Version May 2024
INTRODUCTION — Most patients with metastatic colorectal cancer (mCRC) are treated with systemic therapy. This topic will discuss general principles of systemic treatment for mCRC. Specific details on the approach to initial and subsequent systemic therapy in unresectable mCRC are discussed separately.
SYSTEMIC THERAPY
Available agents — Many systemic agents are used to treat mCRC, in combination with other drugs and as monotherapy. These include chemotherapy (fluorouracil [FU], oxaliplatin, irinotecan, among others), antiangiogenic agents, molecularly targeted agents, and immune checkpoint inhibitors. Available agents that are used as part of initial therapy and later lines of therapy for mCRC are discussed separately.
Many patients with mCRC are treated with initial combination systemic therapy, particularly those whose metastases might be potentially resectable after an initial response to chemotherapy. This approach must take into account the potential toxicities of combination therapy. Further details are discussed separately.
PREDICTIVE BIOMARKERS — Predictive biomarkers (specific targetable molecular alterations found in colorectal cancer) are often used to select therapy for mCRC. Gene profiling of tumor tissue (ie, with next-generation sequencing) should be obtained immediately after a diagnosis of mCRC to determine the presence of these molecular alterations, which influence management.
RAS — Metastatic colorectal cancer (mCRC) tumors are either RAS wild-type or RAS mutated. The molecular genetics and frequency of RAS mutations in mCRC are discussed separately. (See "Molecular genetics of colorectal cancer", section on 'RAS'.)
Assessing the RAS status of a tumor permits the selection of individuals who might benefit from specific strategies, particularly those targeting the epidermal growth factor receptor (EGFR).
RAS testing — All patients with mCRC who are eligible for EGFR inhibitors should have tumor tissue tested for mutations in both KRAS and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). This is consistent with guidelines from The American Society of Clinical Oncology (ASCO) [1] and the National Comprehensive Cancer Network (NCCN) [2,3].
The US Food and Drug Administration has approved several companion diagnostic tests for extended RAS testing (KRAS exons 2,3, and 4 and NRAS exons 2, 3, and 4). These include the PRAXIS Extended RAS Panel, FoundationOne CDx, and xT CDx [4].
In patients with mCRC, tumor tissue (either from the primary tumor or metastatic sites) remains the gold standard for evaluating for activating RAS mutations. KRAS or NRAS are detected with good concordance between the primary tumor and synchronous distant metastases, but not lymph node metastases [5,6]. However, in some settings, rebiopsy of metastases for RAS mutation analysis may be warranted. In observational studies of patients with colorectal cancer that assessed RAS mutations in the primary tumor versus recurrent tumors, the rate of discordant results in RAS status was estimated at 20 percent [7].
What is the role of ctDNA? — The use of circulating tumor DNA (ctDNA) to confirm RAS mutation status in mCRC is evolving. Further data are necessary prior to the routine use of ctDNA to select treatment for mCRC, as some studies suggest discordance between the genotyping results on tissue versus ctDNA. Tumor tissue genotyping should be used to confirm the results from ctDNA testing, if obtained. For patients where access to tissue is unavailable or difficult to obtain, treatment may be based on actionable alterations identified on ctDNA analysis [8]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Multipanel somatic (tumor) and germline genomic testing'.)
The use of ctDNA (or "liquid biopsy") obtained from the blood of patients with cancer can be used to detect and quantify tumor-specific genetic alterations, including RAS mutations. One advantage of ctDNA is the potential for reducing turnaround time on mutation results, although this is based on retrospective data with a limited number of cases [9].
Studies are also conflicting for concordance between the genotyping results of ctDNA assays and tumor specimens. In some studies, the overall concordance between tumor and plasma RAS mutational status (a summation of true positives and true negatives) is 82 to 93 percent [9-15]. However, other studies have reported lower rates of concordance (64 to 78 percent), especially in certain metastatic sites including the lung and peritoneum [9,12,16]. In one meta-analysis of 21 studies evaluating the effectiveness of ctDNA for detection of KRAS mutations, sensitivity and specificity were 67 and 96 percent, respectively [15].
Impact of RAS status on the use of EGFR inhibitors — For patients with mCRC whose tumors are RAS mutant, we do not use epidermal growth factor receptor (EGFR) inhibitors (cetuximab or panitumumab) either alone or in addition to chemotherapy. Tumors that harbor activating mutations in RAS (most commonly KRAS but also NRAS) are resistant to EGFR inhibitors due to constitutive activation of the RAS pathway. Clinical trials also confirm that EGFR inhibitors have limited clinical benefit or inferior survival outcomes in RAS-mutated CRC. (See "Molecular genetics of colorectal cancer", section on 'Molecular mechanism of RAS mutations'.)
