0.74; 95% CI, 0.60–0.93) on multivariate analysis. Analyses of the ARIES observational cohort found similar results, with longer postprogression survival with continuation of bevacizumab (HR, 0.84; 95% CI, 0.73–0.97).211

Overall, these data (along with data from the VELOUR trial, discussed later) show that the continuation of VEGF blockade in second-line therapy offers a very modest but statistically significant OS benefit. The panel added the continuation of bevacizumab to the second-line treatment options in the 2013 versions of the NCCN Guidelines for Colon and Rectal Cancers. It may be added to any regimen that does not contain another targeted agent. The panel recognizes the lack of data suggesting a benefit to bevacizumab with irinotecan alone in this setting, but believes that the option is acceptable, especially in patients whose disease progressed on a 5-FU– or capecitabine-based regimen. When an angiogenic agent is used in second-line therapy, bevacizumab is preferred over ziv-aflibercept and ramucirumab (discussed later), based on toxicity and/or cost.212

It may also be appropriate to consider adding bevacizumab to chemotherapy after progression of metastatic disease if it was not used in initial therapy.23 The randomized phase III ECOG E3200 study in patients who experienced progression through a first-line non–bevacizumab-containing regimen showed that the addition of bevacizumab to second-line FOLFOX modestly improved survival.23 Median OS was 12.9 months for patients receiving FOLFOX plus bevacizumab compared with 10.8 months for patients treated with FOLFOX alone (P=.0011).23 Use of single-agent bevacizumab is not recommended because it was shown to have inferior efficacy compared with the FOLFOX alone or FOLFOX plus bevacizumab treatment arms.23

Ziv-Aflibercept: Ziv-aflibercept is a recombinant protein that has part of the human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1.213 It is designed to function as a VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis. The VELOUR trial tested second-line ziv-aflibercept in patients with metastatic CRC that progressed after one regimen containing oxaliplatin. The trial met its primary end point with a small improvement in OS (13.5 months for FOLFIRI/ziv-aflibercept vs 12.1 months for FOLFIRI/placebo; HR, 0.82; 95% CI, 0.71–0.94; P=.003).47 A prespecified subgroup analysis from the VELOUR trial found that median OS in the ziv-aflibercept arm versus the placebo arm was 12.5 months (95% CI, 10.8–15.5) versus 11.7 months (95% CI, 9.8–13.8) in patients with prior bevacizumab treatment and 13.9 months (95% CI, 12.7–15.6) versus 12.4 months (95% CI, 11.2–13.5) in patients with no prior bevacizumab treatment.214

Adverse events associated with ziv-aflibercept treatment in the VELOUR trial led to discontinuation in 26.6% of patients compared with a 12.1% discontinuation in the placebo group.47 The most common causes for discontinuation were asthenia/fatigue, infections, diarrhea, hypertension, and venous thromboembolic events.

Ziv-aflibercept has only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients. No data suggest activity of FOLFIRI plus ziv-aflibercept in patients who progressed on FOLFIRI plus bevacizumab or vice versa, and no data suggest activity of single-agent ziv-aflibercept. Furthermore, the addition of ziv-aflibercept to FOLFIRI in first-line therapy of patients with metastatic CRC in the phase II AFFIRM study had no benefit and increased toxicity.215 Thus, the panel added ziv-aflibercept as a second-line treatment option in combination with FOLFIRI or irinotecan only after progression on therapy not containing irinotecan. However, the panel prefers bevacizumab over zivaflibercept and ramucirumab in this setting, based on toxicity and/or cost.212

Ramucirumab: Another antiangiogenic agent, ramucirumab, is a human monoclonal antibody that targets the extracellular domain of VEGF receptor 2 to block VEGF signaling.216 In the multicenter, phase III RAISE trial, 1,072 patients with metastatic CRC whose disease progressed on first-line therapy with fluoropyrimidine/oxaliplatin/bevacizumab were randomized to FOLFIRI with either ramucirumab or placebo.217 The primary end point of OS in the intent-to-treat population was met at 13.3 and 11.7 months in the ramucirumab and placebo groups, respectively, for an HR of 0.84 (95% CI, 0.73–0.98; P=.02). PFS was also improved with the addition of ramucirumab, at 5.7 and 4.5 months for the 2 arms (HR, 0.79; 95% CI, 0.70–0.90; P<.0005).

Rates of discontinuation due to adverse events in the RAISE trial were 11.5% in the ramucirumab arm and 4.5% in the placebo arm. The most common grade 3 or worse adverse events were neutropenia, hypertension, diarrhea, and fatigue.

Considering the results of the RAISE trial, the panel added ramucirumab as a second-line treatment option in combination with FOLFIRI or irinotecan after progression on therapy not containing irinotecan. As with ziv-aflibercept, no data suggest activity of FOLFIRI plus ramucirumab in patients whose disease progressed on FOLFIRI plus bevacizumab or vice versa, and no data suggest activity of single-agent ramucirumab. When an angiogenic agent is used in this setting, the panel prefers bevacizumab over ziv-aflibercept and ramucirumab, because of toxicity and/or cost.212

Regorafenib: Regorafenib is a small molecule inhibitor of multiple kinases (including VEGF receptors, fibroblast growth factor [FGF] receptors, platelet-derived growth factor [PDGF] receptors, BRAF, KIT, and RET) that are involved with various processes, including tumor growth and angiogenesis.218 The phase III CORRECT trial randomized 760 patients whose disease progressed on standard therapy to best supportive care with placebo or regorafenib.27 The trial met its primary endpoint of OS (6.4 months for regorafenib vs 5.0 months for placebo; HR, 0.77; 95% CI, 0.64–0.94; P=.005). PFS was also significantly but modestly improved (1.9 vs 1.7 months; HR, 0.49; 95% CI, 0.42–0.58; P<.000001).

The randomized, double-blind, phase III CONCUR trial was performed in China, Hong Kong, South Korea, Taiwan, and Vietnam.219 Patients with progressive metastatic CRC were randomized 2:1 to receive regorafenib or placebo after ≥2 previous treatment regimens. After a median follow-up of 7.4 months, the primary end point of OS was met in the 204 randomized patients (8.8 months in the regorafenib arm vs 6.3 months in the placebo arm; HR, 0.55; 95% CI, 0.40–0.77; P<.001).

Regorafenib has only shown activity in patients whose disease has progressed on all standard therapy. Therefore, the panel added regorafenib as an additional line of therapy for patients with metastatic CRC refractory to chemotherapy. It can be given before or after trifluridine/tipiracil; no data inform the best order of these therapies.

The most common ≥grade 3 adverse events in the regorafenib arm of the CORRECT trial were hand-foot skin reaction (17%), fatigue (10%), hypertension (7%), diarrhea (7%), and rash/desquamation (6%).27 Severe and fatal liver toxicity occurred in 0.3% of 1,100 patients treated with regorafenib across all trials.218 In a meta-analysis of 4 studies that included 1,078 patients treated with regorafenib for CRC, gastrointestinal stromal tumor, renal cell carcinoma, or hepatocellular carcinoma, the overall incidence of all-grade and high-grade hand-foot skin reactions was 60.5% and 20.4%, respectively.220 In the subset of 500 patients with CRC, the incidence of all-grade hand-foot skin reaction was 46.6%.

