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Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach

Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach
Literature review current through: Jan 2024.
This topic last updated: Oct 17, 2023.

INTRODUCTION — The treatment of metastatic colorectal cancer (mCRC) is evolving. In addition to chemotherapy, many active agents for mCRC have been developed that are associated with improved overall survival. Management is also increasingly being driven by tumor biology and gene expression analysis of individual tumors. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

The approach to initial systemic therapy for patients with inoperable mCRC is discussed here. General principles of chemotherapy treatment for mCRC (including the role of maintenance therapy), approach to later lines of systemic therapy for inoperable metastatic CRC, recommendations for systemic chemotherapy in older adult patients with mCRC, the integration of chemotherapy with surgery for patients with potentially resectable liver metastases, and a compilation of chemotherapy regimens used for advanced CRC are discussed separately. (See "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status" and "Treatment protocols for small and large bowel cancer".)

OVERVIEW OF THE THERAPEUTIC APPROACH

Available agents and strategy for selection of the approach — There are now several classes of drugs that are available for first-line therapy of mCRC:

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

Irinotecan, which is active as monotherapy as well as in combination with other active agents.

Oxaliplatin, which is only active when partnered with a second cytotoxic agent, most commonly a fluoropyrimidine.

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).

Immunotherapy with an immune checkpoint inhibitor that targets the programmed death receptor 1 (PD-1; ie, the MoAb pembrolizumab). (See 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' below.)

HER2-targeted agents may be useful for selected patients with HER2-overexpressing tumors, although these agents are more commonly used for later lines of therapy and this is not our preferred approach.

Predictive biomarkers — Increasingly, biomarker expression is driving therapeutic decision-making in oncology, including mCRC. Gene profiling of tumor tissue (ie, with next-generation sequencing) should be undertaken as quickly as possible after a diagnosis of metastatic colorectal cancer. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Predictive biomarkers'.)

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 either alone or in combination with chemotherapy is unlikely in patients whose tumors harbor a BRAF V600E mutation, although EGFR inhibitors have shown activity in combination with a BRAF inhibitor [1]. Emerging data also suggest that the location of the primary tumor is another factor that influences the efficacy of EGFR inhibitors. (See 'RAS/BRAF wild-type tumors' below and 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' below and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Impact of RAS status on the use of EGFR inhibitors'.)

Benefit from immunotherapy with a PD-1 inhibitor appears to be limited to the subset of tumors with high levels of microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) or, in the second-line setting and beyond, high levels of tumor mutational burden. (See 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' below and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'dMMR or MSI-H tumors'.)

Although more commonly used for later lines of therapy, some patients with HER2-overexpressing mCRC may be eligible for first-line therapies targeting HER2. (See 'Not candidates for intensive therapy' below and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

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

However, some patients with stage IV disease (particularly those with liver- or lung-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 "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)

Initial therapy — We select initial therapy for patients with nonoperable disease based upon patient fitness and comorbidity, RAS and BRAF mutation status, the presence of dMMR/MSI-H, 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), and the data supporting this approach are discussed below.

The optimal duration of initial chemotherapy for categorically 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 chemotherapy for patients who have initially unresectable metastases, but that responds to treatment such that their disease becomes potentially resectable, is discussed elsewhere. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with 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. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

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], treatment-free intervals, as well as reutilization of previously administered chemotherapy agents in combination with other active drugs.

An important principle is that exposure to all active drugs during the course of treatment for mCRC, as appropriate, is more important than the specific sequence of drug administration in order to maximize OS. The proportion of patients receiving all active agents correlates strongly with median survival in all large published phase III trials over the last decade [2,7,8]. Our general approach to treatment at progression after the first-line regimen is discussed elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Options for treatment at progression'.)

Resource-constrained settings — The approach outlined above assumes that health care resources are not a limiting factor to selecting treatment. There are few data to guide the treatment strategy for mCRC in resource-constrained settings. The American Society of Clinical Oncology (ASCO) has developed consensus-based guidelines for treatment of late-stage colorectal cancer that stratify recommendations based on the available level of services (basic, limited, enhanced, and maximal (table 1)) [9]. They include specific recommendations for initial diagnostic evaluation, systemic therapy in the first-line setting and beyond, and surgical management of patients with potentially resectable disease.

PATIENTS WITH PROFICIENT DNA MISMATCH REPAIR/MICROSATELLITE STABLE TUMORS

Candidates for intensive systemic therapy

The cytotoxic chemotherapy backbone

Three- versus two-drug combinations — For patients with a good performance status who are able to tolerate intensive therapy, particularly those with a high tumor burden and those who need conversion therapy for initially unresectable but potentially resectable liver metastases we suggest an initial course of three to six months of triplet therapy with FOLFOXIRI (irinotecan and oxaliplatin with fluorouracil [FU]/leucovorin [LV]), rather than an initial chemotherapy doublet (ie, oxaliplatin plus LV and short-term infusional FU [FOLFOX], capecitabine plus oxaliplatin [CAPOX, XELOX], or irinotecan plus LV and short-term infusional FU [FOLFIRI]) for first-line chemotherapy. For other patients with mCRC and a good performance status, we suggest a balanced discussion of values and preferences to decide whether the added toxicity of triplet therapy is worth the relatively small incremental improvement in survival as compared with a chemotherapy doublet containing either oxaliplatin or irinotecan. This recommendation is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and a year 2022 guideline on management of mCRC from the American Society of Clinical Oncology (ASCO) [10-12]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF' and "Treatment protocols for small and large bowel cancer" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)

Compared with doublet regimens that contain either oxaliplatin or irinotecan, high rates of objective response and favorable long-term disease-free and overall survival (OS) rates have been reported in most (but not all) trials of regimens that combine FU and LV plus both irinotecan and oxaliplatin (such as the FOLFOXIRI (table 2) regimen), with or without bevacizumab or panitumumab [13-28].

The following reflects the range of findings:

FOLFOXIRI versus FOLFIRI – Two phase III trials comparing FOLFOXIRI versus the Douillard irinotecan/FU/LV (which is less dose-intensive than FOLFIRI) regimen (table 3) have come to opposite conclusions about the benefit of triplet therapy [18-21], while a third phase III trial comparing FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab suggests superiority for FOLFOXIRI in terms of response rate and progression-free survival (PFS) but comparable rates of subsequent complete resection of liver metastases [17]:

In an Italian trial that randomly assigned 244 patients with previously untreated inoperable mCRC to the Douillard FU plus irinotecan 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 (15 versus 6 percent), median PFS, and median OS (23 versus 17 months) [18,19]. These benefits came at a cost of treatment-related neuropathy with FOLFOXIRI (19 percent grade 2 or 3), and higher rates of grade 3 or 4 neutropenia (50 versus 28 percent) with triplet therapy [18].

Similar high rates of objective response and significantly better median OS (29.8 versus 25.8 months) were noted with FOLFOXIRI plus bevacizumab (table 4) as compared with FOLFIRI plus bevacizumab in the TRIBE trial, but it did not confirm the higher rates of secondary surgical resection of liver metastases with an initial three-drug chemotherapy backbone (15 versus 12 percent with FOLFIRI) [17].

A benefit for initial FOLFOXIRI as compared with a preplanned sequential strategy of exposure to the same agents in two subsequent lines of therapy was shown in a later trial by this same group (the TRIBE2 trial) [20]. The benefits of upfront FOLFOXIRI/bevacizumab included a significantly greater time to second disease progression, a greater objective response rate, and longer OS (27.4 versus 22.5 months). These benefits came at the cost of significantly more grade 3 or 4 diarrhea, neutropenia, and febrile neutropenia.

In contrast to these two trials, a Hellenic Oncology Research Group (HORG) trial of 283 patients with previously untreated mCRC noted no significant benefit for FOLFOXIRI over the Douillard regimen of FU/LV/irinotecan (table 3) in terms of median OS (21.5 versus 19.5 months), time to tumor progression (8.4 versus 6.9 months), or objective response rate (43 versus 34 percent) [21]. However, the FOLFOXIRI regimen used in this trial contained smaller doses of irinotecan, oxaliplatin, and FU.

FOLFOXIRI versus FOLFOX – Additional data supporting the benefit of initial triplet therapy come from trials comparing FOLFOXIRI versus FOLFOX, with or without bevacizumab [22,23,26]. As examples:

The phase III STEAM trial randomly assigned 280 patients with previously untreated mCRC to bevacizumab plus FOLFOX, concurrent FOLFOXIRI, or sequential FOLFOXIRI, which consisted of alternating courses of FOLFOX and FOLFIRI every four weeks [22]. The objective response rates were higher for concurrent FOLFOXIRI/bevacizumab (73 versus 62 percent for FOLFOX/bevacizumab), median PFS was modestly but significantly better (11.7 versus 9.5 months, hazard ratio [HR] 0.7, 95% CI 0.5-0.9), and almost twice as many patients were able to undergo secondary liver resection (17.2 versus 9.8 percent). Results did not differ significantly for sequential administration of alternating FOLFOX and FOLFIRI compared with concurrent FOLFOXIRI.

