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Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations
Authors:
Jeffrey W Clark, MD
Axel Grothey, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Diane MF Savarese, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Feb 16, 2018.

INTRODUCTION — The last 10 to 15 years have seen major advances in the treatment of metastatic colorectal cancer (mCRC). In the era when fluorouracil (FU) was the sole active agent, overall survival in phase III trials was approximately 11 to 12 months. In the modern era, the average median survival duration is now approaching three years, and five-year survival rates as high as 20 percent are reported in some trials of patients treated with chemotherapy alone [1]. These improvements have been mainly driven by the availability of new active agents, which include conventional cytotoxic agents other than FU, and biologic agents targeting angiogenesis and the epidermal growth factor receptor (EGFR).

This topic review will address the practical issues that arise when choosing the appropriate treatment strategy for individual patients with inoperable mCRC. General principles of chemotherapy treatment for mCRC, data from the clinical trials that support the recommendations, recommendations for systemic chemotherapy in older adult patients with mCRC, management of patients with potentially resectable liver metastases, and a compilation of chemotherapy regimens used for advanced CRC are discussed elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials" and "Management of potentially resectable colorectal cancer liver metastases" and "Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status" and "Treatment protocols for small and large bowel cancer".)

OVERVIEW OF THE THERAPEUTIC APPROACH — There are now nine different classes of drugs with antitumor activity in mCRC:

Fluoropyrimidines (including fluorouracil [FU], which is usually given intravenously (IV) with leucovorin [LV], and the oral agents capecitabine, S-1, and tegafur plus uracil [UFT]).

Irinotecan.

Oxaliplatin.

Cetuximab and panitumumab, two monoclonal antibodies (MoAbs) directed against the epidermal growth factor receptor (EGFR).

Bevacizumab, a MoAb targeting the vascular endothelial growth factor (VEGF), and ramucirumab, a recombinant MoAb that binds to the VEGF receptor 2 (VEGFR-2), blocking receptor activation.

Intravenous aflibercept, a recombinant fusion protein consisting of VEGF-binding portions from the human VEGF receptor 1 (VEGFR-1) and VEGFR-2 fused to the Fc portion of human immunoglobulin G1 (IgG1), functions as a decoy receptor that prevents intravascular and extravascular VEGF-A, VEGF-B, and placenta growth factor (PlGF) from binding to their receptors.

Regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3), as well as other membrane and intracellular kinases.

Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthase and, after modification within tumor cells, is incorporated into DNA, causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well.

Immunotherapy with an immune checkpoint inhibitor that targets the programmed death receptor-1 (PD-1; ie, nivolumab, pembrolizumab) may be beneficial for advanced high microsatellite instability or deficient mismatch repair (dMMR) mCRC that has progressed following conventional chemotherapy.

Despite the pace of clinical research, the best way to combine and sequence all of these drugs to optimize treatment is not yet established. In general, exposure to all active drugs, as appropriate, is more important than the specific sequence of administration.

Increasingly, biomarker expression is driving therapeutic decision-making in medicine. However, the biologic target(s) for most of the agents that are active against mCRC are unknown, with the following exceptions:

Benefit from MoAbs targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes. Furthermore, evidence increasingly suggests that response to EGFR-targeted agents is unlikely in patients whose tumors harbor a BRAF V600E mutation. Emerging data also suggest that the location of the primary tumor is another factor that influences the efficacy of anti-EGFR agents. (See 'Agents targeting the EGFR' below.)

Benefit for immunotherapy with PD-1 inhibitors appears to be limited to the subset of tumors with high levels of microsatellite instability/dMMR.

Furthermore, the choice of regimen (particularly the cytotoxic chemotherapy backbone) is also influenced by the goals of chemotherapy, which differ according to the clinical scenario:

For most patients, treatment will be palliative and not curative, and the treatment goals are to prolong overall survival and maintain quality of life (QOL) for as long as possible. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Treatment goals'.)

However, some patients with stage IV disease (particularly those with liver-limited metastases) can be surgically cured of their disease. Even selected patients with initially unresectable liver metastases may become eligible for resection if the response to chemotherapy is sufficient, although this is uncommon. This approach has been termed "conversion therapy" to distinguish it from neoadjuvant therapy that is given to patients who present upfront with apparently resectable disease. The key parameter for selecting the specific regimen in this scenario is not survival or improved QOL, but instead, response rate (ie, the ability of the regimen to shrink metastases). (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Conversion therapy for initially unresectable metastases'.)

Initial therapy — We select initial therapy based upon patient fitness, RAS and BRAF mutation status, the location of the primary tumor, and the intent of therapy. An algorithmic approach to selecting initial therapy based upon these factors is presented in the algorithm (algorithm 1).

The optimal duration of initial chemotherapy for unresectable disease in the absence of disease progression is debated. In general, the decision to permit treatment breaks during initial therapy (ie, intermittent rather than continuous therapy) must be individualized and based upon several factors, including tolerance of and response to chemotherapy, disease bulk and location, and symptomatology. (See 'Duration of initial chemotherapy' below.)

The optimal duration of therapy for patients who have potentially resectable metastases is discussed elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Conversion therapy for initially unresectable metastases'.)

Subsequent treatment and the continuum of care model — The approach to subsequent therapy is variable and might include maintenance chemotherapy (particularly for patients treated initially with an oxaliplatin-containing regimen) or a switch to a different regimen altogether because of disease progression or intolerance to the initial regimen. For patients with mCRC, the model of distinct "lines" of chemotherapy (in which regimens containing non-cross-resistant drugs are each used in succession until disease progression) is being abandoned in favor of a "continuum of care" approach [2]. This approach emphasizes an individualized treatment strategy that might include phases of maintenance chemotherapy interspersed with more aggressive treatment protocols, rechallenging patients who responded to first-line treatment with the same agents used first-line [3-6], as well as reutilization of previously administered chemotherapy agents in combination with other active drugs. (See 'Treatment at progression' below and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

Our general approach to therapy at progression is as follows:

For medically unfit patients with a poor performance status or extensive comorbidity, supportive care without chemotherapy is an option.

For fit patients initially treated with an oxaliplatin-containing chemotherapy doublet (ie, oxaliplatin plus LV and short-term infusional FU [FOLFOX] or oxaliplatin plus capecitabine [XELOX]), we switch to irinotecan plus LV and short-term infusional FU (FOLFIRI) or irinotecan alone at the time of disease progression. For patients initially treated with FOLFIRI, we switch to an oxaliplatin-based regimen at the time of progression. (See 'The chemotherapy backbone' below.)

For patients initially treated with bevacizumab plus a doublet chemotherapy regimen, the continuation of bevacizumab in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach, particularly if an anti-EGFR agent is not indicated (eg, those with a RAS or BRAF V600E mutation or a right-sided primary tumor, regardless of RAS/BRAF status), as long as drug therapy is well tolerated. (See 'Continuation of bevacizumab beyond progression' below.)

Another option for patients treated initially with FOLFOX plus bevacizumab is FOLFIRI with or without intravenous aflibercept or ramucirumab, but costs and side effects are worse with these drugs than with bevacizumab. (See 'Aflibercept' below and 'Ramucirumab' below.)

Subsequent regimens could incorporate cetuximab or panitumumab, if the tumor is RAS and BRAF wild type.

If bevacizumab, aflibercept, or ramucirumab is used as a component of the second-line chemotherapy regimen for patients with RAS and BRAF wild-type tumors, an EGFR-targeting MoAb should not be used concurrently. (See 'Dual antibody therapy' below.)

For patients with RAS/BRAF wild-type tumors initially treated with cetuximab or panitumumab plus either FOLFOX or FOLFIRI, one option is to add bevacizumab to second-line treatment with the alternative chemotherapy doublet (or XELOX, if initially treated with FOLFIRI), as long as the patient is a reasonable candidate for bevacizumab. There are scant data supporting benefit for continuing an anti-EGFR agent after first progression, and in this situation, we would consider treatment with cytotoxic chemotherapy alone.

For patients not able to tolerate intensive therapy, treatment with sequential single agents (irinotecan alone if the initial regimen was oxaliplatin-based), or cetuximab or panitumumab alone (for RAS and BRAF wild-type tumors) is a reasonable approach.

Another option for treatment at progression (second line or beyond) for patients who have tumors with a high level of microsatellite instability or who are dMMR is immunotherapy with an immune checkpoint inhibitor (ie, nivolumab, pembrolizumab). (See 'Patients with microsatellite unstable/deficient mismatch repair tumors' below.)

For patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and (if RAS and BRAF wild type) an anti-EGFR agent and who require additional therapy, single-agent regorafenib or trifluridine-tipiracil is an option, if performance status is adequate. (See 'Regorafenib' below and 'Trifluridine-tipiracil' below.)

After failure of all conventional agents/combinations, if performance status is adequate and a tumor-directed therapeutic approach is still warranted, we prefer enrollment in a phase I or II trial testing novel agents/combinations. An assessment of tumor mutational burden or gene amplification (eg, HER2) using genotyping platforms such as those available from Foundation Medicine may discover actionable mutations to narrow choices for targeted/experimental therapy. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immunotherapeutic approaches' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'HER2-targeted therapy'.)

If protocol treatment is not available or declined, reutilizing the regimen initially used in the treatment sequence (eg, FOLFOX) is a reasonable option, especially if the regimen was abandoned because of toxicity rather than progressive disease. During the often lengthy phase of sequential therapy, tumors may retain or regain sensitivity to previously used drugs [7,8].

PREDICTIVE BIOMARKERS — Among patients with metastatic colorectal cancer (mCRC), RAS mutation status permits the selection of individuals who might benefit from strategies targeting the epidermal growth factor receptor (EGFR). Anti-EGFR monoclonal antibodies (cetuximab, panitumumab) should only be prescribed for patients whose tumors are RAS wild type.

There are no as yet accepted biologic or molecular markers of responsiveness to bevacizumab or to conventional cytotoxics, although these are active areas of research.

The following sections will review the available data on predictive biomarkers for selecting therapy in mCRC.

Agents targeting the EGFR — Particularly in view of their expense and toxicity [9], the identification of patients who are most likely to respond to the anti-EGFR monoclonal antibodies cetuximab or panitumumab is an important clinical question. Selection or exclusion of patients for either drug based upon immunohistochemical staining (IHC) for EGFR expression is not justified, since only a minority of otherwise unselected EGFR-positive tumors respond (see 'EGFR amplification' below) [10-13], and objective responses are seen with EGFR-negative tumors [11,14,15]. Likewise, somatic mutations in the EGFR tyrosine kinase domain are not associated with cetuximab sensitivity [16].

Tumor overexpression of several genes involved in the EGFR signaling pathway and downstream events might identify patients who are most likely to respond to anti-EGFR agents.

RAS mutations — It is now well established that activating mutations in KRAS, which result in constitutive activation of the RAS-RAF-ERK pathway, result in resistance to anti-EGFR therapy [17-29]. Activating mutations in KRAS are detected in approximately 40 percent of mCRCs, with good concordance between the primary and synchronous distant metastases (but not lymph node metastases) [30,31]. The rate of discordance between primary and recurrent tumors may be higher (20 percent in one report [32]), but we recommend confirmation of this finding before recommending routine rebiopsy of metastases for RAS mutation analysis.