By contrast, patients with mCRC and whose tumors are RAS and BRAF V600E wild-type are eligible for treatment with EGFR inhibitors (cetuximab or panitumumab). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'RAS/BRAF wild-type tumors' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)
Clinical studies in patients with RAS-mutated mCRC have demonstrated no benefit for EGFR inhibitors. Data are as follows:
●KRAS mutations in exon 2 – The most common RAS mutations in mCRC are KRAS mutations in exon 2 (codons 12 and 13). Patients with these tumors derive limited benefit from the use of EGFR inhibitor-based therapy [17-29]. In addition, some studies also demonstrated inferior progression-free survival (PFS) with this approach [19,30]. As examples:
•In a systematic review of four randomized trials [18,19], among patients with KRAS exon 2 mutant mCRC, the addition of an EGFR inhibitor to either chemotherapy (for treatment-naïve mCRC in the CRYSTAL and OPUS trials [18,19]) or best supportive care (for treatment-refractory mCRC in the C0.17 trial and in another trial [20,23]) did not confer a PFS (hazard ratio [HR] 1.0) or overall survival (OS; HR 1.0) advantage [28]. Further details on these individual trials are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'No prior initial therapy with cetuximab/panitumumab' and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'RAS/BRAF wild-type disease'.)
•A randomized phase III trial (PRIME) of patients with previously untreated mCRC included a subgroup of 440 patients with KRAS exon 2 mutations. In this subgroup, the addition of panitumumab to FOLFOX worsened PFS (median 7.3 versus 8.8 months, HR 1.29, 95% CI 1.04-1.62) and failed to improve OS (median 16 versus 19 months, HR 1.24, 95% CI 0.98-1.57) [30]. Further details on the PRIME trial are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Benefit of cetuximab and panitumumab'.)
Similar results were also seen in a separate randomized phase II trial (OPUS) evaluating the addition of cetuximab to FOLFOX. In this study, among the subgroup of 99 patients with KRAS exon 2 mutated tumors, FOLFOX plus cetuximab resulted in inferior PFS relative to FOLFOX alone (median PFS 6 versus 9 months, HR 1.83, 95% CI 1.10 to 3.06) [19]. Further details on the OPUS trial are discussed separately. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'RAS/BRAF wild-type disease'.)
The KRAS G13D mutation may be an exception. Data, including several meta-analyses, are conflicting are conflicting as to whether this mutation confers resistance to EGFR inhibitors or not [31-37].
KRAS G12C inhibitors are being investigated alone and in combination with other agents in patients with KRAS G12C mutated mCRC. Further details are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS-mutated tumors'.)
●Other RAS mutations – Similarly, tumors with lower frequency KRAS mutations outside of exon 2 and NRAS mutations also do not benefit from EGFR inhibitors [6,25,38-44]. As examples,
•In a meta-analysis of nine randomized trials that evaluated EGFR inhibitor-based therapy in mCRC, no difference in PFS or OS benefit was demonstrated between tumors with RAS mutations other than exon 2 (KRAS exon 3 and 4 and NRAS exons 2, 3, and 4) and tumors with KRAS exon 2 mutations [44].
•In a subgroup analysis of the PRIME trial by mutational status, relative to the absence of a RAS mutation, RAS mutations other than KRAS exon 2 was a negative effect modifier for the addition of panitumumab to FOLFOX on both OS and PFS [38]. These data suggest that RAS mutations outside of exon 2 are also negative predictive factors for survival.
BRAF mutations — For patients with mCRC that are BRAF V600E mutated and RAS wild-type, we do not use EGFR inhibitors (cetuximab or panitumumab) as single agents in this population. This mutation induces resistance to EGFR inhibitors, and randomized trials conducted in this population suggest limited benefits. This approach is consistent with guidelines from the American Joint Committee on Cancer (AJCC) [45], NCCN [2], and European Society for Medical Oncology (ESMO) [46].
For those with treatment-refractory disease, cetuximab or panitumumab can be combined with encorafenib, a BRAF inhibitor, to overcome tumor resistance to EGFR inhibitors. Further details are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, BRAF mutated tumors'.)
BRAF is a component of the RAS-RAF-MAPK signaling pathway. Activating BRAF mutations, which are mutually exclusive with KRAS mutations, are found in approximately 5 to 12 percent of mCRCs. BRAF mutations (most of which are V600E mutations) have consistently been associated with poor prognosis in mCRC [47-53]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF'.)