The phase III VISNU-1 trial randomly assigned 349 patients younger than age 70 with three or more circulating tumor cells (a poor prognostic factor for survival) to bevacizumab plus FOLFOXIRI or FOLFOX [26]. In a preliminary report presented at the 2019 annual American Society of Clinical Oncology (ASCO) meeting, initial triplet therapy was associated with significantly improved disease-free survival, the primary endpoint (median 12.4 versus 9.3 months); there was a trend toward improved OS that was not statistically significant (22.3 versus 17.6 months). Patients treated with the triplet regimen had significantly higher rates of grade 3 or 4 asthenia, diarrhea, and febrile neutropenia. The use of circulating tumor cells for clinical decision-making is not yet a standard approach, but it is the subject of active ongoing research.

The benefits of initial triplet therapy combined with a biologic agent are further supported by two additional studies:

In the phase II randomized VOLFI trial, in which 96 patients with RAS wild-type mCRC were randomly assigned to modified FOLFOXIRI with or without panitumumab [24], the addition of panitumumab to modified FOLFOXIRI significantly improved the objective response rate (87 versus 61 percent) and the rate of secondary resection of metastases (33 versus 12 percent).

An individual patient data meta-analysis of five trials comparing FOLFOXIRI plus bevacizumab versus a doublet plus bevacizumab (from the CHARTA, OLIVIA, STEAM, TRIBE and TRIBE2 trials) concluded that patients assigned to a triplet regimen plus bevacizumab had significantly better median OS (28.9 versus 24.5 months), median PFS (12.2 versus 9.9 months), objective response rate (65 versus 54 percent), and a modestly but significantly higher R0 resection rate (16 versus 12 percent, p = 0.07) [25]. These benefits were counterbalanced by higher rates of grade 3 or 4 neutropenia (46 versus 22 percent), febrile neutropenia (6.3 versus 3.7 percent), and diarrhea (18 versus 8 percent).

Initial doublet combinations versus sequential single agents — For patients who are able to tolerate it, we suggest combination chemotherapy with a doublet (FOLFOX, CAPOX [XELOX], or FOLFIRI (table 3)) rather than sequential single-agent therapy for initial treatment of mCRC, particularly for those who have limited liver metastases that might become potentially resectable. This recommendation is consistent with consensus-based guidelines from the NCCN, ESMO, and ASCO [10-12]. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)

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 for mCRC correlates strongly with median survival in all large published phase III trials over the last decade. (See 'Subsequent treatment and the continuum of care model' above.)

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 OS 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), neither of which showed that survival was adversely impacted by initial single-agent therapy [29,30] However, the median survival for all groups in both trials was lower than expected for modern chemotherapy.

One possible reason is the low number of patients who eventually received all three active drugs in both trials. Furthermore, neither trial used bevacizumab or cetuximab as either first-line or salvage therapy. These agents improve PFS, and bevacizumab also improves OS when used in the first-line regimen. (See 'Role of biologics' below.)

Some of these issues were addressed in a third trial, the XELAVIRI trial, which randomly assigned 421 patients with untreated mCRC to a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at progression, versus initial combined therapy with all three agents [31]. Only 63 percent of patients treated with initial sequential therapy received irinotecan at some point in the course of their treatment, compared with 100 percent in the combination therapy group. Although sequential therapy was shown not to be noninferior to combination therapy for time to failure of strategy (the primary endpoint), survival was not significantly different (median OS 23.5 versus 21.1 months). An unplanned subgroup analysis suggested that initial combination therapy particularly benefited patients with wild-type RAS/BRAF tumors.

Thus, the available evidence continues to support initial combination chemotherapy for most patients, particularly for those whose metastases might be potentially resectable after an initial chemotherapy response. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)

FOLFOX versus FOLFIRI — FOLFOX and FOLFIRI (table 3) are both considered acceptable choices for doublet first-line therapy, with similar efficacy and a comparable, albeit different, side effect profile; the now obsolete bolus irinotecan/FU/LV (IFL) regimen should not be used. This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [10,11]. (See "Treatment protocols for small and large bowel cancer".)

Multiple trials have demonstrated the benefit of adding oxaliplatin to FU/LV [32-35], and the benefit of adding irinotecan to FU/LV [36-38] for the first-line treatment of mCRC. Furthermore, the available data from head-to-head comparisons suggest that outcomes with first-line oxaliplatin/FU/LV and irinotecan/FU/LV are similar, at least when short-term infusional FU regimens are used:

INT 9741 – 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 3) regimen and to a combination of irinotecan plus oxaliplatin without FU (IROX) [39]. All efficacy parameters as well as the toxicity profile favored FOLFOX4 over IFL. 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 5), has become the most commonly used first-line chemotherapy backbone for mCRC in the United States [40].

European/Asian trials – In contrast to bolus IFL, regimens that incorporate irinotecan plus short-term infusional rather than bolus FU/LV (ie, the FOLFIRI regimen) (table 3) appear to be at least as effective as the FOLFOX regimen:

A French phase III trial of 220 patients compared FOLFOX6 versus FOLFIRI; both groups were allowed crossover at progression [41]. There were no differences in pertinent efficacy parameters (response rate, PFS, and OS, approximately 21 months in both groups).

An Italian phase III study of 336 patients randomized to FOLFOX4 versus FOLFIRI confirmed these findings [42].

Noninferiority of FOLFIRI plus bevacizumab as compared with FOLFOX plus bevacizumab for first-line therapy of mCRC was also noted in the West Japan Oncology Group study 4407G and in the United States MAVERICC trials [43,44]

Treatment-related toxicity — In practice, the choice between first-line FOLFIRI or FOLFOX is often based upon expected treatment-related toxicity. The rates of grade 3 or higher adverse effects are very similar between these two regimens, although the types of toxicity differ. FOLFIRI might be preferred over FOLFOX in a patient who received adjuvant therapy with an oxaliplatin-based regimen within the preceding 12 months.

Irinotecan – The main adverse events reported with FOLFIRI-type regimens are diarrhea (which is much less of an issue with short-term infusional rather than bolus FU regimens), fatigue, alopecia, and neutropenia. In general, toxicity is not cumulative and irinotecan can usually be continued until disease progression. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

Hepatic metabolism, hyperbilirubinemia, and UGT1A1 polymorphisms – One major issue with irinotecan is the interpatient variability in pharmacokinetics that correlates poorly with body surface area-based dosing [45-48]. Pharmacokinetic variability has been related to individual differences related to polymorphisms in the enzyme UGT that inactivates the active metabolite of irinotecan (SN-38) and in circumstances that interfere with the biliary excretion of the metabolite [49-51]:

-Even modest elevations in serum bilirubin increase the risk for severe neutropenia and diarrhea [49], and some clinicians advise preemptive dose reduction in this setting. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Irinotecan and liposomal irinotecan'.)

-Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) is a polymorphic enzyme that is involved in irinotecan metabolism; some common variants, especially homozygosity for the *28/*28 variant results in reduced enzymatic activity, and therefore slower inactivation of SN-38, the active metabolite. This leads to excess toxicity, mainly neutropenia, but also diarrhea. Approximately 50 percent of the North American population carries one or two copies of UGT1A1 *28 and therefore experience slower inactivation of SN-38 than those who do not harbor one of these alleles. Individuals who are homozygous for UGT1A1*28 have Gilbert's syndrome (unconjugated hyperbilirubinemia). (See "Gilbert syndrome", section on 'Genetics'.)

The initial irinotecan dose may be reduced for patients known to be homozygous for the UGT1A1 *28 or *6 (alleles (*28/*28, *6/*6) or a compound heterozygote for the UGT1A1 *6/*28 alleles (*6/*28) to limit the likelihood of dose-limiting neutropenia.

There is insufficient evidence to recommend preemptive testing for UGT1A1 genotypes associated with a poor metabolizer phenotype in all patients beginning irinotecan. For individuals with a known UGT1A1 allele that is associated with reduced enzyme activity (eg, those known to have Gilbert's syndrome), lower doses of irinotecan are indicated, although there is no consensus on how low the initial dose should be. Many clinicians would pursue an initial 50 percent dose reduction in such cases with further adjustments based on tolerance of that dose. Patients who experience severe irinotecan toxicity require a dose reduction regardless of the UGT1A1 genotype.

This subject is discussed in detail separately. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'UGT1A1 polymorphisms'.)