In the United States and elsewhere, panitumumab and cetuximab were originally approved only for patients without detectable KRAS mutations [33]. In mCRC, KRAS mutations are mainly found in exon 2 (codons 12, 13) [34,35]. However, whether all exon 2 KRAS mutations (particularly the G13D mutation) confer resistance to EGFR-targeted agents is unclear; the data, even the conclusions of two different meta-analyses on this subject, are conflicting [36-42].

Extended RAS testing — Wild-type KRAS in exon 2 does not guarantee benefit from agents targeting the EGFR, since even in these cohorts, response rates to either drug are 40 percent or less [23,43,44]. More recently, it has become clear that resistance to anti-EGFR therapies can also be mediated by lower-frequency mutations in KRAS outside of exon 2 and in NRAS [25,31,45-50] and exclusion of patients with all RAS mutations identifies a population that is more likely to benefit from an anti-EGFR agent [51,52].

As an example, in the Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) trial, in which 1183 patients with previously untreated mCRC were randomly assigned to FOLFOX with or without panitumumab, 108 patients (17 percent) without exon 2 KRAS mutations had other mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4 [45]. These additional mutations predicted a lack of response to panitumumab, and in fact, their presence was associated with inferior progression-free and overall survival in patients receiving panitumumab plus short-term infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared with FOLFOX alone.

In 2015, an updated Provisional Clinical Opinion from the American Society of Clinical Oncology (ASCO) recommended that all patients who are candidates for anti-EGFR therapy should have their tumor tested for mutations in both KRAS and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146) [53]. Guidelines from the National Comprehensive Cancer Network (NCCN) also mandate comprehensive testing for mutations in KRAS and NRAS exons 2, 3, and 4 in patients being considered for an anti-EGFR agent. The weight of evidence indicates that anti-EGFR monoclonal antibody therapy should be restricted to those patients whose tumors lack mutations after extended RAS testing.

In July 2017, the US Food and Drug Administration (FDA) approved the PRAXIS Extended RAS Panel, a next-generation sequencing test to detect the presence of 56 specific mutations in KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4 in the tumor tissue of patients with mCRC [54].

While tumor tissue remains the "gold standard" for genetic analysis in cancer patients, circulating tumor DNA (ctDNA) can be detected and quantified in the blood of cancer patients and used for detection of tumor-specific genetic alterations, including RAS mutations. The overall concordance between tumor and plasma RAS mutational status is 86 to 93 percent in some reports [55-60], although lower rates (72 to 78 percent) are reported by others [57,58]. One of the advantages of "liquid biopsy" is the potential for reducing data turnaround time [57]. However, only a limited number of cases have been studied, and all of the analyses are retrospective. Additional data are needed before it can be concluded that treatment decisions in mCRC can be made based upon ctDNA.    

Other biomarkers — Even tumors that are wild type after extended RAS testing do not consistently have a response to EGFR-targeted therapies. Mutations of other genes, such as BRAF, PIK3CA [61,62], p53 [63], or PTEN [64], or polymorphisms in EGF [44] or in genes involved in the insulin-like growth factor 1 (IGF1) signaling pathway [65,66], or a low fraction of cells staining for EGFR by IHC [67,68], or expression of certain microRNAs [69], or overexpression of the EGFR ligands epiregulin and amphiregulin [70] may also influence response to EGFR-targeted agents, although the data are conflicting with regard to PTEN and PIK3CA mutations [71]. In addition, heterogeneity in the fraction of neoplastic cells that harbor specific RAS mutations within a single tumor may also influence response to EGFR-targeted agents [72]. All of these additional biomarkers and the concept of quantitative assessment of resistance mutations require further validation before being incorporated into clinical practice [73-75]. It seems likely that a comprehensive biomarker analysis will be required to identify the subgroup of patients with mCRC who will truly benefit from treatment with an anti-EGFR agent.

BRAF — BRAF is a component of the RAS-RAF-MAPK signaling pathway. Activating mutations, which are mutually exclusive with KRAS mutations, are found in approximately 5 to 10 percent of mCRCs. BRAF mutations (most of which are V600E mutations) have consistently been associated with poor prognosis overall [76-81]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF'.)

Moreover, BRAF V600E mutations also appear to have predictive value. Evidence increasingly suggests that response to EGFR-targeted agents is unlikely in patients whose tumors harbor BRAF V600E mutations. At least two meta-analyses have addressed the efficacy of EGFR antibody therapies in patients with RAS wild-type/BRAF V600E mutated tumors [82,83]:

One analysis of 10 randomized trials comparing cetuximab or panitumumab alone or plus chemotherapy with standard therapy or best supportive care included one phase II and nine phase III trials; six were conducted in the first-line treatment setting, two for second-line therapy and two in patients with chemorefractory disease [82]. Among patients with RAS wild-type/BRAF V600E mutant tumors, compared with control regimens, the addition of an anti-EGFR monoclonal antibody did not significantly improve progression-free survival (PFS; hazard ratio [HR] 0.88, 95% CI 0.67-1.14), overall survival (HR 0.91, 965% CI 0.62-1.34), or objective response rate (relative risk [RR] 1.31, 95% CI 0.83-2.08).

The second analysis included eight randomized trials, four conducted in the first-line setting, three in the second-line setting, and one in patients with chemorefractory disease [83]. Among patients with RAS wild-type/BRAF V600E mutant mCRC, there was no significant overall survival benefit for the addition of an anti-EGFR monoclonal antibodies (HR 0.97, 95% CI 0.67-1.41). In contrast, overall survival was significantly greater in patients with RAS wild-type BRAF wild-type tumors (HR 0.81; 95% CI 0.7-0.95). When comparing the overall survival benefit between BRAF V600E mutant and BRAF wild-type tumors, the test for interaction was not statistically significant, leading the authors to conclude that the observed differences in the effect of anti-EGFR monoclonal antibodies on overall survival according to BRAF V600E mutation status could have been due to chance, and that the evidence was insufficient to state that mutant tumors attain a different treatment benefit from anti-EGFR agents compared to individuals with BRAF-wild type tumors.

Nevertheless, in our view and that of others, the preponderance of the available evidence is that response to EGFR-targeted agents is unlikely in patients whose tumors harbor a BRAF V600E mutation. Consensus-based guidelines from the NCCN and the European Society for Medical Oncology (ESMO [84]) both suggest not using cetuximab or panitumumab for patients with BRAF V600E mutated cancers. Furthermore, the American Joint Committee on Cancer (AJCC) in its most recent 2017 TNM staging revision considers that there is level I evidence to support a lack of effect of anti-EGFR antibody therapy in patients whose tumors harbor a BRAF V600E mutation [85].

Less is known about BRAF mutations that occur outside of codon 600, which account for about one-fifth of all BRAF mutations in mCRC [86]. From a prognostic standpoint, at least some data suggest that patients with mCRC whose tumors harbor a non-V600 mutation have a better median overall survival than do those with either a V600E mutation or a BRAF wild-type tumor (61 versus 11 versus 43 months, respectively) [86]. However, there are very few data addressing the predictive value of non-V600 BRAF mutations for response to anti-EGFR agents [87], and this remains an area of active investigation. (See "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF'.)

Whether resistance to EGFR-targeted agents in patients who have mutations in BRAF V600E can be overcome by the addition of BRAF inhibitors is not yet established; the following data are available:

The addition of the BRAF inhibitor vemurafenib to cetuximab plus irinotecan is under study in SWOG 1406. In a preliminary report of 106 patients with BRAF V600E mutation-positive but RAS mutation-negative, previously treated CRC who were randomized to cetuximab plus irinotecan with or without vemurafenib, presented at the 2017 ASCO annual meeting, median PFS was doubled with the addition of the vemurafenib (4.4 versus 2 months), and the objective response rates were significantly higher (16 versus 4 percent) [88].

Additional information should be forthcoming from the phase III BEACON CRC trial, in which patients with BRAF V600E mutant mCRC whose disease has progressed after one or two prior regimens are randomly assigned to cetuximab plus the BRAF inhibitor encorafenib with or without the MEK inhibitor binimetinib or to irinotecan plus cetuximab alone. In a preliminary analysis of the 30 patients who received the triplet combination during the safety lead-in of this trial, the estimated median PFS was eight months, the overall response rate to triplet therapy was 48 percent, and there were three complete responses [89].

Until more mature data are available from these trials, this approach should only be considered in the context of a clinical trial.

EGFR amplification — Some [64,90,91] but not all studies [21,92,93] suggest an association between EGFR copy number and response to anti-EGFR therapy. The clinical use of EGFR amplification to select patients for therapy is limited by the lack of standardization of fluorescence in situ hybridization technology and scoring [64,93].

Bevacizumab — Attempts to discover molecular or pathologic predictive factors for bevacizumab efficacy in order to identify subgroups of patients who gain greater or lesser degrees of benefit from the drug have not been successful to date, although this is an active area of research [94-97]. An important issue is that it is not tumor tissue that is the target for bevacizumab but instead host endothelial cells, which interact with tumor on the microenvironmental level.

Thus, there are no criteria for the selection of patients who will or will not benefit from the addition of bevacizumab to front-line therapy. There are, however, patients in whom the risks associated with bevacizumab might outweigh potential benefits. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Adverse effects'.)

Cytotoxic agents — There are no prospectively validated predictive biomarkers for conventional cytotoxic agents, although this is an area of active research [98-103].

INITIAL THERAPY

The cytotoxic chemotherapy backbone

Patients who are candidates for intensive systemic therapy

Initial doublet combinations versus sequential single agents — For patients who are able to tolerate it, we suggest combination chemotherapy with a doublet (FOLFOX [oxaliplatin plus leucovorin (LV) and short-term infusional fluorouracil (FU)], oxaliplatin plus capecitabine [XELOX (CAPOX)], or FOLFIRI [irinotecan plus LV and short-term infusional FU]) (table 1) rather than a single-agent sequential therapy for initial treatment of metastatic colorectal cancer (mCRC), particularly for those who have limited liver metastases that might become potentially resectable. This recommendation is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and European Society for medical oncology (ESMO) [84]. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)

The three active conventional chemotherapy agents for mCRC are fluoropyrimidines, irinotecan, and oxaliplatin. The proportion of patients exposed to all three drug classes during the course of therapy correlates strongly with median survival in all large published phase III trials over the last decade [2].

In view of this observation, it has been argued that sequential use of active single agents might be preferable to initial combination chemotherapy. This approach could conceivably reduce the overall toxicity of therapy while at the same time providing comparable overall survival since patients would eventually be exposed to all active agents.

The issue of initial combination versus single agent therapy was directly addressed in two European trials (FOCUS and CAIRO) [104,105]. Data from these trials are discussed in more detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Combination versus sequential single agents'.)

In the United Kingdom Medical Research Council's FOCUS (Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing) trial, patients were randomly assigned to one of the following groups [104]:

The control arm (strategy A) received sequential single agent therapy (FU/LV followed by irinotecan monotherapy at the time of progression).

Experimental strategy B was FU/LV initially followed by combination chemotherapy (FU plus either irinotecan or oxaliplatin) at progression.

Experimental strategy C was initial combination therapy with either FOLFOX or FOLFIRI.

Only the comparison of initial FOLFIRI versus sequential single agent therapy was statistically significant (16.7 versus 13.9 months), although the survival in both groups was low by modern standards (median 20 to 22 months). The authors concluded that sequential single agent therapy did not compromise overall survival.