●V600E mutations – Studies demonstrate that a response to EGFR inhibitors (either alone or in combination with chemotherapy) is unlikely in patients whose tumors harbor BRAF V600E mutations, even if they are RAS wild-type [54-56]:
•One analysis of 10 randomized trials comparing cetuximab or panitumumab alone or plus chemotherapy with standard therapy or best supportive care included one phase II and nine phase III trials; six were conducted in the first-line treatment setting, two for second-line therapy, and two in patients with chemorefractory disease [54]. Among patients with RAS wild-type/BRAF V600E mutant tumors, compared with control regimens, the addition of an anti-EGFR monoclonal antibody did not significantly improve PFS (hazard ratio [HR] 0.88, 95% CI 0.67-1.14), OS (HR 0.91, 95% CI 0.62-1.34), or objective response rate.
•A similar conclusion was reached in an individual patient data analysis derived from the ARCAD database of ten randomized trials of first-line targeted therapies [56].
•Another analysis included eight randomized trials, four conducted in the first-line setting, three in the second-line setting, and one in patients with chemorefractory disease [55]. Among patients with RAS wild-type/BRAF V600E mutant mCRC, there was no significant overall survival benefit for the addition of an anti-EGFR monoclonal antibodies (HR 0.97, 95% CI 0.67-1.41). By contrast, overall survival was significantly greater in patients with RAS wild-type BRAF wild-type tumors (HR 0.81, 95% CI 0.7-0.95). When comparing the overall survival benefit between BRAF V600E mutant and BRAF wild-type tumors, the test for interaction was not statistically significant, leading the authors to conclude that the observed differences in the effect of anti-EGFR monoclonal antibodies on overall survival according to BRAF V600E mutation status could have been due to chance, and that the evidence was insufficient to state that mutant tumors attain a different treatment benefit from anti-EGFR agents compared with individuals with BRAF wild-type tumors.
•In a phase II trial (FIRE-4.5; AIO KRK0016), 109 patients with previously untreated RAS wild-type BRAF V600E-mutated mCRC were randomly assigned to oxaliplatin plus irinotecan, leucovorin, and short-term infusional fluorouracil (FU; FOLFOXIRI) plus either bevacizumab or cetuximab [57]. Compared with FOLFOXIRI plus bevacizumab, FOLFOXIRI plus cetuximab decreased the objective response rate (51 versus 67 percent) and PFS (median 7 versus 11 months, HR 1.89). There was a nonstatistically significant trend towards inferior overall survival for FOLFOXIRI plus cetuximab (median 13 versus 17 months).
●Other BRAF mutations – Less is known about BRAF mutations outside of codon 600, which account for about one-fifth of all BRAF mutations in mCRC [58]. From a prognostic standpoint, patients with mCRC whose tumors harbor a non-V600 mutation seem to have a better median overall survival than do those with either a V600E mutation or a BRAF wild-type tumor (61 versus 11 versus 43 months, respectively) [58]. However, there are very few data addressing the predictive value of non-V600 BRAF mutations for response to anti-EGFR agents [59-61], and this remains an area of active investigation. (See "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF'.)
dMMR or MSI-H tumors — Approximately 3.5 to 6.5 percent of stage IV CRCs have mismatch repair deficient (dMMR) enzymes, the biologic footprint of which is microsatellite instability high (MSI-H). Cancers with dMMR/MSI-H appear to be uniquely susceptible to immune checkpoint inhibitors, and this is a reasonable first-line approach for appropriately selected patients. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' 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'.)
HER2-positive tumors — Approximately 3 to 5 percent of CRCs have amplification of the human epidermal growth factor receptor 2 (HER2) oncogene or overexpress its protein product, HER2. HER2-targeted therapies are used to treat patients with HER2-overexpressing mCRC who progress on conventional chemotherapy. Further details on available agents are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)
HER2-targeted therapy may also be considered as a first-line treatment in patients who are not candidates for more intensive therapy; however, it is not our preferred approach. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)
TRK-fusion-positive tumors — Tumors that harbor molecular alterations in the neurotrophic tyrosine receptor kinase (NTRK) gene produce tropomyosin receptor kinase (TRK) fusion oncoproteins. Such tumors can be treated with agents that target these TRK fusion oncoproteins, such as larotrectinib or entrectinib. Further details are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)
Other biomarkers — EGFR amplification is not an established predictive biomarker for mCRC. Some [62-64], but not all studies [21,65-67], suggest an association between EGFR copy number and response to EGFR inhibitors. However, the clinical use of EGFR amplification to select patients for therapy is limited by the lack of standardization of fluorescence in situ hybridization technology and scoring [63,66].