Steatosis and steatohepatitisIrinotecan has also been associated with steatosis, steatohepatitis, and hepatic vascular damage. Steatosis and steatohepatitis are observed more frequently in patients with a higher body mass index (BMI), which may explain why this complication is reported more frequently in United States studies (in which median BMIs are higher than in European populations), while vascular lesions are seen more commonly in Europeans. The potential for altered liver function related to irinotecan-associated steatohepatitis is an important consideration for patients who are candidates for resection of liver metastases. More severe liver dysfunction associated with prolonged irinotecan treatment may affect function of the liver remnant after resection. This subject is discussed in detail elsewhere. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

OxaliplatinOxaliplatin is less likely to cause diarrhea and alopecia than is irinotecan. Severe myelosuppression can be largely avoided if a non-bolus FU-containing regimen is used (eg, modified FOLFOX7, (table 3)) [52,53] or CAPOX. Oxaliplatin is safe in patients with hepatic or renal dysfunction [54,55]. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Oxaliplatin'.)

Neuropathy – 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 [56].

Given the expectation that over the continuum of care, patients will likely be exposed to both FOLFOX and FOLFIRI, patients with preexisting neuropathy and those for whom the development of a severe sensory neuropathy might jeopardize their livelihood (eg, a professional musician), or others who place a high value on delaying potentially debilitating and long-lasting neuropathy for as long as possible 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'.)

However, long-term neurotoxicity can be mitigated by intermittent oxaliplatin-free intervals, as 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 prior to the development of clinically significant neuropathy, while maintaining a fluoropyrimidine with or without bevacizumab. Options for prevention of oxaliplatin-induced peripheral neuropathy and the design and results of trials of intermittent oxaliplatin-free therapy are discussed in more detail elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Oxaliplatin' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

Hepatic sinusoidal injuryOxaliplatin is associated with dose-dependent hepatic sinusoidal injury, which can be identified radiographically by the development of splenomegaly resulting from an increase in portal venous pressure [57-61]. The potential clinical impact of hepatic sinusoidal injury is best described in patients undergoing hepatic metastasectomy for colorectal cancer liver metastases; patients who receive preoperative oxaliplatin have increased bleeding risk and postoperative morbidity. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

Concomitant administration of bevacizumab may protect against the development of oxaliplatin-induced hepatic sinusoidal injury [62,63]. As an example, in an analysis of 200 randomly selected patients with unresectable mCRC who were randomly assigned to a first-line fluoropyrimidine- and oxaliplatin-containing regimen with or without bevacizumab in the NO16966 trial, the six-month cumulative incidence rate of a 50 percent or greater increase in spleen size was 21 versus 48 percent, and the cumulative rate of thrombocytopenia (<100,000/mm3) was 19 versus 51 percent for bevacizumab versus no bevacizumab [63]. Patients with a large spleen prior to chemotherapy appeared to be at highest risk for this toxicity.

In contrast to patients with potentially resectable CRC liver metastases, the clinical impact of a reduction in thrombocytopenia on efficacy outcomes in the setting of unresectable mCRC is uncertain. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Issues related to bevacizumab'.)

Partial splenic embolization may overcome prolonged hypersplenism-related thrombocytopenia, permitting safe continuation of oxaliplatin-containing regimens [64-67].

Infusion reactions – Acute infusion reactions, characterized by rash, fever, and ocular and respiratory symptoms of varying severity, have been reported in up to 25 percent of patients treated with oxaliplatin. Patients with mild reactions can continue to be treated with oxaliplatin by premedication with diphenhydramine and steroids, and by lengthening the infusion duration and/or decreasing the dose. (See "Infusion reactions to systemic chemotherapy", section on 'Oxaliplatin'.)

Oral fluoropyrimidines

Capecitabine doublets — Capecitabine plus oxaliplatin (CAPOX, XELOX) 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. For most patients, our preference remains delivering irinotecan with infusional fluorouracil (FU). This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO [10,11].

Capecitabine plus oxaliplatin – CAPOX (XELOX) is a reasonable alternative for first-line therapy of mCRC in patients for whom ambulatory infusional FU therapy using a pump is not feasible or desired. The available data suggest that CAPOX has approximately similar antitumor efficacy, but there is a possibility of more toxicity (especially thrombocytopenia and hand-foot syndrome, possibly diarrhea) as compared with infusional FU/oxaliplatin combinations.

For American patients, we consider the standard regimen to be capecitabine 850 mg/m2 twice daily for 14 of every 21 days (as was used in the TREE-2 trial) plus oxaliplatin 130 mg/m2 on day 1 over two hours (table 6) [68,69]. Oncologists in Europe and Asia more commonly start with capecitabine 1000 mg/m2 twice daily, as was used in TREE-1 [68]. (See "Treatment protocols for small and large bowel cancer".)

A lower oxaliplatin dose (eg, 85 mg/m2 over two hours on day 1) with capecitabine (850 or 1000 mg/m2 twice daily on days 2 to 15) could be considered for older adult patients [70]. More intensive regimens (eg, week on, week off therapy with both capecitabine and oxaliplatin [71]) may be more active, but direct comparisons with standard doses are not yet available.

Multiple randomized trials and a systematic review comparing CAPOX versus other fluoropyrimidine/oxaliplatin combinations, such as FOLFOX, have concluded comparable efficacy, but a different toxicity profile [68,69,72-75]. As examples:

The phase II TREE-1 trial randomly assigned 150 patients to modified FOLFOX6 (table 5), CAPOX (capecitabine 1000 mg twice daily for 14 of every 21 days plus oxaliplatin 130 mg/m2 on day one), or bFOL (bolus FU 500 mg/m2, and LV 20 mg/m2 weekly for three of every four weeks plus oxaliplatin 85 mg/m2 on days 1 and 15) [68]. The differences between FOLFOX and CAPOX in response rates, time to progression and median survival were not significant (table 7). Patients in the CAPOX group had the highest rates of hand-foot syndrome, grade 3 or 4 nausea/vomiting and neuropathy (38 and 21 percent), and more often discontinued therapy because of toxicity. The FOLFOX6 group had the highest rate of grade 3 or 4 neutropenia (53 versus 15 percent with CAPOX). Rates of grade 3 or 4 diarrhea were the same (31 percent) in both groups.

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 CAPOX versus FOLFOX4 (table 3) for first-line therapy [72]. 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 CAPOX versus FOLFOX4, there was no relevant difference in OS (19.8 versus 19.5 months) [76].

Practicing oncologists should, however, consider the following issues before routinely adopting CAPOX as a preferred alternative to FOLFOX:

The appropriate dose of capecitabine is not well defined, at least for American patients. There appear to be large regional differences in the tolerance to capecitabine and other fluoropyrimidines [77], which might in part be based on population-specific pharmacogenomic variability (eg, Asian patients seem to tolerate fluoropyrimidines better than non-Asian patients [77]). However, lifestyle or dietary differences (eg, folate intake) could also contribute.

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 7) [68]. 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 6).

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.

Capecitabine plus irinotecan – While CAPOX is 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. 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 CAPOX. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

Six early trials (most conducted outside of North America) compared the safety and efficacy of the XELIRI and FOLFIRI regimens with or without bevacizumab [78-83]; the irinotecan doses in the XELIRI arms ranged from 200 to 250 mg/m2 on day 1 of each 21-day cycle, and all trials used capecitabine 1000 mg/m2 twice daily on days 1 to 14; the authors have generally concluded that both regimens had similar efficacy and similar adverse event profiles [84]. However, higher rates of grade 3 or 4 diarrhea have been reported with XELIRI as compared with FOLFIRI in several of the trials [78,79,83].

Regional differences in capecitabine tolerability [77] make it difficult to translate toxicity and efficacy findings generated in trials conducted outside of the United States [30] into American patients. This problem was particularly apparent in the phase III BICC-C trial, which compared three different approaches to combining irinotecan with infusional FU (FOLFIRI), bolus FU (modified IFL), or capecitabine (XELIRI) using the standard European doses of irinotecan (250 mg/m2 day 1) and capecitabine (1000 mg/m2 twice daily, on days 1 to 14 of every three-week cycle) [78]. No prespecified dose reduction for irinotecan and capecitabine for older adult patients (as suggested by other authors [85]) was implemented. FOLFIRI emerged as the undisputed winner of the head-to-head comparison of all three regimens in terms of efficacy and tolerability. XELIRI was associated with a higher rate of grade 3/4 adverse events, in particular, diarrhea (48 versus 14 percent), nausea (18 versus 9 percent), vomiting (16 versus 9 percent), and dehydration (19 versus 6 percent). Higher rates of grade 3 and 4 diarrhea with XELIRI as compared with FOLFIRI have been seen in other trials as well [79,83].

A modified dose XELIRI regimen may be more tolerable, at least in Asian patients [86]. Despite this trial and the conclusions of the meta-analysis [84], our preference remains delivering irinotecan with infusional FU, particularly for older patients, because of potential toxicity concerns.