The phase IIIb CONSIGN trial assessed the safety of regorafenib in 2,872 patients from 25 countries with refractory metastatic CRC.221 The REBECCA study also assessed the safety and efficacy of regorafenib in a cohort of 654 patients with metastatic CRC within a compassionate use program.222 The safety profile of regorafenib in both of these trials was consistent with that seen in the CORRECT trial.

Trifluridine/Tipiracil (TAS-102): Trifluridine/tipiracil is an oral combination drug, consisting of a cytotoxic thymidine analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride, which prevents the degradation of trifluridine. Early clinical studies of the drug in patients with CRC were promising.223,224

Results of the double-blind randomized controlled international phase III RECOURSE trial were published in 2015,35 followed shortly thereafter by FDA approval of trifluridine/tipiracil.225 In this trial, which involved 800 patients with metastatic CRC who progressed through at least 2 prior regimens randomized 2:1 to receive trifluridine/tipiracil or placebo, the primary end point of OS was met (5.3 vs 7.1 months; HR, 0.68; 95% CI, 0.58–0.81; P<.001).35 Improvement was also seen in the secondary end point of PFS (1.7 vs 2.0 months; HR, 0.48; 95% CI, 0.41–0.57; P<.001). The most common adverse events associated with trifluridine/tipiracil were neutropenia (38%), leukopenia (21%), and febrile neutropenia (4%); one drug-related death occurred. A postmarketing surveillance study did not reveal any unexpected safety signals.226

The panel added trifluridine/tipiracil as an additional treatment option for patients whose disease has progressed through standard therapies. It can be given before or after regorafenib; no data inform the best order of these therapies. The 144 patients in RECOURSE who had prior exposure to regorafenib obtained similar OS benefit from trifluridine/tipiracil (HR, 0.69; 95% CI, 0.45–1.05) as the 656 patients who did not (HR, 0.69; 95% CI, 0.57–0.83).

Pembrolizumab and Nivolumab: The percentage of stage IV colorectal tumors characterized as MSI-H (mismatch repair–deficient [dMMR]) ranged from 3.5% to 5.0% in clinical trials and was 6.5% in the Nurses' Health Study and Health Professionals Follow-up Study.227229 dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. However, programmed cell death ligands 1 and 2 (PD-L1 and PD-L2) on tumor cells can suppress the immune response by binding to programmed cell death protein 1 (PD-1) receptor on T-effector cells. This system evolved to protect the host from an unchecked immune response. Many tumors upregulate PD-L1 and thus evade the immune system.230 Therefore, it has been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.

Pembrolizumab is a humanized, IgG4 monoclonal antibody that binds to PD-1 with high affinity, preventing its interaction with PD-L1 and PD-L2 and thus allowing immune recognition and response. Pembrolizumab is FDA-approved for the treatment of some patients with unresectable or metastatic melanoma or metastatic non–small cell lung cancer.231

A recent phase II study evaluated the activity of pembrolizumab in 11 patients with dMMR CRC, 21 patients with MMR-proficient CRC, and 9 patients with dMMR non–colorectal carcinomas.232 All patients had progressive metastatic disease; the patients in the CRC arms had progressed through 2 to 4 previous therapies. The primary end points were the immune-related objective response rate and the 20-week immune-related PFS rate. The immune-related objective response rates were 40% (95% CI, 12%–74%) in the dMMR CRC group, 0% (95% CI, 0%–20%) in the MMR-proficient CRC group, and 71% (95% CI, 29%–96%) in the dMMR non–colorectal carcinoma group. The 20-week immune-related PFS rates were 78% (95% CI, 40–97), 11% (95% CI, 1–35), and 67% (95% CI, 22–96), respectively. These results indicate that MSI is a predictive marker for the effectiveness of pembrolizumab across tumor types. Furthermore, the median PFS and OS were not reached in the arm with dMMR CRC, and were 2.2 and 5.0 months, respectively, in the MMR-proficient CRC group (HR for disease progression or death, 0.10; P<.001).

Nivolumab is another humanized IgG4 PD-1 blocking antibody, with FDA indications in melanoma and non–small cell lung cancer.233 Nivolumab was studied with or without ipilimumab in patients with metastatic CRC in a phase II trial.234 The median PFS was 5.3 months (95% CI, 1.4–not estimable) in the patients with MMR-deficient CRC who received nivolumab monotherapy, not reached in the patients with MMR-deficient CRC who received nivolumab plus ipilimumab, and 1.4 months (95% CI, 1.2–1.9) in the pooled MMR-proficient group.

Based on these data, the panel recommends pembrolizumab or nivolumab as treatment options in patients with metastatic MMR-deficient CRC in second- or third-line therapy. Patients who experience disease progression on either of these drugs should not be offered the other. Additional clinical trials are ongoing to confirm the benefit of these drugs in this setting.

Although PD-1 immune checkpoint inhibitors are generally well tolerated, serious adverse reactions—many immune-mediated—occur in as many as 21% to 41% of patients.232,234,235 The most common immune-mediated side effects are to the skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems.236238 Pneumonitis, occurring in approximately 3% to 7% of patients on pembrolizumab or nivolumab, is one of the most serious side effects of PD-1 inhibitors.236,239241

Cetuximab or Panitumumab Versus Bevacizumab in Second-Line: The randomized, multicenter, phase II SPIRITT trial randomized 182 patients with KRAS wild-type tumors whose disease progressed on first-line oxaliplatin-based therapy plus bevacizumab to FOLFIRI plus bevacizumab or FOLFIRI plus panitumumab.242 No difference was seen in the primary end point of PFS between the arms (7.7 months in the panitumumab arm vs 9.2 months in the bevacizumab arm; HR, 1.01; 95% CI, 0.68–1.50; P=.97).

Individual Disclosures for the Colon Cancer Panel

T1

References

  • 1.

    SiegelRLMillerKDJemalA. Cancer statistics, 2016. CA Cancer J Clin2016;66:730.

  • 2.

    ChengLEngCNiemanLZ. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol2011;34:573580.

    • Search Google Scholar
    • Export Citation
  • 3.

    HenleySJSinghSDKingJ. Invasive cancer incidence and survival—United States, 2011. MMWR Morb Mortal Wkly Rep2015;64:237242.

  • 4.

    SiegelRWardEBrawleyOJemalA. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin2011;61:212236.

    • Search Google Scholar
    • Export Citation
  • 5.

    BaileyCEHuCYYouYN. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surg2014:16.

    • Search Google Scholar
    • Export Citation
  • 6.

    AminMBGreeneFLEdgeS eds. AJCC Cancer Staging Manual8th ed.New York: Springer; 2016.

  • 7.

    AmadoRGWolfMPeetersM. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol2008;26:16261634.

    • Search Google Scholar
    • Export Citation
  • 8.

    AndreTLouvetCMaindrault-GoebelF. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer1999;35:13431347.

    • Search Google Scholar
    • Export Citation
  • 9.

    BartlettDLBerlinJLauwersGY. Chemotherapy and regional therapy of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol2006;13:12841292.