In the Dutch Colorectal Group CAIRO (CApecitabine, IRinotecan, Oxaliplatin) trial, 820 patients with previously untreated mCRC were randomly assigned to initial capecitabine followed by irinotecan monotherapy and then capecitabine/oxaliplatin (XELOX, the sequential strategy), versus initial capecitabine/irinotecan (XELIRI) followed by XELOX (combination strategy) [105]. As was seen in the FOCUS trial, the median overall survival was similar for sequential versus initial combination therapy (as with the FOCUS trial, it was less than expected with modern combination chemotherapy), although progression-free survival (PFS) was superior with combination therapy.

In both the FOCUS and CAIRO trials, the likelihood of receiving all active agents was lower with the sequential single-agent treatment strategy than when patients are treated using a sequence of rationally designed combination therapies. In fact, of those patients who began with monotherapy, only 19 percent (FOCUS) and 36 percent (CAIRO) eventually received all three drugs; the corresponding percentages for those receiving upfront combination chemotherapy in both trials were 33 and 55 percent, respectively. Given the correlation between exposure to all active agents and overall survival in patients with mCRC [106,107], these data support the view that patients who receive first-line combination therapy are more likely to receive all three active agents in the course of their therapy than those who initiate treatment with a single agent.

One possible explanation for the inferior median survivals seen in both of the trials relative to modern combination regimens is that the populations enrolled in these studies might differ from those in other studies, possibly if clinicians preferentially enrolled poorer-risk patients to these trials, choosing to treat more "robust" patients with upfront combination therapy. In fact, 10 percent of the patients enrolled in the FOCUS trial had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (table 2), higher than that usually seen in phase III trials of first-line chemotherapy for mCRC.

Three versus two-drug combinations — For most patients with mCRC, we suggest a chemotherapy doublet containing either oxaliplatin or irinotecan (eg, FOLFOX, XELOX, or FOLFIRI) (table 1) rather than a triplet regimen containing both irinotecan and oxaliplatin. However, FOLFOXIRI (infusional FU, LV, oxaliplatin, and irinotecan) with or without bevacizumab could be considered an option for first-line therapy in selected patients who are able to tolerate intensive therapy and for whom a more aggressive initial approach is chosen (eg, younger age, high tumor load, conversion therapy for initially unresectable liver metastases, contraindication to cetuximab/panitumumab (eg, RAS/BRAF mutation). This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [84]. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy' and 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' below and "Treatment protocols for small and large bowel cancer".)

FOLFOXIRI has been directly compared with doublet therapy in three trials; superiority for FOLFOXIRI was suggested in two of the three:

In an Italian trial that randomly assigned 244 patients with previously untreated inoperable mCRC to the Douillard FOLFIRI regimen versus FOLFOXIRI, FOLFOXIRI was significantly superior in terms of response rate (the primary endpoint, 66 versus 41 percent), the number of patients able to undergo complete secondary surgical cytoreduction of liver metastases, median PFS, and median overall survival (23 versus 17 months) [108,109]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line IROX and FOLFOXIRI'.)

Although similar high rates of objective response and significantly better median overall survival (29.8 versus 25.8 months) were noted with FOLFOXIRI plus bevacizumab as compared to FOLFIRI plus bevacizumab in the TRIBE trial, but it did not confirm higher rates of secondary surgical resection of liver metastases with an initial three-drug chemotherapy backbone [110]. Furthermore, grade 3 to 4 toxic effects that were more common with FOLFOXIRI included diarrhea, stomatitis, neutropenia, and peripheral neuropathy.

Contradictory data from a Hellenic Oncology group trial of 283 patients with previously untreated mCRC noted no significant benefit for a modified FOLFOXIRI regimen over FOLFIRI [111]; however, the doses of oxaliplatin, irinotecan, and FU in the FOLFOXIRI arm were lower in this trial.

Importantly, if a triplet chemotherapy regimen such as FOLFOXIRI is chosen for first-line therapy, bevacizumab is the preferred biologic agent, if one is chosen, even for left-sided primary tumors, because of the absence of data on FOLFOXIRI combined with therapies targeting the epidermal growth factor receptor (EGFR). (See 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' below.)

FOLFOX versus FOLFIRI — FOLFOX and FOLFIRI are both considered acceptable choices for first-line therapy; the now obsolete bolus IFL regimen should not be used (table 1). This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [84]. (See "Treatment protocols for small and large bowel cancer".)

The benefit of FOLFOX was initially established in the pivotal North Central Cancer Treatment Group (NCCTG)/US Intergroup trial N9741, which compared IFL (weekly bolus FU/LV plus irinotecan for four of every six weeks) to the FOLFOX4 (table 1) regimen and to a combination of irinotecan plus oxaliplatin without FU (IROX) [112]. All efficacy parameters as well as the toxicity profile favored FOLFOX4 over IFL.

The significant survival advantage of FOLFOX4 (19.5 versus 15 months) was initially thought to be related to the fact that patients in the FOLFOX arm were able to receive effective irinotecan-salvage therapy, whereas most patients in the IFL arm did not receive salvage therapy because oxaliplatin was not approved at the time. However, the objective response rate (45 versus 31 percent) and time to tumor progression (8.7 versus 6.9 months) also clearly favored FOLFOX4. Furthermore, a later analysis of a separate cohort of patients on this trial who received a modified, dose-reduced IFL regimen (rIFL) again demonstrated the superiority of FOLFOX4 over rIFL, despite no discrepancies in exposure to all three active agents between the groups [113].

Largely based upon these results, FOLFOX, in particular modified FOLFOX6, in which the entire FU dose is given over 46 hours without a day 2 bolus dose of LV (table 3), has become the most commonly used first-line chemotherapy backbone for mCRC in the United States [114].

In contrast to bolus IFL, regimens that incorporate irinotecan plus short-term infusional rather than bolus FU/LV (ie, the FOLFIRI regimen) (table 1) appear to be at least as effective as the FOLFOX regimen:

A phase III trial of 220 patients compared FOLFOX6 versus FOLFIRI; both groups were allowed crossover at progression [115]. There were no differences in pertinent efficacy parameters (response rate, PFS, and overall survival, approximately 21 months in both groups).

A phase III study of 336 patients randomized to FOLFOX4 versus FOLFIRI confirmed these findings [116].

Another phase III trial concluded that first-line bevacizumab plus FOLFIRI was not inferior to bevacizumab plus FOLFOX [117].

Results from these trials are discussed in more detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Oxaliplatin/FU/LV versus irinotecan/FU/LV'.)

Treatment-related toxicity — In practice, the choice between first-line FOLFIRI or FOLFOX is often based upon expected treatment-related toxicity. The main adverse events reported with FOLFIRI-type regimens are diarrhea, alopecia, and a moderate incidence of grade 3 or 4 neutropenia. In general, toxicity is not cumulative and irinotecan can usually be continued until disease progression. Irinotecan is metabolized by the liver, and reduced doses are needed in the setting of hyperbilirubinemia [118]. In addition, The active form of irinotecan (SN-38) is further metabolized by the polymorphic enzyme uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1). In approximately 50 percent of the North American population, intratumoral enzymatic activity is reduced among those who inherit genetic polymorphisms such as the UGT1A1*28 (7/7 variant) allele, which is the cause of Gilbert's syndrome. Affected patients may benefit from a lower initial dose of irinotecan. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Irinotecan and liposomal irinotecan' and "Enterotoxicity of chemotherapeutic agents", section on 'UGT1A1 polymorphisms'.)

Oxaliplatin is less likely to cause diarrhea and alopecia than irinotecan. In conjunction with bolus FU, neutropenia rates are relatively high, although febrile neutropenia is rare. Severe myelosuppression can be largely avoided if a non-bolus FU-containing regimen is used (eg, modified FOLFOX7, of which there are two versions) (table 1) [119,120] or XELOX. Oxaliplatin is safe in patients with hepatic or renal dysfunction [121,122]. (See "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents".)

The dose-limiting side effect of oxaliplatin is a cumulative, late-onset predominantly sensory neuropathy, which may require drug discontinuation despite ongoing tumor response. It occurs with increasing frequency above cumulative doses of 680 mg/m2 [123]. Patients with preexisting neuropathy and those for whom the development of a severe sensory neuropathy might jeopardize their livelihood (eg, a professional musician) might be better served with initial irinotecan-based rather than oxaliplatin-based therapy. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Oxaliplatin'.)

FOLFIRI might also be preferred in a patient who received adjuvant therapy with an oxaliplatin-based regimen within the preceding 12 months.

Oral fluoropyrimidines as substitutes for infusional FU

Capecitabine containing doublets — Capecitabine plus oxaliplatin (XELOX, CAPOX) is a reasonable substitute for FOLFOX in the palliative therapy of mCRC. However, combinations of capecitabine with irinotecan (XELIRI, CAPIRI) cannot be routinely recommended as a valid substitute for FOLFIRI, at least for American patients, because of toxicity concerns. This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [84].

Capecitabine is an orally active fluoropyrimidine carbamate that is absorbed intact through the intestinal wall and then converted to FU in three sequential enzymatic reactions. The final requisite enzyme, thymidine phosphorylase, is present at consistently higher levels in tumor compared to normal tissue, providing the hypothetical basis for enhanced tumor cell selectivity and better tolerability. It was hoped that daily administration of capecitabine would mimic sustained exposure to continuously infused FU without the need for a central venous access line and ambulatory infusion pump.

Two identically designed phase III trials comparing capecitabine monotherapy (1250 mg/m2 twice daily on days 1 to 14 every 21 days) versus the Mayo Clinic regimen of bolus FU/LV demonstrating higher response rates but a similar time to tumor progression and overall survival with capecitabine [124,125]. In both studies, there was less neutropenia, stomatitis, nausea, and alopecia, but a higher rate of hand-foot syndrome and hyperbilirubinemia with capecitabine. No trial has directly compared capecitabine versus infusional FU. Nevertheless, the attractiveness of oral dosing and the potential for eliminating the need for a central venous catheter and ambulatory infusion pump led to various trials comparing capecitabine with short-term infusional FU/LV in regimens such as FOLFOX and FOLFIRI. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Capecitabine'.)

Capecitabine/oxaliplatin regimens are commonly referred to as XELOX or CAPOX; capecitabine/irinotecan combinations are termed XELIRI or CAPIRI. While the actual doses and schedules of these regimens are variable, for the purpose of this overview, the abbreviations XELOX/CAPOX and XELIRI/CAPIRI will be used interchangeably. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Capecitabine plus oxaliplatin' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Irinotecan plus capecitabine or S-1'.)

XELOX - At least five randomized phase III trials have directly compared XELOX versus FOLFOX (or other variants of oxaliplatin plus short-term infusional FU/LV) for first-line [126-129] or second-line [130] chemotherapy in mCRC. None showed that XELOX was inferior to FOLFOX-type regimens in terms of response rate, PFS, or overall survival. However, in nearly all cases, the PFS and overall survival curves for XELOX trailed beneath the curves for FOLFOX. In no case was this effect statistically significant or clinically meaningful. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line XELOX versus FOLFOX'.)

The single most influential trial addressing the relative benefit of capecitabine as a substitute for short-term infusional FU/LV is the Roche-sponsored NO16966 trial in which 634 patients were randomly assigned to XELOX versus FOLFOX4 (table 1) for first-line therapy [126]. An additional 1400 patients were accrued after a protocol amendment added a second randomization to bevacizumab versus placebo. In the latest report, for the direct comparison of XELOX versus FOLFOX4, there was no relevant difference in overall survival (19.8 versus 19.5 months) [131].