Oxaliplatin plus S-1 — Where available, S-1 plus oxaliplatin (SOX) represents an acceptable first-line oxaliplatin-containing chemotherapy regimen, at least for Asian patients.

S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of dihydropyrimidine dehydrogenase [DPD]), 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 SOX compared with capecitabine plus oxaliplatin, or FOLFOX/bevacizumab:

SOX was directly compared with CAPOX in a multicenter randomized Korean phase III trial of 340 patients with previously untreated mCRC [87]. The design was characterized as a noninferiority trial with an upper boundary of the PFS HR of 1.43 (meaning that a 43 percent detriment in PFS would have been considered acceptable to define noninferiority). SOX was statistically noninferior to standard CAPOX in terms of PFS (HR 0.79, 95% CI 0.6-1.04) and demonstrated a significantly higher response rate (48 versus 36 percent), but more grade 3 or 4 neutropenia, thrombocytopenia, and diarrhea.

SOX in combination with bevacizumab was compared with modified FOLFOX6 plus bevacizumab in the randomized SOFT study of 512 Japanese patients with previously untreated mCRC. SOX plus bevacizumab was noninferior to FOLFOX/bevacizumab (median PFS 11.5 versus 11.7 months), and objective response rates were similar (61 versus 62 percent) [88].

UFT-containing doublets — Where available, combinations of tegafur plus uracil (UFT) with oxaliplatin (TEGAFOX, UFOX) or irinotecan (TEGAFIRI) are acceptable first-line options for fluoropyrimidine plus oxaliplatin-containing and irinotecan-containing chemotherapy, respectively.

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 [89]. Combinations of UFT with irinotecan (TEGAFIRI) and oxaliplatin (TEGAFOX, UFOX) appear to be effective and well tolerated, with similar efficacy and tolerability to the corresponding FU- and capecitabine-based regimens [90-94]. UFT is not available in the United States.

IROX — The primary use of the irinotecan plus oxaliplatin (IROX) regimen is in patients who are unable to tolerate FU, typically because of deficiency in the fluoropyrimidine-metabolizing enzyme DPD. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Management of DPD-deficient patients'.)

The available data on IROX as a first-line regimen are as follows:

IROX regimen was inferior to first-line oxaliplatin plus infusional FU and LV (FOLFOX) in United States Intergroup trial 9741, and it was more toxic in older adult individuals [95].

Similarly, a report of the FIRE trial (IROX versus irinotecan plus infusional FU and LV [FOLFIRI] as first-line treatment of colorectal cancer) suggested that the regimens had similar efficacy (objective response rate 41 percent with both regimens; median survival 22 and 19 months for FOLFIRI and IROX, respectively) [96].

Role of biologics — The addition of a biologic agent to the chemotherapy backbone may achieve additional efficacy in some patients; however, potential benefits need to be weighed against potential adverse effects. There are two "biologics" options, bevacizumab and biosimilars (antiangiogenic monoclonal antibodies) and cetuximab/panitumumab, which are both anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, and only effective in RAS/BRAF wild-type tumors. If this approach is chosen, selection of the biologic agent is based on several factors, including RAS/BRAF mutation status, primary tumor site, patient preference, and eligibility for bevacizumab. This approach is discussed in further detail below. (See 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' below.)

Efficacy and toxicity of bevacizumab and biosimilars — 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. Biosimilars for bevacizumab have also been approved by the US Food and Drug Administration (FDA) [97,98].

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 OS (20 versus 16 months) [99]. 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 OS and PFS benefits are relatively modest, especially for relatively more effective chemotherapy backbones such as FOLFOX and FOLFIRI. Nevertheless, the available data support a benefit for adding bevacizumab to cytotoxic backbone regimens that contain either oxaliplatin or irinotecan, both, or a fluoropyrimidine alone.

As an example, in a pooled analysis of trials comparing chemotherapy with and without bevacizumab in the first-line setting, the addition of bevacizumab was associated with a significant 19 percent reduction in the risk of death (HR for death 0.81, 95% CI 0.70-0.93), but this translated into a median OS advantage of only two months (19.8 versus 17.6 months) [100]. PFS was also significantly improved (HR 0.58, 95% CI 0.46-0.73) but the advantage was also limited to approximately two months (median PFS 9.1 versus 6.9 months). These modest advances come at a cost of treatment-related side effects, including bleeding, hypertension, bowel perforation, and thromboembolic events. However, although there are these potentially serious outcomes, they are not common. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

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.

With oxaliplatin regimens — 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 [39] 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. (See 'FOLFOX versus FOLFIRI' above.)

At least four trials support a modest benefit for adding bevacizumab to FOLFOX [68,101-103]. As examples:

In the phase II randomized TREE-2 trial, 223 previously untreated patients were randomly assigned to bevacizumab (5 mg/kg every two weeks) and one of the three different oxaliplatin- and FU-containing regimens used in the TREE-1 trial [68]. Bevacizumab substantially improved the response rates of all of the regimens (table 7). Median OS was 23.7 months for the combined groups receiving bevacizumab (versus 18.2 months for the combined non-bevacizumab-treated groups). However, bevacizumab also increased rates of grade 3 or 4 hypertension (table 7), bowel perforation (2 percent overall), impaired wound healing (n = 3) and bleeding events (45 versus 22 percent in the groups treated with FOLFOX with and without bevacizumab).

Modest benefit for the addition of bevacizumab was also suggested in the NO 16966 trial of FOLFOX or CAPOX with and without bevacizumab [102]. There was a significant PFS for the addition of bevacizumab; however, the magnitude of benefit was smaller than expected, and neither median OS nor response rates were significantly higher in patients who received bevacizumab (table 8). Bevacizumab-treated patients discontinued treatment more often because of toxicity than disease progression; the authors postulated that failure to continue therapy until disease progression offset the benefit of adding bevacizumab.

Irinotecan regimens — In an early trial of 813 patients who were randomly assigned to irinotecan/FU/LV (IFL) with or without bevacizumab, bevacizumab improved the objective response rate (45 versus 35 percent), and significantly improved time to tumor progression (11 versus 6 months) and median survival (20 versus 16 months) [99]. As a result of these data, bevacizumab received broad approval in the United States in combination with FU for first-line treatment of mCRC.

The bolus IFL regimen has fallen out of favor due to the more favorable gastrointestinal toxicity profile of regimens that contain short-term infusional FU/LV (eg, FOLFIRI) (table 3). The available data on bevacizumab plus FOLFIRI are limited and conflicting:

In the complex BICC-C trial, patients with previously untreated mCRC were assigned to FOLFIRI, modified IFL, or capecitabine/irinotecan, all arms with or without celecoxib; a later amendment added bevacizumab to patients on the FOLFIRI and IFL arms [78]. The median PFS was 11.2 months in the small group of 61 patients receiving bevacizumab/FOLFIRI (8.3 months for bevacizumab/IFL), and the objective response rate was 58 percent (53 percent with bevacizumab/IFL). In a later report, at a median follow-up of 34 months, median survival in the group receiving FOLFIRI/bevacizumab was 28 months while it was 19.2 months with bevacizumab/IFL [104].

On the other hand, a lack of survival benefit for the addition of bevacizumab to first-line FOLFIRI was shown in two European trials [105,106].

FOLFOXIRI — The available data using regimens that combine the triplet chemotherapy backbone FOLFOXIRI plus bevacizumab are discussed above. There are no trials of FOLFOXIRI with or without bevacizumab. (See 'Three- versus two-drug combinations' above.)

Is first-line bevacizumab justified in all patients? — 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 [99,107] than to more active regimens such as FOLFOX or FOLFIRI. As a result, the effectiveness of adding bevacizumab to standard first-line treatment with either FOLFOX or FOLFIRI has been challenged [106].

Bevacizumab is expensive (although less expensive biosimilars for bevacizumab are available and approved [97,98]), its benefits are modest at best [101], 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 thromboembolic events and reversible posterior multifocal leukoencephalopathy. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Reversible posterior leukoencephalopathy syndrome".)

The benefit of a bevacizumab-containing regimen is especially debated for patients undergoing initial (neoadjuvant) 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 EGFR inhibitor is contraindicated) who are undergoing conversion therapy for initially unresectable disease [103]. This subject is discussed in detail elsewhere.

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 EGFR inhibitor. Data suggest that first-line bevacizumab containing regimens may provide superior outcomes for patients with RAS/BRAF wild-type mCRC with a primary tumor site in the right colon. (See 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' below.)

Adverse effects — The benefits of bevacizumab are counterbalanced by its side effect profile, which includes proteinuria and potentially serious nephrotic syndrome and hypertension, and potentially fatal bleeding, gastrointestinal tract perforation, and arterial and possibly venous thromboembolic events [108]. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Contraindications — A minority of patients have upfront contraindications to bevacizumab, 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) [109]. The use of bevacizumab in patients with brain metastases is controversial:

Arterial thromboembolic diseaseBevacizumab 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 [110]. As a result, most clinicians consider that prior ATE within the last 6 to 12 months represents a relative contraindication to bevacizumab, particularly in older adult patients. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Bevacizumab and biosimilars'.)