TREATMENT GOALS — The goals of chemotherapy for mCRC differ according to the clinical scenario. For most patients, treatment will be palliative and not curative (a fact that may not be understood by patients [68]), and the treatment goals are to prolong overall survival (OS) and maintain quality of life (QOL) for as long as possible.
Potentially resectable disease — However, some patients with stage IV disease (particularly those with liver-limited metastases) can be surgically cured of their disease. Even selected patients with initially unresectable liver metastases may become eligible for resection if the response to chemotherapy is sufficient.
This approach has been termed "conversion therapy" [69] to distinguish it from "neoadjuvant therapy," which applies to preoperative chemotherapy 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) [70]. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)
Nonresectable disease — The following general principles guide the use of palliative chemotherapy in the setting of nonoperable disease:
●In general, for patients without symptomatic disease (ie, the majority of patients), induction of a tumor response is not as important as is delaying tumor progression for as long as possible. In the palliative setting, objective response rate is not the best indicator of treatment benefit (prolonged survival and/or progression-free survival [PFS]) [71-73]. Thus, achieving stable disease as the best response to therapy might be considered a treatment success. (See 'Assessing treatment response' below.)
●Patients benefit more from access to all active agents than from a particular treatment sequence of specific regimens used as individual "lines" of therapy. In all large published phase III trials testing various combinations of cytotoxic agents and targeted agents conducted over the last decade, the proportion of patients receiving all active agents has correlated strongly with median survival [74,75]. Although no such analysis has yet been performed after the introduction of biologic agents, it is conceivable that the overall principle of optimizing outcomes through exposure to all active agents is still valid.
●Despite these findings, the available evidence suggests that only a minority of American patients with mCRC are exposed to all active agents in the course of their therapy for mCRC [76].
●Because of the survival benefit from second- and even third-line chemotherapy, the routine practice of crossover in clinical trials severely limits the ability to detect an overall survival advantage of one treatment regimen over another. Therefore, the actual activity of a new agent or combination regimen is better captured by the endpoint PFS, in particular in the first-line setting. Improvements in PFS correlate with longer survival [77-79] and are not affected by crossover or subsequent therapy.
These concepts can be illustrated by results from the EPIC trial, in which patients failing initial oxaliplatin-based therapy were randomly assigned to irinotecan with or without cetuximab [80]. There were significant differences in PFS, objective response, and disease control rates that favored combined therapy, but no overall survival advantage. This was attributed to the fact that 50 percent of the patients in the irinotecan arm crossed over to cetuximab at progression. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'No prior initial therapy with cetuximab/panitumumab'.)
●Endpoints other than PFS (eg, duration of disease control, time to failure of strategy) have been proposed, but none are widely used [81,82].
●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 incurable metastatic mCRC in favor of a "continuum of care" approach [83]. This implies an individualized treatment strategy that may include phases of maintenance chemotherapy interspersed with more aggressive treatment protocols, as well as reutilization of previously administered chemotherapy agents in combination with other active drugs.
The following sections will emphasize the practical issues that arise when choosing the appropriate treatment strategy for individual patients with inoperable mCRC. Specific recommendations for therapy as well as management of patients with potentially resectable liver metastases are discussed elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy" and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)
SYSTEMIC THERAPY VERSUS SUPPORTIVE CARE — Systemic fluorouracil (FU)-based chemotherapy produces meaningful improvements in median survival and progression-free survival (PFS) compared with best supportive care (BSC) alone [84-86]. These benefits are most pronounced with regimens containing irinotecan or oxaliplatin in combination with FU. Although no trial has compared these regimens with BSC alone, median survival durations in clinical trials of oxaliplatin- and irinotecan-containing chemotherapy now consistently exceed two years; by contrast, for patients with unresectable mCRC who receive best supportive care (BSC) alone, median survival is approximately five to six months [84-86].
Long-term survival is improving over time with the availability of more active anticancer agents [87-90]. As an example, in a report of pooled data from North Center Cancer Treatment Group (NCCTG) trials conducted in the FU plus leucovorin (LV) era, only 1.1 percent of patients were alive at five years [91]. By contrast, in a report from the phase III FIRE-3 trial (first-line irinotecan with short-term infusional FU plus LV [FOLFIRI] plus either bevacizumab or cetuximab), the five-year survival rate for patients with RAS wild-type tumors treated with FOLFIRI plus cetuximab was approximately 20 percent [92]. Although many of the survival gains are attributable to advances in chemotherapy treatment, more aggressive use of surgical resection of metastatic disease has also contributed [89]. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Colorectal cancer'.)