Thus, the available evidence supports the view that XELOX can be considered as a noninferior substitute for FOLFOX in the palliative therapy of mCRC. Practicing oncologists should, however, consider the following issues before routinely adopting XELOX as an alternative to FOLFOX:

The appropriate dose of capecitabine is not well defined, at least for American patients. The commonly applied dosing schedule of capecitabine in European trials (1000 mg/m2 twice daily, for 14 of every 21 days) when added to oxaliplatin (130 mg/m2 on day 1 of a three-week cycle) was unacceptably toxic in the United States TREE-1 trial (table 4) [132]. Reduction of the capecitabine dose in the TREE-2 trial to 850 mg/m2 twice daily was associated with a markedly improved safety profile. We consider capecitabine 850 mg/m2 twice daily plus oxaliplatin 130 mg/m2 on day 1 of each cycle to represent a standard regimen for American patients (table 5). (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line XELOX versus FOLFOX' and "Treatment protocols for small and large bowel cancer".)

There appear to be large regional differences in the tolerance to capecitabine and other fluoropyrimidines [133,134]. These differences might in part be based on population-specific pharmacogenomic variability (eg, Asian patients seem to tolerate fluoropyrimidines better than non-Asians [133]). However, lifestyle or dietary differences (eg, folate intake) could also contribute. Regardless, Asian oncologists usually use capecitabine 1000 mg/m2 twice daily in conjunction with oxaliplatin 130 mg/m2.

A central venous access line is often needed for reasons other than infusional FU in patients with mCRC. Because a significant number of patients report local pain when oxaliplatin is infused via peripheral vein, many centers routinely infuse the drug centrally. Furthermore, recognizing that mCRC is a chronic disease with the need for multiple sequential chemotherapy regimens, many patients will undergo placement of a central venous line at some point in the course of treatment simply because of inadequate peripheral venous access.

Reimbursement policies for oral cytotoxics such as capecitabine vary greatly between countries and regionally within the United States. While the overall cost of therapy may be less [135,136], the cost of capecitabine is often borne by the patient, particularly if Medicare-covered [137] (in contrast, IV FU is typically covered by the third-party payer). This may influence treatment choice for individual patients [138].

XELIRI – While XELOX may be regarded as a valid substitute for FOLFOX (with the above caveats), the situation is different for combinations of capecitabine with irinotecan (XELIRI, CAPIRI) as an alternative to FOLFIRI (table 1). Capecitabine and irinotecan have partially overlapping toxicity profiles, particularly with regard to diarrhea. The potential for greater toxicity reduces the therapeutic advantage of an irinotecan/capecitabine combination and makes the selection of appropriate doses and schedules for this combination more crucial than for XELOX. (See "Enterotoxicity of chemotherapeutic agents".)

Unfortunately, regional differences in capecitabine tolerability [133] make it difficult to translate toxicity and efficacy findings generated in trials conducted outside of the United States [105] into American patients.

Higher rates of grade 3 and 4 diarrhea with XELIRI as compared to FOLFIRI have been seen in several trials [139-141]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Irinotecan plus capecitabine or S-1'.)

A meta-analysis of six trials directly comparing XELIRI versus FOLFIRI (including the three that showed higher rates of GI toxicity with XELIRI [139-141]) concluded that both regimens were associated with similar efficacy and tolerability [142]. However, in our view, the potential for increased toxicity should be considered when XELIRI is used, at least for American patients. The question of whether dose reductions of both drugs can make XELIRI more tolerable, and perhaps more effective, particularly in older adult patients, will have to be explored in future clinical trials.

S-1 — Where available, S-1 plus oxaliplatin represents an acceptable first-line oxaliplatin-containing chemotherapy regimen, at least for Asian patients. In addition, S-1 plus irinotecan is a valid alternative to FOLFIRI for patients who have progressed while receiving FOLFOX.

S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in most countries outside of the United States. At least two randomized trials, both conducted in Asian populations, have demonstrated the noninferiority of S-1 plus oxaliplatin compared to capecitabine plus oxaliplatin, and for S-1 plus oxaliplatin and bevacizumab compared to FOLFOX/bevacizumab. Furthermore, the noninferiority of S-1 plus irinotecan compared to FOLFIRI has been shown in patients failing initial FOLFOX. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'S-1 plus oxaliplatin' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Irinotecan plus capecitabine or S-1'.)

UFT — UFT is a 1:4 molar combination of ftorafur (tegafur) with uracil, which competitively inhibits the degradation of FU, resulting in sustained plasma and intratumoral concentrations [143]. Where available, combinations of UFT with irinotecan (TEGAFIRI) and oxaliplatin (TEGAFOX, UFOX) are acceptable first-line options for oxaliplatin-containing and irinotecan-containing chemotherapy, respectively. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'UFT'.)

Patients who are not candidates for intensive therapy — For patients who are not candidates for an intensive first-line oxaliplatin or irinotecan-based combination regimen, we suggest fluoropyrimidine therapy alone [2]. This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [84]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Leucovorin plus FU' and "Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status", section on 'Management of patients with a poor performance status'.)

We prefer short-term infusional FU/LV rather than bolus administration, because of its favorable toxicity profile. We prefer the modified de Gramont regimen without the day 2 bolus doses of FU and leucovorin (table 6). (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Leucovorin plus FU'.)

Capecitabine monotherapy is an equally effective alternative first-line regimen, when fluoropyrimidines alone are indicated. The appropriate capecitabine dose is unclear. The on-label dose (1250 mg/m2 twice daily for 14 of every 21 days) is toxic in Americans, presumably due to higher nutritional folate intake, among other factors. Most American oncologists start with 1000 mg/m2 twice daily for 14 of every 21 days and titrate the dose upward if tolerated. Capecitabine also requires dose reduction in those with renal function impairment and in those being crossed over from FU/LV [144]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Capecitabine'.)

Where available, S-1 or UFT are also appropriate options for first-line therapy.

Role of biologics

Bevacizumab — Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A), a member of a family of VEGF receptor-activating ligands. CRC was the first malignancy for which clear evidence for efficacy of an anti-VEGF strategy was demonstrated in randomized trials. In a pivotal early trial, the addition of bevacizumab to the bolus IFL regimen significantly improved response rates (45 versus 35 percent), time to tumor progression (11 versus 6 months), and overall survival (20 versus 16 months) [145]. Since then, benefit for adding bevacizumab to a variety of fluoropyrimidine, irinotecan, and oxaliplatin-containing regimens used for first-line therapy has been confirmed, although the magnitude of both the overall and progression-free survival benefits are relatively modest [146]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Bevacizumab'.)

Immediately following the approval of bevacizumab in the United States in 2004, the significant difference in outcome favoring FOLFOX over bolus IFL reported shortly thereafter in the US Intergroup N9741 trial [112] led many oncologists to choose FOLFOX as the chemotherapy backbone for the addition of bevacizumab, despite the lack of clinical trial results demonstrating that this regimen was better than any other. To date, there are still only limited data on the benefit of adding bevacizumab to an oxaliplatin-based regimen [147], and no randomized trial comparing FOLFIRI versus FOLFIRI plus bevacizumab has been published. The effectiveness of adding bevacizumab to standard first-line treatment with either FOLFOX or FOLFIRI has been challenged [148]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Oxaliplatin regimens'.)

Nevertheless, since 2004, the majority of patients with mCRC in the United States have received bevacizumab as a component of first-line therapy regardless of the specific regimen chosen for the chemotherapy backbone (FOLFOX, FOLFIRI, FU/LV). The situation differs in other parts of the world where fewer than 50 percent of patients are treated with bevacizumab first-line, conceivably due, in part, to different reimbursement policies. Bevacizumab is expensive, its benefits are modest, at best [149], and use of the drug is associated with a number of potentially serious side effects, including proteinuria, hypertension, bleeding, bowel perforation, impaired wound healing, arterial (but not venous) thromboembolic events (such as transient ischemic attack, stroke, angina, myocardial infarction), and reversible posterior multifocal leukoencephalopathy. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Reversible posterior leukoencephalopathy syndrome".)

These issues have prompted debate as to whether there is enough evidence to justify the routine use of bevacizumab as a component of first-line chemotherapy in patients with inoperable mCRC, whether there are subgroups of patients for whom the benefit of bevacizumab does not outweigh its risks, and whether there are patients who should not receive bevacizumab at all. This remains a controversial area.

Should all patients receive first-line bevacizumab — In the absence of validated predictive factors for treatment benefit, the default position in the palliative management of mCRC had been to add bevacizumab to the chemotherapy backbone chosen for the individual patient, particularly for patients with RAS mutated tumors, for whom an anti-EGFR agents is contraindicated. (See 'RAS mutations' above.)

When added to cytotoxic FU-based chemotherapy for mCRC, bevacizumab routinely improves outcomes, regardless of the specific chemotherapy backbone that is chosen. However, in some trials, bevacizumab appears to provide greater incremental gain in PFS when it is added to "weaker" chemotherapy regimens such as FU/LV or bolus IFL [145,150] than to more active regimens such as FOLFOX [147]. In the first adequately powered randomized trial (XELOX-1/NO16966) for first-line therapy, the addition of bevacizumab to oxaliplatin was of little incremental benefit, but the study was somewhat flawed by the discontinuation of chemotherapy before evidence of tumor progression in a substantial number of patients [147]. Other data (although not derived from randomized trials evaluating oxaliplatin-based chemotherapy with or without bevacizumab) suggest a similar magnitude of benefit when bevacizumab is added to oxaliplatin-based as compared with non-oxaliplatin based regimens [132]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Oxaliplatin regimens'.)

Bevacizumab also appears to provide a survival benefit even in the absence of an objective response to therapy. In the pivotal trial of IFL with or without bevacizumab, the gain from adding bevacizumab on PFS and overall survival was more profound than the impact on response rates [145]. Further analysis showed that patients who were classified as "nonresponders" according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria (table 7) benefited as much from the addition of bevacizumab as did those who had an objective response [151]. This is a phenomenon that is not unique to bevacizumab, and it serves to underscore the relative lack of importance of objective response rate as a predictor of treatment benefit in patients undergoing palliative treatment. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Treatment goals'.)

However, the benefit of a bevacizumab-containing regimen is debated among patients undergoing initial chemotherapy for potentially resectable liver metastases. Many clinicians do not use bevacizumab in conjunction with a cytotoxic chemotherapy backbone in this setting, citing the marginal benefits and risk for major complications. Others restrict the use of bevacizumab to those patients with RAS/BRAF mutated tumors (ie, those for which use of an anti-EGFR agent is contraindicated) who are undergoing conversion therapy for initially unresectable disease. This subject is discussed in detail elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)

For patients with RAS and BRAF wild-type tumors, an important question is whether a bevacizumab-containing regimen provides superior outcomes as compared with an initial regimen that contains an anti-EGFR agent. Emerging data suggest that first-line cetuximab-containing regimens may provide superior outcomes for patients with RAS/BRAF wild-type mCRC with a primary tumor site in the left colon. (See 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' below.)

Contraindications — A minority of patients have upfront contraindications to bevacizumab therapy, although these are not well defined. According to the product labeling, bevacizumab is contraindicated in the setting of recent hemoptysis of >2.5 mL (although this applies mainly to patients with non-small cell lung cancer) and major surgery within 28 days of treatment (and only following complete healing of the incision) [152]. The use of bevacizumab in patients with brain metastases is controversial (see below).