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 "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Arterial thromboembolic events'.)

Active wound Bevacizumab 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 "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Bevacizumab'.)

HemorrhageBevacizumab is contraindicated if there is a recent history of significant hemoptysis; however, an increased risk of pulmonary hemorrhage has not been described in patients with pulmonary metastases from non-lung primaries. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Special categories of bleeding'.)

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 "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intracranial bleeding'.)

Bevacizumab should be discontinued permanently in patients who develop severe adverse events during treatment, including gastrointestinal perforation (fistula formation, intra-abdominal abscess), an ATE, 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 "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

RAS/BRAF wild-type tumors — Therapy with an EGFR inhibitor, either alone or in conjunction with cytotoxic chemotherapy, is an appropriate option for individuals with RAS/BRAF wild-type tumors with a left-sided primary. If an EGFR inhibitor is chosen, 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Are cetuximab and panitumumab interchangeable?'.)

However, the incidence of infusion reactions is lower with panitumumab, which 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 'Cetuximab' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Panitumumab'.)

If cetuximab or panitumumab are chosen for first-line therapy, the chemotherapy backbone should contain infusional FU (ie, FOLFIRI, FOLFOX). Triplet combinations of an EGFR inhibitor plus FOLFOXIRI may also be appropriate in patients who can tolerate more intensive therapy.

However:

The benefit of an oxaliplatin-containing regimen plus an EGFR inhibitor prior to resection in patients with potentially resectable colorectal liver metastases is still debated, and many clinicians avoid this combination in such patients. 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 'Benefit of cetuximab and panitumumab' below and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Choice of regimen'.)

We also avoid combining either cetuximab or panitumumab with a bevacizumab-containing regimen, a policy that is also supported by the FDA labeling and consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) [10,11]. (See 'Dual antibody therapy' below.)

Benefit of cetuximab and panitumumab — Cetuximab, a mouse/human chimeric monoclonal antibody (MoAb), binds to the EGFR of both tumor and normal cells, competitively inhibiting ligand binding, and inducing receptor dimerization and internalization. It is unclear whether these actions represent the mechanism of antitumor action. Panitumumab is a fully human MoAb specific for the extracellular domain of EGFR. Because it is fully human, the incidence of infusion reactions is lower as compared with cetuximab.

Plus irinotecan

First-line cetuximab was explored in the CRYSTAL trial, in which 1198 patients with previously untreated mCRC were randomly assigned to FOLFIRI with or without cetuximab [111]. Median PFS was modestly but significantly better with cetuximab (8.9 versus 8 months), as was the overall response rate (47 versus 39 percent), but this did not translate into a significant OS benefit. However, in a later report, among patients with wild-type KRAS, response rates were significantly higher in those who received cetuximab in conjunction with chemotherapy (57 versus 40 percent), as was median PFS and OS (median 23.5 versus 20 months) [112]. Adverse effects that were more frequent with cetuximab were grade 3 or 4 diarrhea (16 versus 11 percent), skin toxicity (19.7 versus 0.2 percent), and infusion reactions (2.5 versus 0 percent).

While there are no randomized trials in the first-line setting, the safety and efficacy of adding panitumumab to first line FOLFIRI has been shown in two single arm phase II trials [113,114]. Panitumumab is indicated for first-line therapy in combination with oxaliplatin plus short-term infusional FU and LV (FOLFOX). However, panitumumab can be safely and acceptably combined with either an irinotecan- or oxaliplatin-based regimen in patients with RAS and BRAF wild-type tumors.

Plus oxaliplatin

In contrast to irinotecan, the benefit of adding cetuximab or panitumumab to a first-line oxaliplatin-based regimen is less certain. The data are mixed, with two trials suggesting benefit for combined therapy [115,116], but four others suggesting a lack of benefit or even detrimental outcomes:

-MRC COIN trial – United Kingdom MRC COIN trial, which compared first-line FOLFOX/CAPOX with or without cetuximab in 1630 patients with mCRC, demonstrated a modest improvement in response rate from the addition of cetuximab in the 729 patients with KRAS wild-type tumors (64 versus 57 percent), but there was no significant improvement in PFS (8.6 months in both groups) [117].

-NORDIC VII – Likewise, the NORDIC VII trial indicated a lack of benefit from the addition of cetuximab to a bolus FU/LV/oxaliplatin (FLOX) regimen in 571 patients with mCRC, even when the 348 patients with KRAS wild-type tumors were analyzed separately [118]. These and other data support the view that the addition of EGFR inhibitor to oxaliplatin-based regimens in which noninfusional fluoropyrimidines were used has not resulted in benefit [117].

-EPOC – The randomized New EPOC trial of FOLFOX with or without cetuximab for patients with potentially resectable isolated colorectal cancer liver metastases suggested an inferior outcome with the addition of cetuximab [119,120].

-A PFS benefit for adding panitumumab to FOLFOX was shown in the phase III PRIME trial (median PFS 9.6 versus 8 months) [121]; a later exploratory analysis also suggested a modest survival benefit at a median follow-up of 80 weeks (HR for death 0.83, 95% CI 0.70-0.98) [122]. However, survival was impaired in patients with exon 2 KRAS-mutant mCRC who received combined therapy. Furthermore, in a later analysis, 108 patients (17 percent) without KRAS mutations in exon 2 had other RAS mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4 [123]. These additional mutations predicted a lack of response to panitumumab, and in fact, their presence was associated with inferior PFS and OS in patients receiving panitumumab plus FOLFOX compared with FOLFOX alone.

Patients with potentially resectable liver metastases – In particular, the advisability of combining cetuximab (or panitumumab) with an oxaliplatin-based regimen in patients with potentially resectable colorectal cancer liver metastases continues to be debated, with disparate results from published trials:

-The randomized phase II CELIM trial of cetuximab plus either FOLFIRI or FOLFOX in patients with initially unresectable colorectal cancer liver metastases showed that the chemotherapy backbone did not matter [124].

-On the other hand, as noted above, the randomized New EPOC trial of FOLFOX with or without cetuximab for patients with potentially resectable isolated colorectal cancer liver metastases suggested an inferior outcome with the addition of cetuximab [119,120].

This subject is discussed in more detail elsewhere. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Regimen choice'.)

Plus oxaliplatin and irinotecan – Whether there is benefit to adding cetuximab or panitumumab to triplet combination regimens such as FOLFOXIRI (table 2) is unclear, as the data are mixed [24,125-127]:

High objective response rates (>70 percent), and high rates of secondary complete (R0) metastasectomy are reported with combinations of cetuximab plus FOLFOXIRI, but there are no randomized trials comparing this strategy versus FOLFOXIRI alone or cetuximab plus a chemotherapy backbone doublet such as FOLFOX [125,126].

The randomized phase II VOLFI trial reported a very high objective response rate (87 versus 61 percent) and a higher secondary complete (R0) metastasectomy rate (33 versus 12 percent) for initial FOLFOXIRI plus panitumumab, albeit with similar PFS and higher rates of grade ≥3 toxicity (81 versus 67 percent) when compared with FOLFOXIRI alone [24].

However, a benefit for panitumumab plus the triplet regimen was not shown relative to FOLFOX plus panitumumab in the later phase III TRIPLETE trial conducted by the same investigators [127]. Intensification of the chemotherapy backbone did not provide a better objective response rate (73 versus 76 percent), or secondary complete (R0) metastasectomy resection rate (25 versus 29 percent), or median PFS (12.7 versus 12.3 months) but it did substantially increase grade ≥3 toxicity, especially neutropenia (32 versus 20 percent) and diarrhea (23 versus 7 percent). There were three treatment-related deaths in the intensified chemotherapy arm versus none in the FOLFOX group.

A triplet regimen such as FOLFOXIRI in combination with an EGFR agent could be considered an alternative to initial doublet therapy plus an EGFR inhibitor 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), as long as they are able to tolerate intensive therapy. Given the very high response rate for FOLFOXIRI plus panitumumab (87 percent) in the phase II randomized VOLFI trial [24], we consider this to be a reasonable regimen for patients who are able to tolerate it and who require a strong anatomic response to be considered for hepatic resection. (See 'Three- versus two-drug combinations' above.)

However, as noted above, the use of combination regimens with oxaliplatin and an EGFR inhibitor in patients with potentially resectable colorectal cancer liver metastases continues to be debated, and many clinicians would avoid this combination in this setting.

Adverse effects — The most common adverse effects associated with cetuximab and panitumumab are weakness, malaise, an acneiform rash, nausea, electrolyte disorders, and, with cetuximab, infusion reactions.