TIMING OF SYSTEMIC THERAPY — Although the value of early chemotherapy versus treatment deferral until symptoms develop is controversial, we suggest instituting chemotherapy at diagnosis for patients with categorically unresectable mCRC, and when possible, before patients become symptomatic.
Many patients with mCRC are asymptomatic. Data are limited on optimal timing of chemotherapy, and the only randomized trials directly addressing this issue studied older regimens like fluorouracil (FU) and leucovorin (LV):
●In an early trial in which 182 patients with asymptomatic mCRC were randomly assigned to initial or deferred chemotherapy with sequential methotrexate, FU, and LV, earlier treatment was associated with improvements in median survival (14 versus 9 months), symptom-free interval, and progression-free survival (PFS) [84].
●In a combined analysis of 168 asymptomatic patients who were enrolled in two trials randomly testing early versus delayed FU-based chemotherapy, there was a non-statistically significant two-month benefit in median survival with early treatment (13 versus 11 months) [93].
Whether these results can be extrapolated to patients treated with irinotecan, oxaliplatin, or biologic therapies, especially in the era of modern diagnostic procedures that can detect lower volume metastatic disease, is unclear. Regimens such as these are associated with clear-cut survival benefits, particularly if patients are serially exposed to all active agents. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Initial doublet combinations versus sequential single agents'.)
The only available data from the era of modern chemotherapy come from a retrospective report of 736 patients with mCRC diagnosed between January 2003 and December 2010 at a single Australian center; 377 (51 percent) received immediate chemotherapy, 167 (23 percent) did not because they were deemed inappropriate for therapy or refused, and 192 (26 percent) adopted a "watch and wait" policy initially, 168 of whom eventually received chemotherapy (at a median of 3.7 months from diagnosis) [94]. Compared with immediate treatment, the fraction of patients in the delayed chemotherapy group who eventually received treatment with all active agents was slightly less (30 versus 39 percent), but the median survival was superior (27 versus 17 months).
Importantly, these data are not from a randomized trial, and interpretation is limited by the potential for selection bias (ie, patients who had treatment deferred were likely to be those with favorable biology [asymptomatic, lower volume metastatic disease, better performance status]), all of which could have contributed to the longer survival in this group. At least in the United States, most patients institute treatment at a time when they are still asymptomatic from their cancer. An alternate approach, which may be particularly appropriate for asymptomatic elderly patients, is an initial period of observation to judge the tempo of disease progression.
CHEMOTHERAPY DOSING IN OBESE PATIENTS — For cancer patients with a large body surface area (BSA), chemotherapy drug doses are often reduced because of concern for excess toxicity. However, there is no evidence that fully dosed obese patients experience greater toxicity from chemotherapy for mCRC; furthermore, obese patients who are given reduced doses may have inferior outcomes [95]. Although limited, the available data do not support the policy of routine dose reduction (or capping the maximal BSA to 2.0 m2) for obese patients with mCRC. Guidelines from the American Society of Clinical Oncology recommend that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer [96]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of initial chemotherapy for unresectable mCRC is controversial. The decision to permit treatment breaks for responding patients must be individualized and based upon the regimen being used, tolerance of and response to chemotherapy, disease bulk and location, symptomatology, and patient preference. For many patients with chemotherapy responsive disease who do not have bulky or severely symptomatic disease, intermittent rather than continuous therapy may mitigate treatment-related toxicity, and does not appear to adversely impact overall survival. For patients initially treated with oxaliplatin, a complete break in therapy represents a valid alternative to fluoropyrimidine-based maintenance chemotherapy without oxaliplatin for patients who have responding or stable disease after the initial course of chemotherapy, particularly for those with a complete clinical response or small-volume metastatic disease.
Rationale for intermittent therapy — When fluorouracil (FU) was the only treatment alternative, patients generally stayed on treatment until their disease progressed or they developed unacceptable toxicity. This typically meant that patients were treated for four to six months (the median progression-free survival [PFS] duration) and then were placed on supportive care alone until they died (median duration of survival approximately one year).
Compared with FU alone, newer combinations are more effective (median survival durations now consistently approach two years), but they are also more toxic. This is particularly true for oxaliplatin-containing regimens, which cause cumulative neurotoxicity; several studies have shown that more patients come off of therapy because of toxic effects than because of progressive disease [97,98]. Intermittent rather than continuous chemotherapy has the potential to improve outcomes and reduce toxicity as well as cost.