    • Search Google Scholar
    • Export Citation
  • 10.

    BurokerTRO'ConnellMJWieandHS. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol1994;12:1420.

    • Search Google Scholar
    • Export Citation
  • 11.

    CassidyJClarkeSDiaz-RubioE. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol2008;26:20062012.

    • Search Google Scholar
    • Export Citation
  • 12.

    CheesemanSLJoelSPChesterJD. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer2002;87:393399.

    • Search Google Scholar
    • Export Citation
  • 13.

    ColucciGGebbiaVPaolettiG. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol2005;23:48664875.

    • Search Google Scholar
    • Export Citation
  • 14.

    CunninghamDHumbletYSienaS. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med2004;351:337345.

    • Search Google Scholar
    • Export Citation
  • 15.

    CunninghamDPyrhonenSJamesRD. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet1998;352:14131418.

    • Search Google Scholar
    • Export Citation
  • 16.

    de GramontABossetJFMilanC. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol1997;15:808815.

    • Search Google Scholar
    • Export Citation
  • 17.

    de GramontAFigerASeymourM. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol2000;18:29382947.

    • Search Google Scholar
    • Export Citation
  • 18.

    DelaunoitTGoldbergRMSargentDJ. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup trial N9741. Cancer2004;101:21702176.

    • Search Google Scholar
    • Export Citation
  • 19.

    DouillardJYCunninghamDRothAD. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet2000;355:10411047.

    • Search Google Scholar
    • Export Citation
  • 20.

    DouillardJYSienaSCassidyJ. 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 Oncol2010;28:46974705.

    • Search Google Scholar
    • Export Citation
  • 21.

    FalconeARicciSBrunettiI. 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 Oncol2007;25:16701676.

    • Search Google Scholar
    • Export Citation
  • 22.

    FuchsCSMooreMRHarkerG. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol2003;21:807814.

    • Search Google Scholar
    • Export Citation
  • 23.

    GiantonioBJCatalanoPJMeropolNJ. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol2007;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 24.

    GoldbergRM. Therapy for metastatic colorectal cancer. Oncologist2006;11:981987.

  • 25.

    GoldbergRMRothenbergMLVan CutsemE. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist2007;12:3850.

    • Search Google Scholar
    • Export Citation
  • 26.

    GoldbergRMSargentDJMortonRF. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol2004;22:2330.

    • Search Google Scholar
    • Export Citation
  • 27.

    GrotheyAVan CutsemESobreroA. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet2013;381:303312.

    • Search Google Scholar
    • Export Citation
  • 28.

    HallerDGRothenbergMLWongAO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol2008;26:45444550.

    • Search Google Scholar
    • Export Citation
  • 29.

    HurwitzHIFehrenbacherLHainsworthJD. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol2005;23:35023508.

    • Search Google Scholar
    • Export Citation
  • 30.

    JagerEHeikeMBernhardH. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol1996;14:22742279.

    • Search Google Scholar
    • Export Citation
  • 31.

    KabbinavarFFHambletonJMassRD. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol2005;23:37063712.

    • Search Google Scholar
    • Export Citation
  • 32.

    KellyHGoldbergRM. Systemic therapy for metastatic colorectal cancer: current options, current evidence. J Clin Oncol2005;23:45534560.

    • Search Google Scholar
    • Export Citation
  • 33.

    KohneCHHofheinzRMineurL. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol2012;138:6572.

    • Search Google Scholar
    • Export Citation
  • 34.

    Maindrault-GoebelFLouvetCAndreT. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer1999;35:13381342.

    • Search Google Scholar
    • Export Citation
  • 35.

    MayerRJVan CutsemEFalconeA. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med2015;372:19091919.

  • 36.

    PeetersMPriceTJCervantesA. 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 Oncol2010;28:47064713.

    • Search Google Scholar
    • Export Citation
  • 37.

    PetrelliNHerreraLRustumY. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol1987;5:15591565.

    • Search Google Scholar
    • Export Citation
  • 38.

    ReidyDLChungKYTimoneyJP. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol2007;25:26912695.

  • 39.

    SaltzLBClarkeSDiaz-RubioE. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol2008;26:20132019.

    • Search Google Scholar
    • Export Citation
  • 40.

    SouglakosJAndroulakisNSyrigosK. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer2006;94:798805.

    • Search Google Scholar
    • Export Citation
  • 41.

    TolJKoopmanMCatsA. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med2009;360:563572.

  • 42.

    Van CutsemE. Challenges in the use of epidermal growth factor receptor inhibitors in colorectal cancer. Oncologist2006;11:10101017.

  • 43.

    Van CutsemEHoffPMHarperP. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer2004;90:11901197.

    • Search Google Scholar
    • Export Citation
  • 44.

    Van CutsemEKohneCHHitreE. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med2009;360:14081417.

    • Search Google Scholar
    • Export Citation
  • 45.

    Van CutsemEPeetersMSienaS. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol2007;25:16581664.

    • Search Google Scholar
    • Export Citation
  • 46.

    Van CutsemETwelvesCCassidyJ. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol2001;19:40974106.

    • Search Google Scholar
    • Export Citation
  • 47.

    Van CutsemETaberneroJLakomyR. 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 Oncol2012;30:34993506.

    • Search Google Scholar
    • Export Citation
  • 48.

    WolmarkNRocketteHFisherB. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol1993;11:18791887.

    • Search Google Scholar
    • Export Citation
  • 49.

    LentzFTranAReyE. Pharmacogenomics of fluorouracil, irinotecan, and oxaliplatin in hepatic metastases of colorectal cancer: clinical implications. Am J Pharmacogenomics2005;5:2133.

    • Search Google Scholar
    • Export Citation
  • 50.

    O'DwyerPJ. The present and future of angiogenesis-directed treatments of colorectal cancer. Oncologist2006;11:992998.

  • 51.

    RaymondEFaivreSWoynarowskiJMChaneySG. Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol1998;25:412.

  • 52.

    RothenbergMLBlankeCD. Topoisomerase I inhibitors in the treatment of colorectal cancer. Semin Oncol1999;26:632639.

  • 53.

    TournigandCAndreTAchilleE. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol2004;22:229237.

    • Search Google Scholar
    • Export Citation
  • 54.

    CassidyJTaberneroJTwelvesC. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol2004;22:20842091.

    • Search Google Scholar
    • Export Citation
  • 55.

    PorschenRArkenauHTKubickaS. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol2007;25:42174223.

    • Search Google Scholar
    • Export Citation
  • 56.

    KirsteinMMLangeAPrenzlerA. Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data. Oncologist2014;19:11561168.

    • Search Google Scholar
    • Export Citation
  • 57.

    DucreuxMMalkaDMendiboureJ. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol2011;12:10321044.

    • Search Google Scholar
    • Export Citation
  • 58.

    KoopmanMAntoniniNFDoumaJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet2007;370:135142.

    • Search Google Scholar
    • Export Citation
  • 59.

    SeymourMTMaughanTSLedermannJA. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet2007;370:143152.

    • Search Google Scholar
    • Export Citation
  • 60.