Infusion reactions – Infusion reactions occur in up to 25 percent of patients treated with cetuximab, and rates are highest in some areas of the middle southeastern United States. The majority of these reactions are the result of pre-existing IgE antibodies to galactose-alpha-1,3-galactose which cross-react with cetuximab. Most reactions are severe, and 90 percent occur after the first infusion, most within three hours. Premedication with an H1 receptor antagonist and a glucocorticoid is recommended, and drug infusion should not exceed 5 mL/minute.

For patients who develop a severe reaction to cetuximab, switching to panitumumab is a better alternative to proceeding with cetuximab desensitization given what appears to be very similar efficacy between agents. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

The risk of infusion reactions with panitumumab is lower than with cetuximab (4 percent overall, with 1 percent severe). Given the low rates of infusion reactions, routine premedication is not recommended prior to panitumumab infusion. The lower rate of infusion reactions provides a rationale for choosing panitumumab over cetuximab, particularly in high-risk geographic regions such as the middle southeastern United States. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Panitumumab'.)

Cutaneous and ocular toxicity – As with all agents that target the EGFR, skin reactions are frequent and may be severe in patients treated with panitumumab or cetuximab (table 9).

The most common side effect is an acneiform type rash (picture 1), which occurs in up to two-thirds of treated patients, and may impact quality of life. Grading of the severity of the acneiform eruption that is most typical of this class of agents, management of cutaneous toxicity, and the use of prophylactic systemic antibiotics are addressed in detail elsewhere. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

Rash severity appears to correlate with better outcomes [128-131]. A report from the EVEREST trial suggests that cetuximab dose escalation (by 50 mg/m2 every two weeks, up to 500 mg/m2 weekly) is safe and increases response rates in patients who have no or a mild skin reaction within three weeks of starting therapy [132]. The response rate among patients with ≤grade 1 skin toxicity (table 10) who were randomized to dose escalation was 30 versus 16 percent in a concurrently randomized group continuing standard dose therapy, and there was also an improvement in disease control rate (70 versus 58 percent) but no indication of improved OS.

Pruritus is particularly common in patients treated with panitumumab. In a systematic review, the incidence of any grade pruritus was 55 percent with panitumumab (2.6 percent high-grade) and 18 percent with cetuximab (2.1 percent severe) [133]. Management includes patient education and topical agents (emollients, corticosteroids, anesthetics, capsaicin, menthol); for highly symptomatic patients, oral antihistamines, anticonvulsants, antidepressants, and possibly aprepitant may be helpful. An overview of management of pruritus is presented elsewhere. (See "Pruritus: Therapies for localized pruritus".)

Multiple ocular toxicities are reported with both cetuximab and panitumumab. (See "Ocular side effects of systemically administered chemotherapy", section on 'Epidermal growth factor receptor (EGFR) inhibitor'.)

Electrolyte disordersCetuximab and panitumumab both cause a magnesium-wasting syndrome, which, in one report, affected 22 percent of 154 patients treated with cetuximab [134,135]. Hypomagnesemia may be more prominent in patients receiving concomitant treatment with oxaliplatin [136]. In addition, hypokalemia is also reported (incidence 8 percent in a meta-analysis of patients treated with cetuximab [137]). Hypomagnesemia may lead to secondary hypocalcemia. Serum levels of magnesium, potassium, and calcium should be monitored periodically during and for at least eight weeks following therapy. (See "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'Anti-EGFR monoclonal antibodies' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)

EGFR inhibitors versus bevacizumab and the influence of tumor sidedness — For patients with previously untreated mCRC, the site of the primary tumor influences the choice of biologic agent added to chemotherapy. Analyses of randomized trials suggest that right-sided tumors, including those that are RAS and BRAF wild-type, derive relatively more benefit from treatment with bevacizumab whereas left-sided tumors that are RAS and BRAF-wildtype derive relatively more benefit from treatment with EGFR inhibitors (eg, cetuximab, panitumumab) [138-145]. Our approach to selecting the biologic agent to combine with chemotherapy is generally consistent with clinical guidelines from the NCCN, ESMO, and ASCO [10-12].

RAS/BRAF wild-type right-sided tumors – For patients with RAS and BRAF wild-type mCRC and a right-sided primary tumor (ie, proximal to the splenic flexure [146]), we suggest adding bevacizumab rather than an EGFR inhibitor to chemotherapy as initial treatment. For those with a contraindication to bevacizumab, we use chemotherapy alone rather than adding an EGFR inhibitor to chemotherapy, as the latter approach does not confer an OS benefit. Contraindications to bevacizumab therapy are discussed separately. (See 'Contraindications' above.)

RAS/BRAF wild-type left-sided tumors – For patients with RAS or BRAF wild-type mCRC and a left-sided primary tumor (ie, located at or distal to the splenic flexure [146]), we suggest adding an EGFR inhibitor (cetuximab or panitumumab) rather than bevacizumab to chemotherapy as initial treatment. For those patients who wish to avoid the toxicities associated with EGFR inhibitors (eg, diarrhea and rash) for quality of life, the addition of bevacizumab to chemotherapy is an alternative option. However, most studies suggest inferior survival outcomes for bevacizumab compared with EGFR inhibitors in this population.

Cetuximab versus bevacizumab – A pooled analysis of twelve randomized trials consisting of 9277 patients with previously untreated mCRC included a subgroup of 555 patients with KRAS wild-type tumors. Among those with right-sided KRAS wild-type tumors, an OS benefit was demonstrated for treatment regimens that included bevacizumab versus regimens that included cetuximab [144].  

For the 555 patients with KRAS wild-type tumors, compared with cetuximab plus chemotherapy, bevacizumab plus chemotherapy improved OS among the 300 patients with right-sided tumors (median 26 versus 12.5 months, HR 1.89, 95% CI 1.33-2.67) but not the 255 patients with left-sided tumors (median 24.6 versus 25.5 months, HR 1.10, 95% CI 0.77-1.56).

Patients with a right-sided tumor who are ineligible for bevacizumab may be offered chemotherapy alone, as the addition of cetuximab did not confer an OS benefit in this study. Among patients with a KRAS wild-type right-sided tumor, the addition of cetuximab to chemotherapy did not improve OS (median 12 versus 14.8 months, HR 1.26, 95% CI 0.98-1.63) or PFS (median 7.2 months each, HR 1.02, 95% CI 0.77-1.34).

For RAS wild-type left-sided tumors, the benefits of initial therapy with cetuximab-based regimens were seen in a meta-analysis of three randomized trials directly comparing chemotherapy plus either cetuximab or bevacizumab [142]. For patients with RAS wild-type left-sided colorectal tumors, treatment that included an EGFR inhibitor conferred a greater overall survival benefit than treatment than included a VEGF inhibitor (HR 0.71, 95% CI 0.58-0.85). In contrast, for patients with right-sided tumors, there was a non-statistically significant trend toward longer survival with bevacizumab-based therapy compared with other standard therapies (HR 1.3, 95% CI 0.979-1.74).

Panitumumab versus bevacizumab – In a phase III trial (PARADIGM), initial therapy with the EGFR inhibitor panitumumab plus chemotherapy conferred an OS benefit over bevacizumab plus chemotherapy among all patients with mCRC as well as those with left-sided tumors [147]. For patients with right-sided tumors, panitumumab plus chemotherapy demonstrated similar OS but lower PFS compared with bevacizumab plus chemotherapy.

In this study, 802 patients with chemotherapy-naïve RAS wild-type mCRC were randomly assigned to mFOLFOX6 plus either bevacizumab or panitumumab [147,148]. The study included 604 patients with left-sided tumors, 187 patients with right-sided tumors, and 11 patients with tumors on both sides. At median follow-up of 61 months, compared with bevacizumab plus chemotherapy, panitumumab plus chemotherapy resulted in the following:

Left-sided tumors – Improved OS (median OS 38 versus 34 months, HR 0.82, 96% CI 0.68-0.99), similar PFS (median PFS 13 versus 11 months, HR 0.86, 95% CI 0.70-1.10), and higher objective response rates (80 versus 69 percent)

Entire study population – Improved OS (median OS 36 versus 31 months, HR 0.84, 95% CI 0.72-0.98) and similar PFS (median PFS 12 vs 11 months, HR 1.05, 95% CI 0.90-1.24). Objective response rates for chemotherapy plus either panitumumab or bevacizumab were 75 and 67 percent, respectively.

Right-sided tumors – Similar OS (median OS 20 versus 23 months, HR 1.09, 95% CI 0.79-1.51) but lower PFS (median PFS 7 versus 9 months, HR 1.43, 95% CI, 1.03-1.97). Objective response rates for chemotherapy plus either panitumumab or bevacizumab were 55 and 63 percent, respectively.