However, intermittent therapy may be appropriate for some patients and not others:
●There are many patients with small volume but multiple sites of disease who respond well to chemotherapy or have a prolonged period of disease stability. Even if their disease triples in volume off therapy, they will not likely be symptomatic or develop organ dysfunction. Patients with favorable characteristics may be able to tolerate chemotherapy-free (or at least oxaliplatin-free) intervals of multiple months per year and go on to respond favorably to drugs for many years.
●On the other end of the spectrum are patients with retained primary tumors, bulky disease, poor performance scores due to tumor related symptoms, peritoneal disease that may lead to unsalvageable bowel obstruction as the first sign of progression, and those with extensive symptomatic disease who progress through treatment regimens in quick succession with either short-lived responses or no response. These patients may be better approached with continuous chemotherapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Duration of initial chemotherapy'.)
Whether continued chemotherapy provides better outcomes than intermittent therapy to best response followed by a chemotherapy "holiday" has been addressed in several trials, most of which have studied chemotherapy regimens that contain oxaliplatin, a drug that is associated with dose-limiting neurotoxicity. Intermittent oxaliplatin-free therapy can be achieved through a complete break in therapy or the use of a non-oxaliplatin-containing "maintenance regimen." (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Cumulative sensory neuropathy' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI'.)
Patients receiving oxaliplatin — Oxaliplatin-based regimens (eg, FOLFOX [oxaliplatin plus LV and short-term infusional FU]) are commonly used for first-line chemotherapy in mCRC [76]. However, oxaliplatin is associated with a cumulative sensory neuropathy, which may be dose limiting.
Whether long-term neurotoxicity can by mitigated by intermittent oxaliplatin-free intervals has been addressed in several trials. The following represents an overview of the most important findings.
Maintenance fluoropyrimidines only
●OPTIMOX-1 – The OPTIMOX1 trial randomly assigned 620 previously untreated patients to FOLFOX, administered every two weeks until disease progression (arm A), or FOLFOX (table 1) for six cycles only, followed by reintroduction of oxaliplatin at the time of progression after 12 cycles of a non-oxaliplatin-containing maintenance regimen (leucovorin-modulated FU) [81]. The duration of disease control and overall survival between the continuous (arm A) and maintenance (arm B) approaches were very similar (9 versus 8.7 months, and 19.3 versus 21.2 months, respectively). Individuals in arm B had a significantly lower risk of developing grade 3 or 4 toxicity during cycles 6 to 18 (but not overall) [99].
●OPTIMOX-2 – The subsequent OPTIMOX-2 trial was initially designed as a 600 patient phase III trial, but when bevacizumab became available, accrual was halted with 202 patients enrolled [100]. OPTIMOX-2 compared six cycles of modified FOLFOX7 followed by maintenance with FU/LV (arm A) to six cycles of modified FOLFOX7 followed by a complete stop in chemotherapy (arm B). The primary endpoint was the duration of disease control, calculated as the sum of the duration of PFS both following the initial three-month course of modified FOLFOX7 (mFOLFOX7) (table 1), as well as after the subsequent reintroduction of oxaliplatin. An important characteristic of OPTIMOX-2 was that randomization occurred after six cycles of therapy regardless of response, and metastases were allowed to progress back to baseline levels before FOLFOX was reintroduced.
Complete discontinuation of therapy seemed to have an adverse impact on prognosis; the group receiving maintenance therapy had significantly longer median duration of disease control and median PFS from the time of randomization; there was also a trend toward improved median overall survival (24 versus 20 months, p = 0.42). These data mandate caution and both careful patient selection and vigilant patient monitoring so that therapy can be reinstated promptly at progression when considering chemotherapy-free intervals.
●Another multicenter trial, the CONcePT trial, in which patients were randomly assigned to continuous versus intermittent oxaliplatin (alternating every eight cycles with and without oxaliplatin) also confirmed the benefit of intermittent rather than continuous oxaliplatin for increasing time on first-line therapy for oxaliplatin/bevacizumab-based combinations [101]. Rates of peripheral sensory neuropathy were significantly lower in the intermittent therapy group.
Maintenance bevacizumab — Several trials have explored the benefit of maintenance bevacizumab in patients initially treated with a bevacizumab-containing regimen, both alone and in combination with a fluoropyrimidine.