Arterial thromboembolic disease – A major issue is whether to withhold bevacizumab from older adult patients who have a history of an arterial thromboembolic event (ATE) within the past 6 to 12 months. Bevacizumab increases the risk of an ATE. In one meta-analysis, the risk appeared to be higher in those over the age of 65 and in those with a prior history of an ATE [153]. On the other hand, a pooled age subgroup analysis from two prospective trials of FU-based chemotherapy with and without bevacizumab failed to show that the higher incidence of arterial thromboembolic events in patients receiving bevacizumab was of a greater magnitude in patients 65 and older as compared to younger individuals [154].

Nevertheless, most clinicians consider that prior ATE within the last 6 to 12 months represents a relative contraindication to bevacizumab, particularly in older adult patients. However, the decision as to whether to withhold bevacizumab in older adult patients with a history of prior ATE (stroke, myocardial infarction) must take into account the potential harm from less effective anti-tumor therapy. These patients have been routinely excluded from clinical trials testing the value of bevacizumab. However, there is no evidence that patients at highest risk for bevacizumab-related ATEs derive less benefit from the drug. In an exploratory analysis of the pivotal IFL bevacizumab trial [145], the patient subgroup with both risk factors for ATEs gained a similar degree of benefit from bevacizumab as did the rest of the population [153].

Whether aspirin or other antiplatelet therapy can reduce the risk of ATEs in patients receiving bevacizumab is unclear; at least some data suggest that the use of aspirin does not increase the risk of bleeding during bevacizumab therapy. We tend to avoid bevacizumab in older adult patients with a history of an ATE within six months and consider the use of aspirin in other high-risk patients. This subject is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial thromboembolic events'.)

Wound healingBevacizumab impairs wound healing. This fact, plus the relatively long half-life of bevacizumab (20 days), has prompted the general recommendation that elective surgical intervention (eg, liver resection) be deferred for at least 28 days (and preferably for six to eight weeks) after the last dose of the drug. Minor surgery (ie, the need for a central venous access catheter) can safely be performed in patients receiving bevacizumab, but at least two weeks should elapse before additional doses of the drug are administered. In the case of surgical emergencies (eg, bowel perforations), bevacizumab treatment should not be considered an absolute contraindication to surgery. This subject is addressed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bevacizumab'.)

Hemorrhage – There are two distinct patters of bleeding in patients receiving bevacizumab; the most common is mild epistaxis, which affects about one-third of patients. The second is rare but serious (potentially fatal) hemorrhagic events including hemoptysis, gastrointestinal bleeding, hematemesis, intracerebral hemorrhage, epistaxis, and vaginal bleeding. Bevacizumab is contraindicated if there is a recent history of significant hemoptysis. An increased risk of pulmonary hemorrhage has not been described in patients with pulmonary metastases of non-lung primaries. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bevacizumab and aflibercept'.)

Concerns have been raised about a potential increase in the risk of intracerebral hemorrhage in patients treated with bevacizumab who have brain metastases. However, the available data suggest that patients with a history of treated nonhemorrhagic brain metastases probably should not be excluded from systemic therapy with bevacizumab as long as they are not on concurrent anticoagulation. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Intracranial bleeding'.)

Bevacizumab should be discontinued permanently in patients who develop severe adverse events during treatment, including gastrointestinal perforation (fistula formation, intraabdominal abscess), an arterial thromboembolic event, wound dehiscence requiring medical intervention, nephrotic syndrome, hypertensive crisis or encephalopathy, or a posterior leukoencephalopathy syndrome. The subject of bevacizumab side effects is discussed in detail elsewhere. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

RAS/BRAF wild-type tumors — For patients with mCRC and a left-sided primary tumor who have no mutations in RAS or BRAF V600E, we suggest a cetuximab- or panitumumab-containing regimen as initial therapy, although a bevacizumab-containing regimen is also an option. We suggest against using first-line anti-EGFR agents for initial therapy of mCRC in patients with right-sided tumors, even if they are RAS and BRAF wild type. (See 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' below.)

If cetuximab or panitumumab is chosen for initial therapy, the chemotherapy doublet should be FOLFOX or FOLFIRI. If triple-drug therapy is chosen (eg, FOLFOXIRI) we do not add an anti-EGFR agent, given the lack of data on safety and efficacy of combined therapy. In this setting, the biologic agent, if one is used, should be bevacizumab. (See 'Bevacizumab' above.)

Benefit of cetuximab and panitumumab — Combinations of cetuximab or panitumumab plus an irinotecan- or oxaliplatin-based cytotoxic doublet regimen that contains infusional FU (ie, FOLFIRI, FOLFOX) are safe and effective, and a reasonable first-line option for patients with RAS and BRAF wild-type tumors, especially for patients with a primary tumor on the left side. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Agents targeting the EGFR'.)

However:

The benefit of an oxaliplatin-containing regimen plus an anti-EGFR agent prior to resection in patients with potentially resectable colorectal liver metastases is still debated, and many clinicians avoid this combination. Furthermore, the addition of EGFR antibodies to oxaliplatin-based regimens in which noninfusional fluoropyrimidines are used (eg, XELOX) has not resulted in any benefit, and we recommend against the use of this combination. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Plus oxaliplatin'.)

We also avoid combining either cetuximab or panitumumab with a bevacizumab-containing regimen, a policy that is also supported by the US Food and Drug Administration (FDA) labeling, and consensus-based guidelines from the NCCN and ESMO [84]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Dual antibody therapy'.)

The choice between cetuximab and panitumumab is empiric. The available evidence suggests that antitumor efficacy of single-agent panitumumab is similar to that of cetuximab, and that the two drugs might be interchangeable. (See 'Are cetuximab and panitumumab interchangeable?' below.)

However, compared with cetuximab, panitumumab is a fully human monoclonal antibody, and the incidence of infusion reactions is lower. This may be relatively more important in geographic areas that have a high incidence of cetuximab infusion reactions (ie, the middle southeastern region of the United States (North Carolina, Arkansas, Missouri, Virginia, Florida, and Tennessee). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Incidence' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Panitumumab'.)

Anti-EGFR agent versus bevacizumab with first-line chemotherapy — If a biologic agent is chosen in conjunction with first-line chemotherapy of RAS/BRAF wild-type mCRC, we suggest an anti-EGFR antibody rather than bevacizumab for patients with a left-sided primary. However, if a triplet chemotherapy regimen such as FOLFOXIRI is chosen for first-line therapy, bevacizumab is the preferred biologic agent, even for left-sided primary tumors, because of the absence of data on FOLFOXIRI combined with anti-EGFR therapies. (See 'Three versus two-drug combinations' above.)

For patients who are candidates for bevacizumab, we suggest bevacizumab rather than cetuximab or panitumumab in conjunction with first-line chemotherapy for most patients with mCRC and a right-sided primary tumor. However, we would allow use of these agents in later lines of therapy. This approach is consistent with guidelines from the NCCN and ESMO [84].

In our view, patients with RAS and BRAF wild-type right-sided tumors who have a contraindication to the use of bevacizumab (eg, active bleeding, history of arterial thromboembolism in the 6 to 12 months prior to treatment, untreated hemorrhagic brain metastases) should be treated with chemotherapy alone without a biologic agent. (See 'Contraindications' above.)

A major unanswered clinical question has been the relative benefit of starting with bevacizumab versus an anti-EGFR agent as the initial biologic agent to be added to the chemotherapy backbone for RAS and BRAF wild-type mCRC. Accumulating data suggest that the site of the primary tumor might be predictive of benefit from EGFR-targeted therapies in these patients:

In the FIRE-3 trial, 735 patients with previously untreated mCRC were randomly assigned to FOLFIRI with either bevacizumab or cetuximab. In a report of the 400 patients with tumors that were wild type for both KRAS and NRAS, objective response rates, the primary endpoint of the study, were significantly higher with cetuximab (72 versus 56 percent). Median overall survival was significantly longer with cetuximab (33 versus 25 months), but median PFS was almost identical (10.3 versus 10.2 months) [155]. In a subsequent analysis, the benefit of cetuximab over bevacizumab was limited to those patients with a left-sided primary tumor (median overall survival 38 versus 28 months), while for right-sided tumors, bevacizumab was better (median overall survival 23 versus 18.3 months) [156].

A similar result was noted in a retrospective analysis of CALGB/SWOG 80405, which tested initial cetuximab versus bevacizumab in combination with either FOLFIRI or FOLFOX in patients with KRAS exon 2 wild-type tumors [157]. For the entire group, median overall survival was similar (30 versus 29 months for cetuximab and bevacizumab, respectively), as was PFS.

A later preliminary report of a retrospective analysis found that among patients with RAS wild-type tumors, cetuximab provided superior survival for those with left-sided primary tumors (median 39 versus 33 months), while bevacizumab was superior to cetuximab for patients with right-sided primary tumors (median 29 versus 13 months) [158].

These findings were confirmed in a subsequent meta-analysis [159] of these two trials and a third randomized phase II trial of FOLFOX plus either panitumumab or bevacizumab [160]. Patients with RAS wild-type left-sided colorectal tumors had a significantly greater survival benefit from anti-EGFR treatment compared with anti-VEGF treatment when added to standard chemotherapy (hazard ratio [HR] 0.71, 95% CI 0.58-0.85). In contrast, for patients with right-sided tumors, there was a trend toward longer survival with bevacizumab-based therapy (HR 1.3, 95% CI 0.979-1.74).

This subject is discussed in detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Bevacizumab versus an EGFR agent with first-line chemotherapy backbone'.)

Duration of initial chemotherapy

Oxaliplatin-based regimens — In the United States, FOLFOX plus bevacizumab (table 8) has emerged as the most commonly used first-line therapy for mCRC. Oxaliplatin-related toxicity, particularly neurotoxicity, limits the amount of effective therapy that can be administered. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Cumulative sensory neuropathy'.)

Whether long-term neurotoxicity can by mitigated by intermittent oxaliplatin-free intervals has been addressed in multiple randomized trials. When FOLFOX with or without bevacizumab is used for first-line therapy, the available data suggest that it is reasonable to discontinue oxaliplatin temporarily while maintaining a fluoropyrimidine with or without bevacizumab. This approach is consistent with consensus-based guidelines from the NCCN and ESMO [84]. Oxaliplatin continuation is also an option if the patient is responding to therapy and there is no evidence of neuropathy. Another option is a complete break from chemotherapy. Although early data suggested inferior outcomes, compared with continued chemotherapy, with an oxaliplatin-free regimen, these results have been called into question by a more recent meta-analysis. We reserve this approach for patients with small volume disease. The subjects of oxaliplatin-free intervals and intermittent versus continuous therapy are addressed in detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Oxaliplatin'.)

Irinotecan-based regimens — The advantage of intermittent treatment with irinotecan-based regimens is unclear given the relative lack of cumulative toxicity. Furthermore, the available data suggest similar overall outcomes (PFS and overall survival) whether or not the regimen is administered continuously until progression or toxicity, or in "two months on/two months off" intervals. These data are discussed elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Irinotecan'.)

Issues related to vitamin D — An association between vitamin D levels and prognosis of mCRC has been suggested [161,162]. In a preliminary report of a retrospective analysis of 1043 patients with mCRC who were treated on the phase III CALGB (Alliance) 80405 trial comparing chemotherapy plus bevacizumab, cetuximab, or both, those in the highest quintile of vitamin D levels had a significantly improved overall survival compared with those in the lowest quintile (median overall survival 32.6 versus 24.5 months) [161].