Toxicity profiles were consistent with those known for each agent. Compared with bevacizumab, panitumumab had higher grade ≥3 toxicity rates of acneiform rash (17 versus 0 percent) stomatitis (7 versus 2 percent), diarrhea (6 versus 3 percent) and hypomagnesemia (8 versus 0 percent). In contrast, compared with panitumumab, bevacizumab had higher rates of grade ≥3 hypertension (6 versus <1 percent) and epistaxis of any grade (20 versus 3 percent). The rate of treatment discontinuation due to adverse events for the panitumumab- and bevacizumab-treated groups were 24 and 18 percent, respectively.

RAS or BRAF mutant tumors — For patients with RAS mutated mCRC and any primary tumor site location who are treated with a biologic agent, we recommend the addition of bevacizumab rather than an EGFR inhibitor to chemotherapy. Patients who are ineligible for bevacizumab may be offered chemotherapy alone. EGFR inhibitors are not used to treat RAS mutated mCRC since such tumors are resistant to these agents. Further details are discussed separately. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS'.)

A pooled analysis of twelve randomized trials consisting of 9277 patients with previously untreated mCRC included a subgroup of patients with 522 KRAS mutant tumors [144]. In this subgroup, compared with bevacizumab plus chemotherapy, cetuximab plus chemotherapy demonstrated inferior OS for both patients with left-sided (median OS 13.1 versus 24.8 months, HR 2.09, 95% CI 1.40-3.12) and right-sided (median OS 15.9 versus 26.1 months, HR 1.84, 95% CI 1.37-2.47) tumors.

Although such data are limited for BRAF mutant tumors [149,150], we extrapolate a similar approach using studies from KRAS mutant tumors, given the shared biologic signaling pathway. Furthermore, data suggest no benefit for EGFR inhibitors in BRAF mutant cancers. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'BRAF mutations'.)

Dual antibody therapy — Dual antibody therapy (simultaneously targeting both VEGF and EGFR) cannot be recommended for first-line therapy of mCRC.

The results of two trials suggest worse outcomes with dual antibody therapy when used in the first-line setting:

The PACCE trial tested the addition of panitumumab to standard first-line oxaliplatin-based (n = 823) or irinotecan-based therapy (n = 230) plus bevacizumab [151]. Enrollment was halted after a preplanned interim analysis detected significantly inferior PFS in the panitumumab/bevacizumab group; median OS was also lower (19.4 versus 24.5 months).

The CAIRO2 trial studied first-line bevacizumab plus CAPOX with or without cetuximab [152]. PFS was significantly worse with dual antibody therapy. Even patients with wild-type KRAS tumors did not benefit from the addition of cetuximab.

Is there benefit from immunotherapy? — Although a small subset of mCRC have deficient mismatch repair and might be eligible for upfront immunotherapy as an alternative to chemotherapy, the majority are proficient in mismatch repair (pMMR) and a benefit for immune checkpoint inhibitor immunotherapy without high levels of tumor mutational burden is not yet established. (See 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' below and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'MMR-proficient tumors with high tumor mutational burden'.)

Given that pMMR tumors are typically characterized by an immune-excluded microenvironment, with absent or inactive CD8 T-cell lymphocytes, and diminished expression of immune checkpoint proteins on the tumor cells [153,154], trials are ongoing to attempt to increase cellular immunogenicity by combining checkpoint inhibitors with antitumoral agents with immunomodulatory properties [155-157]. However, whether there is benefit for combined therapy in this setting remains an open research question.

Duration of initial chemotherapy

Oxaliplatin-based regimens — Oxaliplatin-related 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 [158]. This approach is consistent with consensus-based guidelines from ESMO [10]. For patients initially treated with an agent targeting EGFR, cetuximab alone is an acceptable alternative for maintenance treatment in patients initially treated with a cetuximab-containing regimen, but for patients initially treated with a panitumumab-containing regimen, panitumumab plus LV-modulated FU is preferred over panitumumab alone.

In both of these settings, 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 therapy for metastatic colorectal cancer: General principles", section on 'Patients receiving oxaliplatin'.)

Irinotecan-based regimens — Though cumulative neurotoxicity is not an issue with irinotecan-based regimens, most patients experience some cumulative toxicity albeit that may not require dose modification. The available data suggest similar overall outcomes (PFS and OS) 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. We consider it reasonable to extrapolate data on maintenance therapy and chemotherapy-free intervals to patients treated with first-line FOLFIRI. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

FOLFOXIRI — Patients who start on triplet therapy should proceed with this as induction for a three to four month period as per the TRIBE clinical trials [17,20], and then transition to a non-oxaliplatin-containing maintenance chemotherapy regimen (FU plus leucovorin with or without bevacizumab). (See 'Three- versus two-drug combinations' above.)

In practice, we try to treat to maximal response (as long as triplet therapy is tolerated) before decreasing to a maintenance regimen.

Not candidates for intensive therapy — For patients without MMR deficiency who are not candidates for an intensive first-line standard-dose oxaliplatin- or irinotecan-based regimen because of age, poor performance status or associated comorbidity, but who are fit enough to tolerate some form of systemic therapy, options include dose-reduced FOLFOX, a fluoropyrimidine alone or, for patients with no contraindication, a fluoropyrimidine plus bevacizumab. Nonchemotherapy options can also be considered for patients with RAS/BRAF wild-type cancers (cetuximab or panitumumab) and HER2-targeted therapy can be considered for the small proportion of patients whose colorectal cancers express high levels of HER2 expression, although there are no data specifically in the first-line setting. Consensus-based guidelines from the NCCN include HER2-targeted therapy as a first line option for patients with metastatic colorectal cancer who are unable to tolerate intensive therapy [11]. Individuals with a poor PS (eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 11), Karnofsky PS <60 (table 12)) usually tolerate chemotherapy poorly and have a poor short-term prognosis. For most patients, supportive care should be emphasized. However, some selected patients with mCRC who have a PS of ≥2 can be considered for trial of chemotherapy, particularly if their PS decline is cancer related. This subject is discussed elsewhere. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Less fit patients with an ECOG PS 0 or 1' and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Frail, significant functional impairment, poor performance status'.)

PATIENTS WITH DEFICIENT DNA MISMATCH REPAIR/MICROSATELLITE UNSTABLE TUMORS — For patients with nonoperable mCRC that is deficient in deficient mismatch repair (dMMR), we suggest first-line pembrolizumab monotherapy rather than cytotoxic chemotherapy. Another option for immune checkpoint inhibitor therapy is nivolumab with or without ipilimumab. If a first-line immunotherapy approach is chosen, patients should be followed closely for the first 10 weeks to assess response and rule out early progression. For patients with high tumor burden, it is also reasonable to consider upfront chemotherapy, either alone or with pembrolizumab, to mitigate this risk of primary progressive disease. Whether the combination of cytotoxic chemotherapy plus immunotherapy is superior to immunotherapy alone is unknown and currently the focus of phase III trials.

Approximately 3.5 to 6.5 percent of stage IV CRCs have deficiency in dMMR enzymes, the biologic footprint of which is high microsatellite instability (MSI-H). Cancers with dMMR/MSI-H appear to be uniquely susceptible to inhibition of immune checkpoints, tolerance mechanisms that suppress the body's immune response to self-antigens in order to minimize autoimmune disease, which may also serve to blunt the immune response to tumor antigens in vivo. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Biology of mismatch repair and tumor mutational burden'.)

Most of the data on benefits of immune checkpoint inhibitor immunotherapy are in previously treated patients, after failure of conventional cytotoxic chemotherapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors'.)

However, results from the KEYNOTE-177 trial suggest that first-line pembrolizumab, a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) pathway, offers better outcomes than first-line chemotherapy.

Pembrolizumab monotherapy – In the KEYNOTE-177 (KN-177) trial, first-line pembrolizumab monotherapy (200 mg every three weeks, (table 13)) was compared with conventional chemotherapy with either an oxaliplatin- or irinotecan-containing regimen in 307 patients with dMMR/MSI-H tumors [159]. Pembrolizumab was superior to upfront chemotherapy in terms of progression-free survival (median 16.5 versus 8.2 months), objective response rate (44 versus 33 percent), and duration of response. Among patients with an overall response, 83 percent in the pembrolizumab group versus 35 percent of those in the chemotherapy group had ongoing responses at 24 months. Pembrolizumab was also associated with better tolerability (grade 3 to 5 adverse reaction rates 22 versus 66 percent).

Two subsequent analyses of the KN-177 trial have addressed quality of life (QOL) and overall survival (OS):

In one report, patients receiving pembrolizumab had clinically meaningful improvements in their health-related QOL when compared with those receiving chemotherapy [160].