    GrotheyASargentDGoldbergRMSchmollHJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol2004;22:12091214.

    • Search Google Scholar
    • Export Citation
  • 61.

    SargentDJKohneCHSanoffHK. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol2009;27:19481955.

    • Search Google Scholar
    • Export Citation
  • 62.

    SimkensLHvan TinterenHMayA. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet2015;385:18431852.

    • Search Google Scholar
    • Export Citation
  • 63.

    Hegewisch-BeckerSGraevenULerchenmullerCA. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol2015;16:13551369.

    • Search Google Scholar
    • Export Citation
  • 64.

    KoeberleDBetticherDCvon MoosR. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol2015;26:709714.

    • Search Google Scholar
    • Export Citation
  • 65.

    TournigandCChibaudelBSamsonB. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol2015;16:14931505.

    • Search Google Scholar
    • Export Citation
  • 66.

    HagmanHFrodinJEBerglundA. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol2016;27:140147.

    • Search Google Scholar
    • Export Citation
  • 67.

    XuWGongYKuangM. Survival benefit and safety of bevacizumab in combination with erlotinib as maintenance therapy in patients with metastatic colorectal cancer: a meta-analysis. Clin Drug Investig2017;37:155165.

    • Search Google Scholar
    • Export Citation
  • 68.

    LuoHYLiYHWangW. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol2016;27:10741081.

    • Search Google Scholar
    • Export Citation
  • 69.

    AVASTIN [package insert]. South San Francisco, CA: Genentech, Inc.; 2015.

  • 70.

    HurwitzHFehrenbacherLNovotnyW. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 71.

    KabbinavarFHurwitzHIFehrenbacherL. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol2003;21:6065.

    • Search Google Scholar
    • Export Citation
  • 72.

    KabbinavarFFSchulzJMcCleodM. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol2005;23:36973705.

    • Search Google Scholar
    • Export Citation
  • 73.

    PetrelliFBorgonovoKCabidduM. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin Colorectal Cancer2013;12:145151.

    • Search Google Scholar
    • Export Citation
  • 74.

    HurwitzHIBekaii-SaabTSBendellJC. Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin((R)) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study. Clin Oncol (R Coll Radiol)2014;26:323332.

    • Search Google Scholar
    • Export Citation
  • 75.

    Fourrier-ReglatASmithDRouyerM. Survival outcomes of bevacizumab in first-line metastatic colorectal cancer in a real-life setting: results of the ETNA cohort. Target Oncol2014;9:311319.

    • Search Google Scholar
    • Export Citation
  • 76.

    BotrelTEClarkLGPaladiniLClarkOA. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer2016;16:677.

    • Search Google Scholar
    • Export Citation
  • 77.

    CaoYTanAGaoF. A meta-analysis of randomized controlled trials comparing chemotherapy plus bevacizumab with chemotherapy alone in metastatic colorectal cancer. Int J Colorectal Dis2009;24:677685.

    • Search Google Scholar
    • Export Citation
  • 78.

    HuWXuWLiaoXHeH. Bevacizumab in combination with first-line chemotherapy in patients with metastatic colorectal cancer: a meta-analysis. Minerva Chir2015;70:451458.

    • Search Google Scholar
    • Export Citation
  • 79.

    HurwitzHITebbuttNCKabbinavarF. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist2013;18:10041012.

    • Search Google Scholar
    • Export Citation
  • 80.

    LoupakisFBriaEVaccaroV. Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials. J Exp Clin Cancer Res2010;29:58.

    • Search Google Scholar
    • Export Citation
  • 81.

    LvCWuSZhengD. The efficacy of additional bevacizumab to cytotoxic chemotherapy regimens for the treatment of colorectal cancer: an updated meta-analysis for randomized trials. Cancer Biother Radiopharm2013;28:501509.

    • Search Google Scholar
    • Export Citation
  • 82.

    QuCYZhengYZhouM. Value of bevacizumab in treatment of colorectal cancer: a meta-analysis. World J Gastroenterol2015;21:50725080.

  • 83.

    WelchSSpithoffKRumbleRBMarounJ. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol2010;21:11521162.

    • Search Google Scholar
    • Export Citation
  • 84.

    ZhangGZhouXLinC. Efficacy of chemotherapy plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer: a meta-analysis and up-date. Int J Clin Exp Med2015;8:14341445.

    • Search Google Scholar
    • Export Citation
  • 85.

    MacedoLTda Costa LimaABSasseAD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer2012;12:89.

    • Search Google Scholar
    • Export Citation
  • 86.

    MeyerhardtJALiLSanoffHK. Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol2012;30:608615.

    • Search Google Scholar
    • Export Citation
  • 87.

    HartmannHMullerJMarschnerN. Is there a difference in demography and clinical characteristics in patients treated with and without bevacizumab?J Clin Oncol2012;30:33173318; author reply 3318.

    • Search Google Scholar
    • Export Citation
  • 88.

    HurwitzHILymanGH. Registries and randomized trials in assessing the effects of bevacizumab in colorectal cancer: is there a common theme?J Clin Oncol2012;30:580581.

    • Search Google Scholar
    • Export Citation
  • 89.

    AllegraCJYothersGO'ConnellMJ. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol2011;29:1116.

    • Search Google Scholar
    • Export Citation
  • 90.

    de GramontAVan CutsemESchmollHJ. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol2012;13:12251233.

    • Search Google Scholar
    • Export Citation
  • 91.

    RanpuraVHapaniSWuS. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA2011;305:487494.

  • 92.

    HurwitzHISaltzLBVan CutsemE. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol2011;29:17571764.

    • Search Google Scholar
    • Export Citation
  • 93.

    DaiFShuLBianY. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig2013;33:779788.

    • Search Google Scholar
    • Export Citation
  • 94.

    HochsterHSHartLLRamanathanRK. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol2008;26:35233529.

    • Search Google Scholar
    • Export Citation
  • 95.

    ScappaticciFAFehrenbacherLCartwrightT. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol2005;91:173180.

    • Search Google Scholar
    • Export Citation
  • 96.

    CannistraSAMatulonisUAPensonRT. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol2007;25:51805186.

    • Search Google Scholar
    • Export Citation
  • 97.

    GruenbergerBTamandlDSchuellerJ. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol2008;26:18301835.

    • Search Google Scholar
    • Export Citation
  • 98.

    ReddySKMorseMAHurwitzHI. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg2008;206:969106.

    • Search Google Scholar
    • Export Citation
  • 99.

    MilesDHarbeckNEscudierB. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol2011;29:8388.

    • Search Google Scholar
    • Export Citation
  • 100.

    MilesDW. Reply to P. Potemski. J Clin Oncol2011;29:e386.

  • 101.

    PotemskiP. Is the postprogression survival time really not shortened in the bevacizumab-containing arms of phase III clinical trials?J Clin Oncol2011;29:e384385.

    • Search Google Scholar
    • Export Citation
  • 102.

    Cetuximab [package insert]. Branchburg, NJ: ImClone Systems Incorporated; 2015.

  • 103.

    Vectibix [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015.

  • 104.

    PietrantonioFCremoliniCPetrelliF. First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol2015;96:156166.