One concern that has been raised is that higher vitamin D levels may be acting as a surrogate for other healthy behaviors or biologically more favorable disease. The issue of whether higher levels of vitamin D supplementation can improve prognosis in conjunction with chemotherapy was addressed in the randomized, phase II SUNSHINE trial, in which 139 patients with previously untreated mCRC who were receiving first-line chemotherapy were randomly assigned to high-dose vitamin D3 (8000 international units [IU] daily for two weeks followed by 4000 IU daily) or standard-dose vitamin D3 (400 IU per day) [163]. In a preliminary report presented at the 2017 annual American Society for Clinical Oncology (ASCO) meeting, the group receiving high-dose vitamin D experienced modestly but significantly longer PFS (12.4 versus 10.7 months, p = 0.03). A larger confirmatory phase III trial is planned.

Given the benefits of vitamin D repletion in terms of skeletal health and the possibility of better cancer-related outcomes, it seems reasonable to test serum vitamin D levels in patients with newly diagnosed mCRC and to replete those with low levels (serum 25[OH]D <20 ng/mL [50 nmol/L]). (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

TREATMENT AT PROGRESSION

The chemotherapy backbone — Most patients initially treated with FOLFOX (or XELOX) are offered FOLFIRI, while for those initially treated with FOLFIRI, FOLFOX (or XELOX) is generally offered. The treatment model of FOLFOX followed by FOLFIRI, or FOLFIRI followed by FOLFOX was the treatment model in the Tournigand trial, which still represents one of the longest median survivals (21 months) reported in the prebiologics era of treating metastatic colorectal cancer (mCRC) [115].

RAS/BRAF wild-type tumors — Both of the therapeutic monoclonal antibodies (MoAbs) that target the epidermal growth factor receptor (EGFR) have well-documented and comparable single-agent activity in patients with previously treated mCRC that lacks mutations in RAS and BRAF V600E [164-166]. Regimens that combine an anti-EGFR agent with irinotecan alone or a chemotherapy doublet are also efficacious, with the exception of regimens that contain oxaliplatin with a noninfusional fluoropyrimidine (ie, XELOX). (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Agents targeting the EGFR'.)

Patients not initially treated with cetuximab/panitumumab — Cetuximab (or panitumumab) is useful in combination with irinotecan for patients with RAS and BRAF wild-type tumors who are refractory to irinotecan and as a single agent for those who are intolerant of irinotecan-based chemotherapy. If rapid tumor growth is observed after first-line oxaliplatin plus bevacizumab-based therapy, we suggest adding cetuximab (or panitumumab) to irinotecan-based therapy to elicit higher anti-tumor activity, particularly because the biology of the disease in these patients might not allow for a step-wise, sequential therapeutic approach. By contrast, in a case of a rather indolent, slowly progressive tumor, sequential use of agents (irinotecan first, followed by irinotecan plus cetuximab (or panitumumab) might be preferable. Another alternative is to continue bevacizumab with the second-line cytotoxic chemotherapy backbone. (See 'Continuation of bevacizumab beyond progression' below.)

Two randomized trials have explored the activity of cetuximab or panitumumab in combination with second-line FOLFIRI after failure of initial FOLFOX; neither included bevacizumab as a component of the first-line regimen in all patients.

In the large EPIC (Erbitux Plus Irinotecan in Colorectal cancer) trial, in which 1300 patients with EGFR-expressing, but not RAS-selected, mCRC who had failed initial FOLFOX therapy were randomly assigned to single-agent irinotecan with or without cetuximab, the addition of cetuximab quadrupled the response rate (16 versus 4 percent), significantly prolonged progression-free survival (PFS) (4 versus 2.6 months), and despite the higher frequency of side effects, was associated with better quality of life [167].

Similarly, a randomized trial of panitumumab plus FOLFIRI versus FOLFIRI alone after failure of initial 5-fluorouracil (FU)-containing chemotherapy (two-thirds prior oxaliplatin, 20 percent prior bevacizumab) showed that, in the KRAS wild-type group (n = 597), the addition of panitumumab was associated with a significant improvement in response rate (35 versus 10 percent) and median PFS (5.9 versus 3.9 months) [168].

These results confirm that the addition of cetuximab or panitumumab to an irinotecan-based chemotherapy regimen after failure of initial FU-containing chemotherapy is associated with greater treatment activity. Although the US Prescribing information for panitumumab does not include use of panitumumab in combination with irinotecan, we disagree with this viewpoint and consider that the addition of panitumumab to a non-bevacizumab containing irinotecan-based chemotherapy regimen in patients with RAS and BRAF wild-type mCRC is safe and effective. This approach is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO). (See 'Benefit of cetuximab and panitumumab' above.)

A separate question, given the demonstrated benefit of second-line bevacizumab in patients progressing on an initial bevacizumab-containing regimen, is whether it is preferable to continue second-line bevacizumab or switch to a regimen containing an anti-EGFR agent. (See 'Continuation of bevacizumab beyond progression' below.)

The benefit of adding bevacizumab or cetuximab to the cytotoxic chemotherapy backbone in RAS wild-type tumors that have progressed after first-line bevacizumab was directly addressed in the PRODIGE 18 trial [169]. In a preliminary report presented at the 2016 American Society of Clinical Oncology (ASCO) annual meeting, continuation with bevacizumab was associated with a numerically higher but not statistically significant median progression-free and overall survival advantage compared with cetuximab plus chemotherapy. In our view, there is insufficient evidence to draw any conclusions from these data, and either bevacizumab or an anti-EGFR agent is acceptable. As noted above, emerging data support the view that anti-EGFR antibodies do not appear to be useful for right-sided tumors in the setting of first-line therapy. However, whether these results can be extrapolated to later lines of therapy is not clear. Nevertheless, some clinicians would favor the use of continued bevacizumab over an anti-EGFR antibody for right-sided tumors. (See 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' above and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Second-line bevacizumab'.)

Are cetuximab and panitumumab interchangeable? — Cetuximab and panitumumab appear to have comparable efficacy when used for single agents for salvage therapy in patients with chemotherapy-refractory mCRC [164,165,170,171], and when used for first-line and second-line therapy of mCRC in conjunction with an irinotecan-based chemotherapy regimen. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Panitumumab'.)

Both MoAbs target the same antigen (the EGFR), and preclinical data suggest a similar mode of action (interference with ligand binding, downregulation of signaling activity, internalization of receptors) [172]. From a pharmacologic standpoint, the main difference between both agents lies in their IgG backbones: cetuximab is a chimeric mouse/human MoAb, while panitumumab is a completely human MoAb. As a result, the incidence of hypersensitivity reactions with panitumumab is lower, and this eliminates the need for routine premedication before therapy. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

The difference in on-label dosing schedules (every two weeks for panitumumab, weekly for cetuximab) are based more on how the respective trials leading to approval by the US Food and Drug Administration (FDA) were designed than on true pharmacokinetic, pharmacodynamic, or pharmacogenomic differences. The two drugs have similar half-lives (approximately seven days) and pharmacokinetics [173]. Results from a nonrandomized phase II trial [174] and a multicenter retrospective analysis [175] suggest that cetuximab at a dose of 500 mg/m2 every two weeks results in similar plasma concentrations and single-agent activity as does weekly dosing. Results of randomized comparisons of weekly versus every two-week dosing are not yet available.

In clinical practice, there is no therapeutic preference for using cetuximab versus panitumumab either as monotherapy, or in combination with chemotherapy. However, the lower rate of infusion reactions with panitumumab favors the use of this agent in regions with a high rate of cetuximab-related infusion reactions (eg, middle southeastern region of the United States, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee). We consider that the addition of panitumumab to an irinotecan or oxaliplatin-containing chemotherapy regimen in patients with RAS and BRAF wild-type tumors is appropriate, an approach that is also allowed in consensus-based guidelines from the NCCN and ESMO [84]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab' and 'Benefit of cetuximab and panitumumab' above.)

Patients receiving either drug should undergo periodic monitoring of serum electrolytes, including magnesium and potassium. (See "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Molecularly targeted agents", section on 'Anti-EGFR monoclonal antibodies'.)

Patients initially treated with cetuximab or panitumumab — For patients with RAS and BRAF wild-type tumors initially treated with cetuximab or panitumumab plus either FOLFOX or FOLFIRI, we would add bevacizumab to second-line treatment with the alternative chemotherapy doublet (or XELOX, if initially treated with FOLFIRI), as long as the patient is a reasonable candidate for bevacizumab. Treatment with cytotoxic chemotherapy alone is another option. There are no good-quality data that support benefit for continuing an anti-EGFR agent after first progression.

Continuation of an anti-EGFR agent at progression — There are scant data supporting benefit for continuing an anti-EGFR agent at progression. A single phase II trial randomly assigned 153 patients with RAS wild-type mCRC initially treated with FOLFIRI plus cetuximab to FOLFOX with or without cetuximab [176]. There was a statistically significant improvement in PFS when the analysis was restricted to RAS wild-type patients (median 6.9 versus 5.3 months), but the difference in overall survival was not statistically significant (median 23.7 versus 19.8 months). ESMO guidelines from 2016 state that a chemotherapy doublet plus bevacizumab is their first choice in this setting, but that the chemotherapy doublet plus an anti-EGFR agent would be an appropriate second choice [84].

Panitumumab after failure of cetuximab — A small subset of patients with RAS wild-type tumors who are resistant to cetuximab will respond to panitumumab, but the best way to identify this subset is unclear. Testing for specific mutations in the EGFR that might confer cetuximab resistance but panitumumab sensitivity is currently only available in research labs. In addition, the duration of benefit that these patients might achieve is unknown. Given the evidence that the majority of patients who have been evaluated in a trial setting do not achieve durable benefit, in our view, the use of panitumumab in patients who progress on cetuximab should only be undertaken in the context of a clinical trial aimed at better defining this question. This approach is consistent with consensus-based guidelines from the NCCN and ESMO [84].

Whether panitumumab is active in patients who have failed cetuximab therapy (and vice versa) is unclear. The similar mode of action would seem to support the existence of cross resistance, but there are few data that inform this issue. Two clinical trials of panitumumab in patients progressing on a cetuximab-containing regimen have come to different conclusions:

In the first, presented in abstract form at the 2010 ASCO meeting, 32 patients with KRAS wild-type mCRC received panitumumab after progressing on cetuximab plus irinotecan [177]. The objective response rate was 22 percent, and the disease control rate (objective response plus stable disease) among the 11 patients who had responded to prior cetuximab was 73 percent.

A second trial, also reported in preliminary form only, included 20 patients with KRAS wild-type mCRC who had progressed on cetuximab [178]. No patient responded, although 45 percent had stable disease (no progression for at least two cycles). The authors concluded that panitumumab was of minimal benefit in cetuximab-refractory disease.

A possible explanation for these discrepant results has been provided by studies examining the mutational landscape of cetuximab-refractory tumors:

In one study, investigators used a cetuximab-sensitive human CRC cell line to develop a resistant version by prolonged in vitro exposure to cetuximab [179]. The cetuximab-resistant cells contained a secondary EGFR mutation in the extracellular domain of the receptor that impaired binding of cetuximab but not other EGFR ligands, including panitumumab. This specific mutation was identified in 2 of 10 tumors from people with cetuximab resistance, one of whom received panitumumab and had an objective response.