In the final analysis of OS data, there was a trend toward reduced risk of death that favored pembrolizumab (HR 0.74, 95% CI 0.53-1.03), but interpretation was complicated by the fact that 60 percent of the patients treated with first-line chemotherapy crossed over to pembrolizumab at some point, either on or off protocol [161].

Notably, more patients in the pembrolizumab arm had progressive disease as their best response (30 versus 12 percent), and if this approach is chosen, patients should be followed closely for the first 10 weeks to assess response, especially those with a high tumor burden or rapidly progressive disease. One potential alternative in these settings is to combine immunotherapy and chemotherapy or start with cytotoxic chemotherapy, followed by maintenance immunotherapy.

Individuals treated with immune checkpoint inhibitors for any cancer, including dMMR/MSI-H mCRC, can have pseudoprogression within the first several months of treatment [162], and response criteria specifically geared toward these drugs (ie, immune-modified RECIST (table 14)) should be used. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Largely based upon these data, in June 2020, the US Food and Drug Administration (FDA) approved pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer [163].

A year 2022 guideline on management of mCRC from ASCO concluded that based on the results of the KN-177 trial, pembrolizumab should be offered as first-line therapy to patients with dMMR mCRC (evidence-based, benefits outweigh harms, evidence quality moderate, strength of recommendation: strong) [12].

Nivolumab plus ipilimumab – Additional data on first-line immunotherapy using nivolumab (a different anti-PD-1 antibody) plus ipilimumab (which targets a different immune checkpoint, cytotoxic T-lymphocyte associated antigen 4) are available from the phase II Checkmate 142 trial [164]. Forty-five patients with dMMR mCRC and no prior treatment in the metastatic disease setting received nivolumab 3 mg/kg every two weeks plus low dose ipilimumab (1 mg/kg every six weeks) with both drugs continued until disease progression or discontinuation for other reason. The median overall response rate was 69 percent by investigator assessment and 62 percent by blinded central review; six patients (13 percent) had progressive disease as the best initial response. The median duration of response was not reached, and at data cutoff (median duration of follow-up 29 months) 23 of 31 responders (74 percent ) had ongoing response. Even while off treatment, further tumor shrinkage was observed in some patients. Treatment-related grade 3 or 4 toxicities were reported in only 22 percent of patients, and only six discontinued therapy because of a treatment-related adverse event. Whether these results are better than can be achieved with pembrolizumab monotherapy will require a randomized trial.

Updated consensus-based guidelines from the National Comprehensive Cancer Network now include nivolumab with or without ipilimumab as options for first-line therapy of dMMR/MSI-H mCRC, but pembrolizumab monotherapy is preferred.

ISSUES RELATED TO VITAMIN D — An association between vitamin D levels and prognosis of mCRC has been suggested [165-167]. In a report of a retrospective analysis of 1041 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 (OS) compared with those in the lowest quintile (median OS 33 versus 25 months, multivariate adjusted HR 0.66, 95% CI 0.53-0.83) [167]. 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). The group receiving high-dose vitamin D experienced a statistically insignificant two-month increase in median PFS (13 versus 11 months, one-sided p value 0.07) [168]. However, in adjusted analysis, patients in the high-dose group were less likely to experience progression or death at any point during the median follow-up of 22 months (adjusted HR 0.64, one-sided 95% CI 0-0.9). There was no indication of an OS benefit for high-dose vitamin D. Larger confirmatory phase III trials are needed to evaluate these preliminary findings. (See "Vitamin D and extraskeletal health", section on 'Treatment'.)

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".)

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

General principles The majority of patients with metastatic colorectal cancer (mCRC) cannot be cured. The goals of palliative chemotherapy are to relieve symptoms, improve quality of life, and prolong survival. The best way to combine and sequence all of the active agents is not yet established. Exposure to all active drugs is more important than specific sequence. (See 'Overview of the therapeutic approach' above.)

Biomarker testing – Biomarker expression drives therapeutic decision-making, and gene profiling of tumor tissue should be undertaken as quickly as possible after diagnosis. (See 'Predictive biomarkers' above.)

Treatment approach – Our general approach to initial chemotherapy for nonoperable mCRC is outlined in the algorithm (algorithm 1) and summarized below. Specific recommendations for patients with hepatic metastases who are potential candidates for resection are provided elsewhere. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

Patients with dMMR tumors – For patients with mCRC that is deficient in DNA mismatch repair (dMMR), we suggest first-line pembrolizumab rather than cytotoxic chemotherapy (Grade 2B). Other options for immunotherapy include nivolumab with or without ipilimumab. If upfront immunotherapy is chosen, patients should be followed closely for the first 10 weeks to assess response. (See 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' above.)

Patients without dMMR who are eligible for intensive therapy

Chemotherapy backbone (triplet therapy) For patients with a good performance status (PS) who are able to tolerate intensive therapy, and have a large tumor volume, we suggest triplet therapy with FOLFOXIRI (irinotecan and oxaliplatin with fluorouracil [FU]/leucovorin [LV] (table 2)), rather than initial doublet therapy containing either oxaliplatin or irinotecan (Grade 2B). If chosen, the triplet regimen should be restricted to an induction period of three to six months, followed by maintenance treatment with a fluoropyrimidine alone. (See 'Three- versus two-drug combinations' above.)

Chemotherapy backbone (doublet therapy) – For other patients, we suggest a chemotherapy doublet (FOLFOX [oxaliplatin plus LV plus infusional FU, (table 5)], XELOX [oxaliplatin plus capecitabine; also known as CAPOX (table 6)], or FOLFIRI [irinotecan plus LV and short-term infusional FU]) (table 3) 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".)

-Selecting between FOLFOX versus FOLFIRI – FOLFOX and FOLFIRI have similar first-line efficacy, and the choice should be based on the expected toxicity. FOLFIRI (table 15) is preferred for patients who received an adjuvant oxaliplatin-based regimen within the prior 12 months. (See 'Treatment-related toxicity' above and 'FOLFOX versus FOLFIRI' above.)

Biologic agent – The potential benefits of adding a biologic agent to the chemotherapy backbone must be weighed against potential adverse effects. If this approach is chosen, we select the biologic agent (bevacizumab or an EGFR inhibitor) based on several factors, including RAS/BRAF mutation status, primary tumor site, and eligibility for bevacizumab (See 'Role of biologics' above.):

-RAS and BRAF wild-type, right-sided tumors – For patients with a RAS and BRAF wild-type CRC and a right-sided primary tumor (ie, proximal to the splenic flexure), we suggest adding bevacizumab rather than an EGFR inhibitor to chemotherapy as initial treatment (Grade 2C). For those with a contraindication to bevacizumab, we use chemotherapy alone rather than adding an EGFR inhibitor to chemotherapy. (See 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' above and 'Contraindications' above.)

-RAS and BRAF wild-type, left-sided tumors – For patients with RAS and BRAF wild-type mCRC and a left-sided primary (ie, located at or distal to the splenic flexure), we suggest adding an EGFR inhibitor (cetuximab or panitumumab) rather than bevacizumab to chemotherapy as initial treatment (Grade 2B). For those patients who wish to avoid the toxicities associated with an EGFR inhibitor (ie, diarrhea and acneiform rash) for quality of life, the addition of bevacizumab to chemotherapy is an alternative option, although data suggest that survival outcomes are inferior. (See 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' above.)

-RAS or BRAF mutant tumors – For patients with RAS mutated mCRC and any primary tumor site, we recommend the addition of bevacizumab rather than an EGFR inhibitor to chemotherapy (Grade 1B). For patients with BRAF mutant tumors and any primary tumor site, we also suggest the addition of bevacizumab rather an EGFR inhibitor to chemotherapy (Grade 2C). Patients who are ineligible for bevacizumab may be offered chemotherapy alone. EGFR inhibitors are not used in patients with RAS or BRAF mutant tumors due to disease resistance. (See 'RAS or BRAF mutant tumors' above and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'BRAF mutations'.)

Patients who are not candidates for intensive therapy

For patients who are not candidates for an intensive first-line chemotherapy because of age, poor PS or associated comorbidity, but who are fit enough to tolerate some form of systemic therapy, options include dose-reduced FOLFOX, a fluoropyrimidine alone, or, for patients with no contraindication, a fluoropyrimidine plus bevacizumab. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Less fit patients with an ECOG PS 0 or 1'.)

Individuals with a poor PS (eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 11)) usually tolerate chemotherapy poorly, and in most cases, supportive care should be emphasized. Specific recommendations are provided separately. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Frail, significant functional impairment, poor performance status'.)

Adjunctive treatment with vitamin D – 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, we test serum vitamin D levels in patients with newly diagnosed mCRC, and replete those with low levels (serum 25[OH]D <20 ng/mL [50 nmol/L]). (See 'Issues related to vitamin D' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Axel Grothey, MD, who contributed to an earlier version of this topic review.

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Topic 2503 Version 136.0

References

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