    • Search Google Scholar
    • Export Citation
  • 105.

    SorichMJWieseMDRowlandA. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol2015;26:1321.

    • Search Google Scholar
    • Export Citation
  • 106.

    HelblingDBornerM. Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with the chimeric EGFR antibody cetuximab. Ann Oncol2007;18:963964.

    • Search Google Scholar
    • Export Citation
  • 107.

    HeunJHolenK. Treatment with panitumumab after a severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer: a case report. Clin Colorectal Cancer2007;6:529531.

    • Search Google Scholar
    • Export Citation
  • 108.

    ReschGSchaberl-MoserRKierP. Infusion reactions to the chimeric EGFR inhibitor cetuximab—change to the fully human anti-EGFR monoclonal antibody panitumumab is safe. Ann Oncol2011;22:486487.

    • Search Google Scholar
    • Export Citation
  • 109.

    JonkerDJO'CallaghanCJKarapetisCS. Cetuximab for the treatment of colorectal cancer. N Engl J Med2007;357:20402048.

  • 110.

    LievreABachetJBBoigeV. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol2008;26:374379.

    • Search Google Scholar
    • Export Citation
  • 111.

    PetrelliFBorgonovoKBarniS. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol2013;8:173181.

    • Search Google Scholar
    • Export Citation
  • 112.

    StintzingSKapaunCLaubenderRP. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer2013;132:236245.

    • Search Google Scholar
    • Export Citation
  • 113.

    Van CutsemETejparSVanbeckevoortD. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol2012;30:28612868.

    • Search Google Scholar
    • Export Citation
  • 114.

    BurtnessBAnadkatMBastiS. NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw2009;7(Suppl 1):S521; quiz S22–24.

    • Search Google Scholar
    • Export Citation
  • 115.

    PetrelliFCabidduMBorgonovoKBarniS. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol2012;23:16721679.

    • Search Google Scholar
    • Export Citation
  • 116.

    ZhangDYeJXuTXiongB. Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis. J Chemother2013;25:170175.

    • Search Google Scholar
    • Export Citation
  • 117.

    HechtJRMitchellEChidiacT. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol2009;27:672680.

    • Search Google Scholar
    • Export Citation
  • 118.

    BruleSYJonkerDJKarapetisCS. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer2015;51:14051414.

    • Search Google Scholar
    • Export Citation
  • 119.

    MorettoRCremoliniCRossiniD. Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer. Oncologist2016;21:988994.

    • Search Google Scholar
    • Export Citation
  • 120.

    LoupakisFYangDYauL. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst2015;107:doi: 10.1093/jnci/dju427.

    • Search Google Scholar
    • Export Citation
  • 121.

    LeeMSAdvaniSMMorrisJ. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy [abstract]. J Clin Oncol2016;34(Suppl):Abstract 3506.

    • Search Google Scholar
    • Export Citation
  • 122.

    ChenKHShaoYYChenHM. Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study. BMC Cancer2016;16:327.

    • Search Google Scholar
    • Export Citation
  • 123.

    WarschkowRSulzMCMartiL. Better survival in right-sided versus left-sided stage I - III colon cancer patients. BMC Cancer2016;16:554.

  • 124.

    SchragDWengSBrooksG. The relationship between primary tumor sidedness and prognosis in colorectal cancer [abstract]. J Clin Oncol2016;34(Suppl):Abstract 3505.

    • Search Google Scholar
    • Export Citation
  • 125.

    VenookAPNiedzwieckiDInnocentiF. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) [abstract]. J Clin Oncol2016;34(Suppl):Abstract 3504.

    • Search Google Scholar
    • Export Citation
  • 126.

    VenookAPNiedzwieckiDInnocentiF. Impact of primary (1°) tumor location on Overall Survival (OS) and Progression Free Survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of All RAS wt patients on CALGB / SWOG 80405 (Alliance) [abstract]. Presented at ESMO Congress 2016; October7–112016; Copenhagen, Denmark.

    • Search Google Scholar
    • Export Citation
  • 127.

    AntonacopoulouAGTsamandasACPetsasT. EGFR, HER-2 and COX-2 levels in colorectal cancer. Histopathology2008;53:698706.

  • 128.

    McKayJAMurrayLJCurranS. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur J Cancer2002;38:22582264.

    • Search Google Scholar
    • Export Citation
  • 129.

    SpanoJPLagorceCAtlanD. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol2005;16:102108.

  • 130.

    YenLCUenYHWuDC. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg2010;251:254260.

    • Search Google Scholar
    • Export Citation
  • 131.

    HechtJRMitchellENeubauerMA. Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res2010;16:22052213.

    • Search Google Scholar
    • Export Citation
  • 132.

    SaltzLBMeropolNJLoehrerPJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol2004;22:12011208.

    • Search Google Scholar
    • Export Citation
  • 133.

    BaselgaJRosenN. Determinants of RASistance to anti-epidermal growth factor receptor agents. J Clin Oncol2008;26:15821584.

  • 134.

    BokemeyerCBondarenkoIMakhsonA. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol2009;27:663671.

    • Search Google Scholar
    • Export Citation
  • 135.

    De RoockWPiessevauxHDe SchutterJ. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol2008;19:508515.

    • Search Google Scholar
    • Export Citation
  • 136.

    KarapetisCSKhambata-FordSJonkerDJ. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med2008;359:17571765.

    • Search Google Scholar
    • Export Citation
  • 137.

    Khambata-FordSGarrettCRMeropolNJ. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol2007;25:32303237.

    • Search Google Scholar
    • Export Citation
  • 138.

    TejparSCelikISchlichtingM. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol2012;30:35703577.

    • Search Google Scholar
    • Export Citation
  • 139.

    DouillardJYOlinerKSSienaS. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med2013;369:10231034.

  • 140.

    AllegraCJRumbleRBHamiltonSR. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology provisional clinical opinion update 2015. J Clin Oncol2016;34:179185.

    • Search Google Scholar
    • Export Citation
  • 141.

    ArtaleSSartore-BianchiAVeroneseSM. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol2008;26:42174219.

    • Search Google Scholar
    • Export Citation
  • 142.

    Etienne-GrimaldiMCFormentoJLFrancoualM. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res2008;14:48304835.

    • Search Google Scholar
    • Export Citation
  • 143.

    KnijnNMekenkampLJKlompM. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer2011;104:10201026.

    • Search Google Scholar
    • Export Citation
  • 144.

    WangHLLopateguiJAminMBPattersonSD. KRAS mutation testing in human cancers: the pathologist's role in the era of personalized medicine. Adv Anat Pathol2010;17:2332.

    • Search Google Scholar
    • Export Citation
  • 145.

    MonzonFAOginoSHammondMEH. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med2009;133:16001606.

    • Search Google Scholar
    • Export Citation
  • 146.

    RothADTejparSDelorenziM. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol2010;28:466474.

    • Search Google Scholar
    • Export Citation
  • 147.

    DahabrehIJTerasawaTCastaldiPJTrikalinosTA. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med2011;154:3749.

    • Search Google Scholar
    • Export Citation
  • 148.

    YoonHHTougeronDShiQ. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res2014;20:30333043.