In another report of tissue samples derived from 37 patients with CRC who became refractory to cetuximab, a complex pattern of mutations was observed, converging on two main patterns of resistance: activating mutations affecting EGFR downstream signaling and mutations in the EGFR ectodomain that disrupt antibody receptor binding, a subset of which prevented binding to cetuximab but not panitumumab [180].

Antiangiogenesis therapy

Continuation of bevacizumab beyond progression — For patients treated with a first-line bevacizumab-containing chemotherapy regimen, the use of bevacizumab beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach. However, if bevacizumab is used as a component of the second-line chemotherapy regimen for patients with RAS wild-type disease, it should not be administered concurrently with an EGFR-targeting MoAb. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Second-line bevacizumab' and 'Dual antibody therapy' below.)

The benefit of continuing bevacizumab beyond progression on a first-line bevacizumab-containing regimen was directly studied in the European phase III TML trial, in which continuation of bevacizumab with a second-line fluoropyrimidine-based chemotherapy regimen was associated with a significant improvement in overall survival (median 11.2 versus 9.8 months) without an increase in bevacizumab-related adverse events [181]. This degree of benefit was more modest than prior retrospective analyses of registry data had suggested. Nevertheless, as a result of these data, for patients treated with a first-line bevacizumab-containing chemotherapy regimen, the use of bevacizumab beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Second-line bevacizumab'.)

If bevacizumab is used as a component of the second-line chemotherapy regimen for patients with KRAS wild-type disease, it should not be administered concurrently with an EGFR-targeting MoAb. (See 'Dual antibody therapy' below.)

Aflibercept — Particularly given the data on benefit from bevacizumab after progression on a first-line bevacizumab-containing regimen, whether aflibercept plus second-line FOLFIRI is the preferred approach after progression on first-line FOLFOX plus bevacizumab is unclear. FOLFIRI plus aflibercept is an alternative to FOLFIRI with bevacizumab (or FOLFIRI alone) in this setting, but it may be more toxic and more costly. (See 'Continuation of bevacizumab beyond progression' above.)

Intravenous aflibercept (VEGF Trap, Zaltrap) is a recombinant fusion protein, consisting of vascular endothelial growth factor (VEGF) binding portions from key domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1. It acts as a soluble "decoy" receptor that binds to human VEGF-A, VEGF-B, and placental growth factor (PIGF), thereby inhibiting the binding of these ligands and activation of their respective receptors.

Aflibercept is approved in the United States for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen. Approval was based on the placebo-controlled VELOUR trial, in which 1226 patients with oxaliplatin-refractory mCRC were randomly assigned to aflibercept (4 mg/kg IV) or placebo, plus FOLFIRI, every two weeks until progression. Median overall survival was significantly longer in patients treated with aflibercept (13.5 versus 12.1 months) [182]. Benefit and safety were similar regardless of prior bevacizumab exposure. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Aflibercept'.)

While the side effect profile of aflibercept plus FOLFIRI in the VELOUR trial was consistent with other agents targeting VEGF (bleeding, hypertension, proteinuria, wound infection, arterial thromboembolic events), rates of diarrhea, mucositis, complicated neutropenia, infection, and fatigue associated with aflibercept in this trial were higher than usually seen with bevacizumab, as were rates of treatment discontinuation for toxicity or refusal (30 versus 12 percent). (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".)

As with bevacizumab, because of the risk of impaired wound healing, at least 28 days (and preferably six to eight weeks) should elapse between major surgery and administration of aflibercept, except in emergency situations. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Delayed wound healing'.)

Ramucirumab — Ramucirumab is a recombinant MoAb of the IgG1 class that binds to the VEGFR-2, blocking receptor activation. The efficacy of ramucirumab for second-line treatment of mCRC was addressed in the double blind phase III RAISE trial in which 1072 patients with progressing after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomly assigned to FOLFIRI with ramucirumab (8 mg/kg IV every two weeks) or placebo until disease progression, unacceptable toxicity, or death [183]. Median survival was modestly but significantly greater with ramucirumab (13.3 versus 11.7 months), as was median PFS.

Based upon these results, ramucirumab was approved in April 2015 for use in combination with irinotecan plus leucovorin and short-term infusional fluorouracil (FOLFIRI) for the treatment of mCRC in patients whose disease has progressed on a first-line bevacizumab, oxaliplatin, and fluoropyrimidine-containing regimen [184]. However, given this modest degree of benefit, the expense of this agent, and the competing data indicating benefit from continuation of second-line bevacizumab in this same setting, we do not consider ramucirumab the agent of choice if continued VEGF inhibition beyond first-line progression is considered. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Second-line bevacizumab'.)

Regorafenib — For patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, anti-EGFR therapy (if RAS wild type), and who require additional therapy, we suggest single agent regorafenib. Based upon preliminary data from the phase II ReDOS study, we suggest initiating therapy with 80 mg per day rather than 160 mg (the approved dose), escalating the dose weekly in the absence of toxicity, and ending at 160 mg daily for 21 days of each 28-day cycle. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Regorafenib'.)

Regorafenib is an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3), as well as other receptor and intracellular kinases. Regorafenib is approved in the United States for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF agent; and if RAS/BRAF wild type, an anti-EGFR therapy. Approval was based up the results of the CORRECT trial, which compared best supportive care plus regorafenib (160 mg orally once daily for three of every four weeks) or placebo in 760 patients with chemotherapy-refractory disease, and demonstrated a significant survival benefit for regorafenib (median 6.4 versus 5 months, hazard ratio 0.77), albeit with little objective antitumor response [185]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Regorafenib'.)

Dual antibody therapy — Based upon the available data, a chemotherapy regimen containing both bevacizumab and an anti-EGFR MoAb should not be considered a standard approach for first- or second-line therapy of mCRC outside of a clinical trial.

The results of the phase II BOND-2 trial, which compared a combination of cetuximab/bevacizumab with (CBI) or without (CB) irinotecan as last-line therapy in patients with chemorefractory mCRC generated interest in dual-antibody combinations [186]. BOND-2 reported unprecedented outcome results for patients previously treated with FU, irinotecan, and (in 85 to 90 percent of cases) oxaliplatin with regard to response rate (20 versus 37 for CB and CBI, respectively), time to tumor progression (4.9 versus 7.3 months), and overall survival (11.4 versus 14.5 months). The toxicity profile was also tolerable.

The following issues must be considered when interpreting these results and their implications for clinical practice:

BOND-2 was a small randomized phase II trial of 83 patients treated in a few highly specialized cancer centers, thus limiting the extrapolation of the findings to the unselected patient population treated by community oncologists.

The unexpectedly long median overall survival in both treatment arms underscores the highly select nature of the patient population enrolled to the study.

Patients who were considered candidates for the trial had already received (and apparently tolerated) several lines of therapy and still maintained a good enough performance status (0 to 1) (table 2) to be enrolled in the trial. This again underscores the fact that the patients enrolled on BOND-2 were highly selected and clearly not representative of the typical patient population with refractory mCRC.

This issue might in part explain the unexpected results of both the PACCE and the CAIRO2 trials, both of which suggested a possible detrimental impact of concurrent use dual antibodies targeting VEGF and the EGFR in the setting of first-line therapy [187,188]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Dual antibody therapy'.)

Patients on BOND-2 were all bevacizumab-naive so that the data cannot necessarily be used to justify therapy with dual antibodies in patients who have already received bevacizumab as part of their prior palliative medical therapy. This approach was being studied for second-line therapy in SWOG S0600; however, the protocol was terminated prematurely due to insufficient accrual.

Trifluridine-tipiracil — Trifluridine-tipiracil (TAS-102) is an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA, causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well [189].

Benefit in refractory mCRC was shown in a phase III trial (RECOURSE) in which 800 patients who were refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and anti-EGFR agents (if wild-type KRAS) were randomly assigned to trifluridine-tipiracil (35 mg/m2 orally twice daily on days 1 through 5 and 8 to 12 of each 28-day cycle) or placebo [190]. Trifluridine-tipiracil was associated with a significant prolongation in median overall survival, the primary endpoint (7.1 versus 5.3 months), and this benefit was irrespective of prior regorafenib use. Largely based upon these results, trifluridine-tipiracil was approved in the United States for treatment of mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antiangiogenic biologic product, and an anti-EGFR MoAb, if RAS wild type [191]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Trifluridine-tipiracil'.)

Molecularly targeted therapy — Several ongoing trials (eg, the National Cancer Institute MATCH and the ASCO TAPUR trials) are using next-generation DNA sequencing to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types.  

In 2017, the FDA approved two gene panel tests (MSK-IMPACT and F1CDx) for analyzing pathogenic changes in solid tumors; these tests can be used on formalin-fixed, paraffin-embedded (FFPE) tissue regardless of the primary organ from which the tumor arose [192-194]. These tests detect variations in the coding regions of over 400 and over 300 genes, respectively, and can provide information about differences between tumor and adjacent noncancerous tissue and about genomic signatures such as microsatellite instability, tumor mutational burden, and the presence of specific mutations/rearrangements for which a molecularly targeted agent may be available. Unfortunately only a minority of patients will be found to have truly actionable mutations. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)

Although the field of molecularly targeted therapy is rapidly evolving in mCRC [195], the most compelling data so far are on the benefits of immune checkpoint inhibitors in patients with high levels of microsatellite instability (MSI-H).

Patients with microsatellite unstable/deficient mismatch repair tumors — Approximately 3.5 to 6.5 percent of stage IV CRCs are characterized as MSI-H, which is the biologic footprint of deficiency in DNA mismatch repair enzymes (dMMR). (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes'.)

Another option for treatment at progression for patients who have MSI-H/dMMR tumors is immunotherapy. Three options are available:

Monotherapy with an immune checkpoint inhibitor that targets the programmed death receptor-1 (PD-1; ie, nivolumab or pembrolizumab) is one option. In clinical trials, objective response rates with these two PD-1 inhibitors are 30 to 50 percent, and some responses are durable. Both drugs have been FDA approved for this indication in the United States, and the choice of one agent over the other is empiric. Patients who experience disease progression on either of these drugs should not be offered the other.

Another option is the combination of nivolumab with ipilimumab, a monoclonal antibody directed against a different immune checkpoint, cytotoxic T-lymphocyte antigen 4 (CTLA-4). Although there are no randomized trials directly comparing dual therapy with monotherapy with either nivolumab or pembrolizumab alone, indirect comparisons from the CheckMate 142 trial suggest that combined immunotherapy provides improved efficacy over anti-PD-1 monotherapy and has a favorable risk:benefit ratio.  

The subject of immunotherapy with immune checkpoint inhibitors for MSI-H/dMMR mCRC is discussed in detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immune checkpoint inhibitors and mismatch repair deficient tumors'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Colon and rectal cancer (The Basics)")

Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — The majority of patients with metastatic colorectal cancer (mCRC) cannot be cured, and the intent of therapy is palliative. Palliative chemotherapy can relieve symptoms, improve quality of life (QOL), and prolong survival. There are eight classes of active agents for treatment of mCRC. The optimal way to combine and sequence these agents is not yet established. In general, exposure to all active drugs is more important than the specific sequence of administration. (See 'Overview of the therapeutic approach' above.)