●Bevacizumab plus a fluoropyrimidine
•CAIRO3 – The utility of maintenance treatment with capecitabine plus bevacizumab was addressed in the Dutch CAIRO3 trial, which randomly assigned 558 patients with stable disease or better after six cycles of XELOX plus bevacizumab who were not eligible for potentially curative metastasectomy to continued capecitabine (625 mg/m2 twice daily every day) plus bevacizumab (7.5 mg/kg every three weeks) or observation alone [102]. Upon first progression (PFS1), patients in both arms were supposed to be treated with XELOX plus bevacizumab until the second progression (PFS2) per protocol. The primary endpoint was PFS2, which was calculated from the time of randomization. Maintenance therapy was associated with a significantly longer PFS2 (11.7 versus 8.5 months, hazard ratio [HR] 0.67, p<0.0001), and there was a trend toward improved overall survival, as well (median 21.6 versus 18.1 months, HR 0.89, p = 0.22).
•German AIO KRK 0207 trial – Similarly, a benefit for continued fluoropyrimidine plus bevacizumab as compared with observation alone was also shown in the German AIO KRK 0207 trial, in which patients without progressive disease after six months of oxaliplatin plus a fluoropyrimidine and bevacizumab were randomly assigned to maintenance with the same fluoropyrimidine plus bevacizumab, bevacizumab alone, or observation only [103]. The primary endpoint was the "time to failure of strategy" or TFS, which included the duration of maintenance plus the time from reinduction after first progression to a second disease progression. The trial was powered to demonstrate noninferiority with a noninferiority margin set at 3.5 months, corresponding to an HR of 1.42. The median TFS in the fluoropyrimidine plus bevacizumab and observations arms was not significantly different (6.9 and 6.4 months, respectively; HR 1.26, 95% CI 0.99-1.60). However, the observation arm was not non-inferior to fluoropyrimidine plus bevacizumab because the upper limit of the 95 percent confidence interval exceeded the threshold set for non-inferiority (1.43). Notably, few patients in either arm were exposed to reinduction treatment (19 percent with combined therapy, and 46 percent of those undergoing observation), rendering the primary endpoint, TFS, non-informative and clinically irrelevant.
•STOP and GO trial – A slightly different approach was tested in the Turkish STOP and GO trial, in which, following six cycles of bevacizumab plus XELOX, 123 patients were randomly assigned to continued therapy or discontinuation of oxaliplatin and maintenance with bevacizumab plus capecitabine until progression [104]. The median PFS was significantly better in the group receiving maintenance therapy with bevacizumab plus capecitabine (11 versus 8.3 months), with less grade 3 or 4 diarrhea (3.3 versus 11.3 percent), hand-foot syndrome (1.6 versus 3.2 percent), and neuropathy (1.6 versus 8.1 percent).
●Bevacizumab monotherapy – For patients who have no disease progression after an initial course of bevacizumab plus oxaliplatin-containing chemotherapy, we suggest not pursuing bevacizumab alone for maintenance therapy; this approach is also not recommended in consensus-based guidelines for the treatment of mCRC from the National Comprehensive Cancer Network (NCCN) [2] and European Society for Medical Oncology (ESMO) [46].
The role of maintenance bevacizumab alone has been studied in three trials, all of which used different comparator arms, and all of which came to different conclusions:
•MACRO – In the Spanish MACRO trial, patients received six cycles of first-line XELOX plus bevacizumab followed by a randomization to continued therapy or bevacizumab maintenance therapy alone until progression or treatment intolerance [105]. There was no arm in which patients received no maintenance therapy. The median PFS and overall survival durations in patients treated with maintenance bevacizumab alone were not significantly worse, and rates of severe neurotoxicity, hand-foot syndrome, and fatigue were significantly lower. However, the trial failed to achieve its primary endpoint of non-inferiority for PFS, because the projected upper limit of the 95 percent confidence interval for PFS exceeded the preset limit.
•SAKK 41-06 – In the Swiss SAKK 41-06 trial, 262 patients with mCRC were randomly assigned to bevacizumab continuation versus no maintenance after four to six months of first-line bevacizumab-containing chemotherapy (62 percent oxaliplatin-containing, 31 percent irinotecan-containing, and the rest fluoropyrimidine alone) [106]. Like the MACRO trial, the trial failed to achieve its primary endpoint of non-inferiority for TTP with the projected upper limit of the 95 percent confidence interval for TTP exceeding the preset limit. The median TTP was 4.1 for bevacizumab continuation versus 2.9 months for no continuation (HR 0.74, 95% CI 0.57-0.95). However, in our view, this study has significant limitations; it includes trials conducted over almost two decades, contains a very heterogenous patient population, and it is heavily influenced by the COIN trial due to its size. As a result, it should not be used to justify use of bevacizumab alone as effective maintenance therapy.