    • Search Google Scholar
    • Export Citation
  • 149.

    De RoockWJonkerDJDi NicolantonioF. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA2010;304:18121820.

    • Search Google Scholar
    • Export Citation
  • 150.

    PeetersMDouillardJYVan CutsemE. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol2013;31:759765.

    • Search Google Scholar
    • Export Citation
  • 151.

    SchirripaMLoupakisFLonardiS. Phase II study of single-agent cetuximab in KRAS G13D mutant metastatic colorectal cancer. Ann Oncol2015;26:2503.

    • Search Google Scholar
    • Export Citation
  • 152.

    SegelovEThavaneswaranSWaringPM. Response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the KRAS G13D mutation: Australasian Gastro-Intestinal Trials Group ICECREAM study. J Clin Oncol2016;34:22582264.

    • Search Google Scholar
    • Export Citation
  • 153.

    PriceTJBruhnMALeeCK. Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX study involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer. Br J Cancer2015;112:963970.

    • Search Google Scholar
    • Export Citation
  • 154.

    HeinemannVvon WeikersthalLFDeckerT. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol2014;15:10651075.

    • Search Google Scholar
    • Export Citation
  • 155.

    TolJNagtegaalIDPuntCJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med2009;361:9899.

  • 156.

    Van CutsemEKohneCHLangI. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol2011;29:20112019.

    • Search Google Scholar
    • Export Citation
  • 157.

    MaughanTSAdamsRASmithCG. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet2011;377:21032114.

    • Search Google Scholar
    • Export Citation
  • 158.

    DaviesHBignellGRCoxC. Mutations of the BRAF gene in human cancer. Nature2002;417:949954.

  • 159.

    IkenoueTHikibaYKanaiF. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res2003;63:81328137.

    • Search Google Scholar
    • Export Citation
  • 160.

    WanPTGarnettMJRoeSM. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell2004;116:855867.

  • 161.

    BokemeyerCCutsemEVRougierP. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer2012;48:14661475.

    • Search Google Scholar
    • Export Citation
  • 162.

    Di NicolantonioFMartiniMMolinariF. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol2008;26:57055712.

    • Search Google Scholar
    • Export Citation
  • 163.

    Laurent-PuigPCayreAManceauG. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol2009;27:59245930.

    • Search Google Scholar
    • Export Citation
  • 164.

    LoupakisFRuzzoACremoliniC. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer2009;101:715721.

    • Search Google Scholar
    • Export Citation
  • 165.

    De RoockWClaesBBernasconiD. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol2010;11:753762.

    • Search Google Scholar
    • Export Citation
  • 166.

    SeymourMTBrownSRMiddletonG. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol2013;14:749759.

    • Search Google Scholar
    • Export Citation
  • 167.

    PietrantonioFPetrelliFCoinuA. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer2015;51:587594.

    • Search Google Scholar
    • Export Citation
  • 168.

    RowlandADiasMMWieseMD. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer2015;112:18881894.

    • Search Google Scholar
    • Export Citation
  • 169.

    ChenDHuangJFLiuK. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One2014;9:e90607.

    • Search Google Scholar
    • Export Citation
  • 170.

    PriceTJHardinghamJELeeCK. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol2011;29:26752682.

    • Search Google Scholar
    • Export Citation
  • 171.

    Safaee ArdekaniGJafarnejadSMTanL. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One2012;7:e47054.

    • Search Google Scholar
    • Export Citation
  • 172.

    SamowitzWSSweeneyCHerrickJ. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res2005;65:60636069.

    • Search Google Scholar
    • Export Citation
  • 173.

    SaridakiZPapadatos-PastosDTzardiM. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome. Br J Cancer2010;102:17621768.

    • Search Google Scholar
    • Export Citation
  • 174.

    XuQXuATZhuMM. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a meta-analysis. J Dig Dis2013;14:409416.

    • Search Google Scholar
    • Export Citation
  • 175.

    ClancyCBurkeJPKaladyMFCoffeyJC. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Colorectal Dis2013;15:e711718.

    • Search Google Scholar
    • Export Citation
  • 176.

    SantiniDSpotoCLoupakisF. High concordance of BRAF status between primary colorectal tumours and related metastatic sites: implications for clinical practice. Ann Oncol2010;21:1565.

    • Search Google Scholar
    • Export Citation
  • 177.

    Sartore-BianchiATrusolinoLMartinoC. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol2016;17:738746.

    • Search Google Scholar
    • Export Citation
  • 178.

    RaghavKPSOvermanMJYuR. HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer [abstract]. J Clin Oncol2016;34(Suppl):Abstract 3517.

    • Search Google Scholar
    • Export Citation
  • 179.

    ValtortaEMartinoCSartore-BianchiA. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol2015;28:14811491.

    • Search Google Scholar
    • Export Citation
  • 180.

    HurwitzHHainsworthJDSwantonC. Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors [abstract]. J Clin Oncol2016;34(Suppl):Abstract 653.

    • Search Google Scholar
    • Export Citation
  • 181.

    WuSWMaCCLiWH. Does overexpression of HER-2 correlate with clinicopathological characteristics and prognosis in colorectal cancer? Evidence from a meta-analysis. Diagn Pathol2015;10:144.

    • Search Google Scholar
    • Export Citation
  • 182.

    MartinVLandiLMolinariF. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer2013;108:668675.

    • Search Google Scholar
    • Export Citation
  • 183.

    LangIKohneCHFolprechtG. Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorouracil and leucovorin. Eur J Cancer2013;49:439448.

    • Search Google Scholar
    • Export Citation
  • 184.

    Van CutsemELenzHJKohneCH. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol2015;33:692700.

    • Search Google Scholar
    • Export Citation
  • 185.

    MitchellEPPiperdiBLacoutureME. The efficacy and safety of panitumumab administered concomitantly with FOLFIRI or Irinotecan in second-line therapy for metastatic colorectal cancer: the secondary analysis from STEPP (Skin Toxicity Evaluation Protocol With Panitumumab) by KRAS status. Clin Colorectal Cancer2011;10:333339.

    • Search Google Scholar
    • Export Citation
  • 186.

    PeetersMPriceTJCervantesA. Final results from a randomized phase 3 study of FOLFIRI {+/–} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol2014;25:107116.

    • Search Google Scholar
    • Export Citation
  • 187.

    BokemeyerCBondarenkoIHartmannJT. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol2011;22:15351546.

    • Search Google Scholar
    • Export Citation
  • 188.

    TaiebJMaughanTBokemeyerC. Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA) and oxaliplatin in metastatic colorectal cancer (mCRC): a pooled analysis of COIN and OPUS study data [abstract]. J Clin Oncol2012;30(Suppl):Abstract 3574.

    • Search Google Scholar
    • Export Citation
  • 189.

    TveitKMGurenTGlimeliusB. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol2012;30:17551762.

    • Search Google Scholar
    • Export Citation
  • 190.

    VenookAPNiedzwieckiDLenzHJ. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) [abstract]. J Clin Oncol2014;32(Suppl):Abstract LBA3.

    • Search Google Scholar
    • Export Citation
  • 191.