Increasingly, biomarker expression is driving therapeutic decision-making. Benefit from monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) is restricted to patients whose tumors do not contain mutated RAS genes. Furthermore, response to EGFR-targeted agents is unlikely in patients whose tumors harbor a BRAF V600E mutation). Emerging data also suggests that the location of the primary tumor is another factor that influences the efficacy of anti-EGFR agents. (See 'Extended RAS testing' above and 'BRAF' above and 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' above.)

The following represents our general approach for patients with nonoperable mCRC. Specific recommendations for patients with isolated hepatic metastases who are potential candidates for resection are provided elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)

Initial therapy

For most patients, we suggest a chemotherapy doublet (FOLFOX: oxaliplatin plus leucovorin [LV] and short-term infusional fluorouracil [FU]; XELOX (CAPOX): oxaliplatin plus capecitabine; or FOLFIRI: irinotecan plus LV and short-term infusional FU) (table 1) rather than sequential use of single agents or an initial triplet regimen containing both oxaliplatin and irinotecan (Grade 2B). (See 'Initial doublet combinations versus sequential single agents' above and "Treatment protocols for small and large bowel cancer".)

FOLFOX and FOLFIRI have similar first-line efficacy, and the decision to use one or the other should mainly be based on the expected toxicity profile of both regimens. In general, FOLFIRI (table 9) is preferred for patients who received an adjuvant oxaliplatin-containing regimen within the prior 12 months. (See 'Treatment-related toxicity' above and 'FOLFOX versus FOLFIRI' above.)

While FOLFOX4 was the regimen used in the palliative and adjuvant registration trials, many American oncologists use a modification of FOLFOX6 (mFOLFOX6) because it does not require a day 2 bolus of LV (table 3). We prefer modified FOLFOX7 (mFOLFOX7), which eliminates bolus FU completely and causes significantly less myelosuppression (table 10). (See "Treatment protocols for small and large bowel cancer".)

The substitution of capecitabine for short-term infusional FU plus LV (ie, the XELOX or CAPOX regimen) increases convenience and is probably as effective but more toxic than FOLFOX. For American patients, we prefer capecitabine 850 mg/m2 twice daily plus oxaliplatin 130 mg/m2 (table 5). Oncologists in Europe and Asia more often use capecitabine 1000 mg/m2 twice daily in conjunction with the same oxaliplatin dose. Due to lingering concerns about toxicity, we do not consider that capecitabine in combination with irinotecan is a valid substitute for FOLFIRI, at least for American patients. (See 'Capecitabine containing doublets' above and "Treatment protocols for small and large bowel cancer".)

Where available, S-1 plus oxaliplatin represents an acceptable alternative to FOLFOX or XELOX, at least for Asian patients. S-1 plus irinotecan also represents a valid alternative to FOLFIRI as a second-line regimen after failure of initial FOLFOX. (See 'S-1' above.)

A triplet regimen (eg, FOLFOXIRI (table 11)) could be considered an option for first-line therapy in selected patients for whom a more aggressive initial approach is chosen (eg, younger age, high tumor load or highly symptomatic disease, conversion therapy for initially unresectable but potentially resectable liver metastases, RAS or BRAF mutation), as long as they are able to tolerate intensive therapy. (See 'Three versus two-drug combinations' above.)

Biologics

Although some experts disagree, regardless of whether an oxaliplatin-based or an irinotecan-based chemotherapy backbone is selected, it is reasonable to add a biologic agent to the first-line regimen for patients who can tolerate an intensive regimen. We base the choice of bevacizumab versus an anti-EGFR agent on several factors, including RAS/BRAF mutation status, primary tumor site, whether the patient is a suitable candidate for bevacizumab, and whether the patient may be a candidate for subsequent liver resection:

For patients with RAS or BRAF V600E mutated tumors, we recommend not using cetuximab or panitumumab (Grade 1A). (See 'Agents targeting the EGFR' above.)

For first-line therapy of patients with RAS/BRAF wild-type mCRC, we suggest an anti-EGFR antibody rather than bevacizumab for patients with a left-sided primary (Grade 2A). However, if a triplet chemotherapy regimen such as FOLFOXIRI is chosen for first-line therapy in patients for whom a more aggressive initial approach is chosen, bevacizumab is the preferred biologic partner, even for left-sided primary tumors, because of the absence of data on FOLFOXIRI combined with an anti-EGFR agent. (See 'Three versus two-drug combinations' above.)

For patients who are candidates for bevacizumab, we suggest bevacizumab rather than an anti-EGFR antibody in conjunction with first-line chemotherapy for most patients with mCRC and a right-sided primary tumor (Grade 2C). However, we would allow the use of anti-EGFR agents in later lines of therapy. (See 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy' above.)

In our view, patients with RAS and BRAF wild-type right-sided tumors who have a contraindication to bevacizumab (eg, active bleeding, history of arterial thromboembolism in the 6 to 12 months prior to treatment, untreated hemorrhagic brain metastases) should be treated with chemotherapy alone, without a biologic agent. (See 'Contraindications' above.)

The potential for improved outcomes from adding bevacizumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. In particular, the use of bevacizumab in older adult patients with a history of an arterial thromboembolic event within 6 to 12 months must be carefully considered. (See "Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status", section on 'Bevacizumab' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial thromboembolic events'.)

In addition, many clinicians do not use bevacizumab in conjunction with a cytotoxic chemotherapy backbone for initial chemotherapy treatment of patients with potentially resectable liver metastases, citing the marginal benefits and risk for major complications. Others limit bevacizumab use to those patients with RAS/BRAF V600E mutated tumors (ie, those for which use of an anti-EGFR agent is contraindicated) who are undergoing conversion therapy for initially unresectable disease. This subject is discussed in detail elsewhere. (See "Management of potentially resectable colorectal cancer liver metastases", section on 'Neoadjuvant chemotherapy'.)

Because of the risk of impaired wound healing, bowel perforation, and fistula formation, at least 28 days (and preferably six to eight weeks) should elapse between major surgery and administration of bevacizumab, except in emergency situations. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bevacizumab'.)

For patients receiving cetuximab or panitumumab in combination with cytotoxic chemotherapy, appropriate chemotherapy doublets are either FOLFIRI or FOLFOX). The benefit of an oxaliplatin-containing regimen plus an anti-EGFR agent prior to resection in patients with potentially resectable colorectal liver metastases is still debated, and many clinicians avoid this combination in this setting. There are no data on the safety of combining an anti-EGFR agent with a chemotherapy triplet (ie, FOLFOXIRI), and if this regimen is chosen, we would use bevacizumab and not an anti-EGFR agent, if the addition of a biologic agent is warranted. (See 'Benefit of cetuximab and panitumumab' above.)

Patients who are not candidates for intensive therapy

For patients who are not candidates for an intensive first-line oxaliplatin or irinotecan-based regimen, we suggest a fluoropyrimidine alone (Grade 2B) [2]. (See 'Patients who are not candidates for intensive therapy' above.)

We prefer short-term infusional FU/LV rather than bolus administration, because of its favorable toxicity profile (table 6). In patients treated with first-line FU/LV, we suggest the addition of bevacizumab (Grade 2A). The survival benefit from adding bevacizumab must be balanced against the potential for serious treatment-related toxicity. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Leucovorin plus FU' and "Treatment protocols for small and large bowel cancer".)

An equally effective alternative first-line regimen, when fluoropyrimidines alone are indicated, is capecitabine with or without bevacizumab. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Orally active fluoropyrimidines'.)

Treatment at progression — In the absence of direct clinical trial data, we suggest the following approach after progression on initial therapy:

For fit patients initially treated with an oxaliplatin-containing chemotherapy doublet (ie, FOLFOX or XELOX), we switch FOLFIRI or irinotecan alone at the time of disease progression. For patients initially treated with FOLFIRI, we switch to an oxaliplatin-based regimen at the time of progression. (See 'The chemotherapy backbone' above.)

For patients initially treated with bevacizumab plus a doublet chemotherapy regimen, the continuation of bevacizumab in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered a standard approach, particularly if an anti-EGFR agent is not indicated (eg, those with a RAS or BRAF mutation), as long as drug therapy is well tolerated. (See 'Continuation of bevacizumab beyond progression' above.)

Another option for patients treated initially with FOLFOX plus bevacizumab is FOLFIRI with or without intravenous aflibercept or ramucirumab. (See 'Aflibercept' above and 'Ramucirumab' above.)

If bevacizumab, aflibercept, or ramucirumab is used as a component of the second-line chemotherapy regimen for patients with RAS and BRAF wild-type tumors, we suggest that an EGFR-targeting monoclonal antibody not be used concurrently (Grade 2B). (See 'Dual antibody therapy' above.)

For patients with RAS/BRAF wild-type tumors initially treated with cetuximab or panitumumab plus either FOLFOX or FOLFIRI, one option is to add bevacizumab to second-line treatment with the alternative chemotherapy doublet (or XELOX, if initially treated with FOLFIRI), as long as the patient is a reasonable candidate for bevacizumab. Treatment with cytotoxic chemotherapy alone is another option. (See 'RAS/BRAF wild-type tumors' above.)

For patients not able to tolerate intensive therapy, treatment with sequential single agents (irinotecan alone if the initial regimen was oxaliplatin-based), or cetuximab or panitumumab alone (for RAS and BRAF wild-type tumors) is a reasonable approach. Supportive care alone is also an option. (See 'Patients who are not candidates for intensive therapy' above.)

Another option for treatment at progression (second line or beyond) for patients who have tumors with a high level of microsatellite instability or who are deficient in DNA mismatch repair enzymes is immunotherapy with either an immune checkpoint inhibitor targeting the programmed death receptor-1 (PD-1) or its ligand (eg, pembrolizumab or nivolumab), or the combination of nivolumab plus ipilimumab, a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4). (See 'Patients with microsatellite unstable/deficient mismatch repair tumors' above.)

For patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and (if RAS and BRAF wild type) an anti-EGFR agent and who require additional therapy, we suggest single-agent regorafenib or trifluridine-tipiracil (Grade 2B). If regorafenib is chosen, we suggest initiating therapy with 80 mg per day rather than 160 mg (the approved dose), escalating the dose weekly in the absence of toxicity, and ending at 160 mg daily for 21 days of each 28-day cycle. (See 'Regorafenib' above and 'Trifluridine-tipiracil' above.)

After failure of all conventional agents/combinations, if performance status is adequate and a tumor-directed therapeutic approach is still warranted, we prefer enrollment in a phase I or II trial testing novel agents/combinations. An assessment of tumor mutational burden and DNA mismatch repair deficiency using genotyping platforms such as those available from Foundation Medicine may discover actionable mutations to narrow choices for targeted/experimental therapy. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immunotherapeutic approaches' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'HER2-targeted therapy'.)

If protocol treatment is not available or declined, reutilizing the regimen initially used in the treatment sequence (eg, FOLFOX) is a reasonable option, especially if the regimen was abandoned because of toxicity and not disease progression. During the often lengthy phase of sequential therapy, tumors may retain or regain sensitivity to previously used drugs.

Adjunctive treatment

Given the potential benefits of vitamin D in terms of skeletal health and the possibility of better cancer-related outcomes in patients with higher serum levels, it seems reasonable to test serum vitamin D levels in patients with newly diagnosed mCRC, and to replete those with low levels (serum 25[OH]D <20 ng/mL [50 nmol/L]). (See 'Issues related to vitamin D' above.)

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