    PrimroseJFalkSFinch-JonesM. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol2014;15:601611.

    • Search Google Scholar
    • Export Citation
  • 192.

    ModestDPStintzingSvon WeikersthalLF. Impact of subsequent therapies on outcome of the FIRE-3/AIO KRK0306 trial: first-line therapy with FOLFIRI plus cetuximab or bevacizumab in patients with KRAS wild-type tumors in metastatic colorectal cancer. J Clin Oncol2015;33:37183726.

    • Search Google Scholar
    • Export Citation
  • 193.

    O'NeilBHVenookAP. Trying to understand differing results of FIRE-3 and 80405: does the first treatment matter more than others?J Clin Oncol2015;33:36863688.

    • Search Google Scholar
    • Export Citation
  • 194.

    SchwartzbergLSRiveraFKarthausM. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol2014;32:22402247.

    • Search Google Scholar
    • Export Citation
  • 195.

    WolpinBMBassAJ. Managing advanced colorectal cancer: have we reached the PEAK with current therapies?J Clin Oncol2014;32:22002202.

  • 196.

    Riesco-MartinezMCBerrySRKoYJ. Cost-effectiveness analysis of different sequences of the use of epidermal growth factor receptor inhibitors for wild-type KRAS unresectable metastatic colorectal cancer. J Oncol Pract2016;12:e710723.

    • Search Google Scholar
    • Export Citation
  • 197.

    SchragDDueckACNaughtonMJ. Cost of chemotherapy for metastatic colorectal cancer with either bevacizumab or cetuximab: economic analysis of CALGB/SWOG 80405 [abstract]. J Clin Oncol2015;33(Suppl):Abstract 6504.

    • Search Google Scholar
    • Export Citation
  • 198.

    HoffPMPazdurRLassereY. Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma. J Clin Oncol2004;22:20782083.

    • Search Google Scholar
    • Export Citation
  • 199.

    RougierPVan CutsemEBajettaE. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet1998;352:14071412.

    • Search Google Scholar
    • Export Citation
  • 200.

    KimGPSargentDJMahoneyMR. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol2009;27:28482854.

    • Search Google Scholar
    • Export Citation
  • 201.

    SegelovEChanDShapiroJ. The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials. Br J Cancer2014;111:11221131.

    • Search Google Scholar
    • Export Citation
  • 202.

    HofheinzRDRonellenfitschUKubickaS. Treatment with antiangiogenic drugs in multiple lines in patients with metastatic colorectal cancer: meta-analysis of randomized trials. Gastroenterol Res Pract2016;2016:9189483.

    • Search Google Scholar
    • Export Citation
  • 203.

    PeetersMOlinerKPriceTJ. Analysis of KRAS/NRAS mutations in a phase 3 study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res2015;21:54695479.

    • Search Google Scholar
    • Export Citation
  • 204.

    SobreroAFMaurelJFehrenbacherL. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol2008;26:23112319.

    • Search Google Scholar
    • Export Citation
  • 205.

    PriceTJPeetersMKimTW. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol2014;15:569579.

    • Search Google Scholar
    • Export Citation
  • 206.

    BennounaJSastreJArnoldD. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol2013;14:2937.

    • Search Google Scholar
    • Export Citation
  • 207.

    KubickaSGreilRAndreT. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings. Ann Oncol2013;24:23422349.

    • Search Google Scholar
    • Export Citation
  • 208.

    MasiGSalvatoreLBoniL. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol2015;26:724730.

    • Search Google Scholar
    • Export Citation
  • 209.

    IwamotoSTakahashiTTamagawaH. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. Ann Oncol2015;26:14271433.

    • Search Google Scholar
    • Export Citation
  • 210.

    CartwrightTHYimYMYuE. Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology. Clin Colorectal Cancer2012;11:238246.

    • Search Google Scholar
    • Export Citation
  • 211.

    GrotheyAFlickEDCohnAL. Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study. Pharmacoepidemiol Drug Saf2014;23:726734.

    • Search Google Scholar
    • Export Citation
  • 212.

    GoldsteinDAEl-RayesBF. Considering efficacy and cost, where does ramucirumab fit in the management of metastatic colorectal cancer?Oncologist2015;20:981982.

    • Search Google Scholar
    • Export Citation
  • 213.

    ZALTRAP [package insert]. Bridgewater, NJ: Regeneron Pharmaceuticals, Inc./sanofi-aventis U.S. LLC; 2016.

  • 214.

    TaberneroJVan CutsemELakomyR. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer2014;50:320331.

    • Search Google Scholar
    • Export Citation
  • 215.

    FolprechtGPericayCSaundersMP. Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study. Ann Oncol2016;27:12731279.

    • Search Google Scholar
    • Export Citation
  • 216.

    CYRAMZA [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.

  • 217.

    TaberneroJYoshinoTCohnAL. 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 randomised, double-blind, multicentre, phase 3 study. Lancet Oncol2015;16:499508.

    • Search Google Scholar
    • Export Citation
  • 218.

    STIVARGA [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2016.

  • 219.

    LiJQinSXuR. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol2015;16:619629.

    • Search Google Scholar
    • Export Citation
  • 220.

    BelumVRWuSLacoutureME. Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs2013;31:10781086.

    • Search Google Scholar
    • Export Citation
  • 221.

    CutsemEVCiardielloFSeitzJF. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer [abstract]. Ann Oncol2015;26(Suppl 4):Abstract LBA-05.

    • Search Google Scholar
    • Export Citation
  • 222.

    AdenisAde la FouchardiereCPauleB. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBACCA) nested within a compassionate use program. BMC Cancer2016;16:412.

    • Search Google Scholar
    • Export Citation
  • 223.

    BendellJCRosenLSMayerRJ. Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. Cancer Chemother Pharmacol2015;76:925932.

    • Search Google Scholar
    • Export Citation
  • 224.

    YoshinoTMizunumaNYamazakiK. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol2012;13:9931001.

    • Search Google Scholar
    • Export Citation
  • 225.

    LONSURF [package insert]. Tokyo, Japan: Taiho Pharmaceutical Co., Ltd.; 2015.

  • 226.

    YoshinoTUetakeHFujitaN. TAS-102 safety in metastatic colorectal cancer: results from the first postmarketing surveillance study. Clin Colorectal Cancer2016;15:e205211.

    • Search Google Scholar
    • Export Citation
  • 227.

    KoopmanMKortmanGAMMekenkampL. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer2009;100:266273.

    • Search Google Scholar
    • Export Citation
  • 228.

    LochheadPKuchibaAImamuraY. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst2013;105:11511156.

    • Search Google Scholar
    • Export Citation
  • 229.

    VenderboschSNagtegaalIDMaughanTS. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res2014;20:53225330.

    • Search Google Scholar
    • Export Citation
  • 230.

    TopalianSLHodiFSBrahmerJR. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med2012;366:24432454.

  • 231.

    KEYTRUDA [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2016.

  • 232.

    LeDTUramJNWangH. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med2015;372:25092520.

  • 233.

    OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

  • 234.

    OvermanMJKopetzSMcDermottRS. Nivolumab {+/–} ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results [abstract]. J Clin Oncol2016;34(Suppl):Abstract 3501.

    • Search Google Scholar
    • Export Citation
  • 235.

    SulJBlumenthalGMJiangX. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist2016;21:643650.

    • Search Google Scholar
    • Export Citation
  • 236.

    LewisC. Programmed death-1 inhibition in cancer with a focus on non-small cell lung cancer: rationale, nursing implications, and patient management strategies. Clin J Oncol Nurs2016;20:319326.

    • Search Google Scholar
    • Export Citation
  • 237.

    HofmannLForschnerALoquaiC. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer2016;60:190209.

    • Search Google Scholar
    • Export Citation
  • 238.

    ZimmerLGoldingerSMHofmannL. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer2016;60:210225.

    • Search Google Scholar
    • Export Citation
  • 239.

    NaidooJWangXWooKM. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy[published online ahead of print September 19 2016]. J Clin Oncolpii: JCO682005.

    • Search Google Scholar
    • Export Citation
  • 240.

    NishinoMChambersESChongCR. Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res2016;4:289293.

  • 241.

    NishinoMShollLMHodiFS. Anti-PD-1-related pneumonitis during cancer immunotherapy. N Engl J Med2015;373:288290.

  • 242.

    HechtJRCohnADakhilS. SPIRITT: a randomized, multicenter, phase II study of panitumumab with FOLFIRI and bevacizumab with FOLFIRI as second-line rreatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer2015;14:7280.

    • Search Google Scholar
    • Export Citation

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    NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

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    NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

    Version 1.2017, 11-23-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, Version 1.2017

    Version 1.2017, 11-23-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • 1.

    SiegelRLMillerKDJemalA. Cancer statistics, 2016. CA Cancer J Clin2016;66:730.

  • 2.

    ChengLEngCNiemanLZ. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol2011;34:573580.

    • Search Google Scholar
    • Export Citation
  • 3.

    HenleySJSinghSDKingJ. Invasive cancer incidence and survival—United States, 2011. MMWR Morb Mortal Wkly Rep2015;64:237242.

  • 4.

    SiegelRWardEBrawleyOJemalA. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin2011;61:212236.

    • Search Google Scholar
    • Export Citation
  • 5.

    BaileyCEHuCYYouYN. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surg2014:16.

    • Search Google Scholar
    • Export Citation
  • 6.

    AminMBGreeneFLEdgeS eds. AJCC Cancer Staging Manual8th ed.New York: Springer; 2016.

  • 7.

    AmadoRGWolfMPeetersM. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol2008;26:16261634.

    • Search Google Scholar
    • Export Citation
  • 8.

    AndreTLouvetCMaindrault-GoebelF. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer1999;35:13431347.

    • Search Google Scholar
    • Export Citation
  • 9.

    BartlettDLBerlinJLauwersGY. Chemotherapy and regional therapy of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol2006;13:12841292.

    • Search Google Scholar
    • Export Citation
  • 10.

    BurokerTRO'ConnellMJWieandHS. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol1994;12:1420.

    • Search Google Scholar
    • Export Citation
  • 11.

    CassidyJClarkeSDiaz-RubioE. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol2008;26:20062012.

    • Search Google Scholar
    • Export Citation
  • 12.

    CheesemanSLJoelSPChesterJD. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer2002;87:393399.

    • Search Google Scholar
    • Export Citation
  • 13.

    ColucciGGebbiaVPaolettiG. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol2005;23:48664875.

    • Search Google Scholar
    • Export Citation
  • 14.

    CunninghamDHumbletYSienaS. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med2004;351:337345.

    • Search Google Scholar
    • Export Citation
  • 15.

    CunninghamDPyrhonenSJamesRD. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet1998;352:14131418.

    • Search Google Scholar
    • Export Citation
  • 16.

    de GramontABossetJFMilanC. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol1997;15:808815.

    • Search Google Scholar
    • Export Citation
  • 17.

    de GramontAFigerASeymourM. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol2000;18:29382947.

    • Search Google Scholar
    • Export Citation
  • 18.

    DelaunoitTGoldbergRMSargentDJ. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup trial N9741. Cancer2004;101:21702176.

    • Search Google Scholar
    • Export Citation
  • 19.

    DouillardJYCunninghamDRothAD. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet2000;355:10411047.

    • Search Google Scholar
    • Export Citation
  • 20.

    DouillardJYSienaSCassidyJ. 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 Oncol2010;28:46974705.

    • Search Google Scholar
    • Export Citation
  • 21.

    FalconeARicciSBrunettiI. 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 Oncol2007;25:16701676.

    • Search Google Scholar
    • Export Citation
  • 22.

    FuchsCSMooreMRHarkerG. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol2003;21:807814.

    • Search Google Scholar
    • Export Citation
  • 23.

    GiantonioBJCatalanoPJMeropolNJ. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol2007;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 24.

    GoldbergRM. Therapy for metastatic colorectal cancer. Oncologist2006;11:981987.

  • 25.

    GoldbergRMRothenbergMLVan CutsemE. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist2007;12:3850.

    • Search Google Scholar
    • Export Citation
  • 26.

    GoldbergRMSargentDJMortonRF. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol2004;22:2330.

    • Search Google Scholar
    • Export Citation
  • 27.

    GrotheyAVan CutsemESobreroA. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet2013;381:303312.

    • Search Google Scholar
    • Export Citation
  • 28.

    HallerDGRothenbergMLWongAO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol2008;26:45444550.

    • Search Google Scholar
    • Export Citation
  • 29.

    HurwitzHIFehrenbacherLHainsworthJD. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol2005;23:35023508.

    • Search Google Scholar
    • Export Citation
  • 30.

    JagerEHeikeMBernhardH. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol1996;14:22742279.

    • Search Google Scholar
    • Export Citation
  • 31.

    KabbinavarFFHambletonJMassRD. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol2005;23:37063712.

    • Search Google Scholar
    • Export Citation
  • 32.

    KellyHGoldbergRM. Systemic therapy for metastatic colorectal cancer: current options, current evidence. J Clin Oncol2005;23:45534560.

    • Search Google Scholar
    • Export Citation
  • 33.

    KohneCHHofheinzRMineurL. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol2012;138:6572.

    • Search Google Scholar
    • Export Citation
  • 34.

    Maindrault-GoebelFLouvetCAndreT. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer1999;35:13381342.

    • Search Google Scholar
    • Export Citation
  • 35.

    MayerRJVan CutsemEFalconeA. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med2015;372:19091919.

  • 36.

    PeetersMPriceTJCervantesA. 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 Oncol2010;28:47064713.

    • Search Google Scholar
    • Export Citation
  • 37.

    PetrelliNHerreraLRustumY. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol1987;5:15591565.

    • Search Google Scholar
    • Export Citation
  • 38.

    ReidyDLChungKYTimoneyJP. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol2007;25:26912695.

  • 39.

    SaltzLBClarkeSDiaz-RubioE. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol2008;26:20132019.

    • Search Google Scholar
    • Export Citation
  • 40.

    SouglakosJAndroulakisNSyrigosK. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer2006;94:798805.

    • Search Google Scholar</