•German AIO KRK 0207 trial – On the other hand, noninferiority of bevacizumab alone compared with bevacizumab plus a fluoropyrimidine was shown in the German AIO KRK 0207 trial, described above [103]. The primary endpoint (the median time to failure of strategy, TFS) in the fluoropyrimidine plus bevacizumab and bevacizumab alone arms was 6.9 and 6.1 months, respectively. Compared with fluoropyrimidine plus bevacizumab, the bevacizumab only arm was non-inferior (HR 1.08, 95% CI 0.85-1.37). However, the upper boundary of the noninferiority margin was very generous (HR 1.43). Notably, few patients in either arm were exposed to reinduction treatment (19 percent with combined therapy, and 43 percent of those receiving bevacizumab alone), rendering the primary endpoint, TFS, non-informative and clinically irrelevant.
Patients initially treated with an EGFR inhibitor — For patients initially treated with an agent targeting the epidermal growth factor receptor (EGFR), we suggest maintenance therapy using FU plus the anti-EGFR agent rather than an anti-EGFR agent or fluoropyrimidine alone.
Benefit from anti-EGFR therapies is limited to patients whose tumors lack mutations in one of the RAS oncogenes (ie, wild-type RAS). (See 'RAS' above.)
Three trials have addressed the benefit of maintenance therapy with an EGFR inhibitor after initial treatment with FOLFOX plus an EGFR inhibitor:
●MACRO – The phase II MACRO-2 trial randomly assigned 193 patients with KRAS (exon 2 only) wild-type tumors to receive FOLFOX plus cetuximab for four months (eight courses) followed by either continued therapy with the same regimen or cetuximab monotherapy alone (250 mg/m2 weekly) [107]. Cetuximab monotherapy was noninferior to the combination of continued FOLFOX plus cetuximab, as judged by the primary endpoint, the proportion of patients who were progression free at nine months (60 versus 72 percent, HR 0.60, 95% CI 0.31-1.15).
●VALENTINO – On the other hand, results with panitumumab alone were inferior to maintenance treatment with FU/LV plus panitumumab following four months of induction therapy with FOLFOX plus panitumumab in the phase II noninferiority VALENTINO trial [108]. Ten-month PFS was inferior with panitumumab alone (49 versus 60 percent).
●PANAMA – A slightly different question, the benefit of adding panitumumab to leucovorin (LV) modulated FU versus FU/LV alone after six cycles of induction therapy with FOLFOX plus panitumumab in RAS wild-type advanced CRC was addressed in the phase III PANAMA trial [109]. Median PFS, the primary endpoint, was significantly better with combined therapy as compared with leucovorin-modulated FU alone (8.8 versus 5.7 months, HR 0.72, 95% CI 0.60-0.85), and there was also a trend to better overall survival that also favored maintenance panitumumab.
Irinotecan — While intermittent treatment approaches appear to be almost mandatory for the majority of patients receiving oxaliplatin because of cumulative neurotoxicity, there are no cumulative dose-dependent toxicities from irinotecan. For most patients, we treat as long as tumor shrinkage continues and treatment is tolerated. Thereafter, as intermittent treatment does not appear to compromise outcomes, treatment breaks could be considered in responding patients, especially those receiving concomitant therapy with an anti-EGFR agent.
The benefits/risks of intermittent chemotherapy with an irinotecan-containing regimen have been addressed in the following reports:
●One trial demonstrated that patients started on FOLFIRI (irinotecan with short-term infusional FU plus LV (table 2)) as first-line therapy had similar overall outcome (PFS and overall survival) whether or not the regimen was administered continuously until progression or toxicity or in "two months on/two months off" intervals [110]. The median chemotherapy-free period in the intermittent treatment group was only three months. However, there were no demonstrable differences in treatment-related toxicity between the continuous versus intermittent treatment groups. Of note, further second- and third-line therapy did not follow a "stop-and-go" approach, so that for overall survival, any potential differences obtained in first-line therapy could have been obscured by subsequent treatment. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Irinotecan-based regimens'.)
●On the other hand, patients treated initially with an irinotecan plus an anti-EGFR agent might benefit from intermittent as compared with continuous therapy. This issue was directly addressed in the prospective IMPROVE trial, in which 137 patients with unresectable, previously untreated RAS/BRAF wild-type mCRC were randomly assigned to FOLFIRI plus panitumumab until disease progression on treatment, or a fixed eight cycles followed by a treatment-free interval, and reintroduction of the same regimen at disease progression [111]. In a preliminary report presented at the 2022 annual American Society of Clinical Oncology meeting, at a median follow-up of 18 months, the overall disease control rate was similar with intermittent as compared with continuous therapy (90 versus 94 percent), and more patients were alive without progression at one year with intermittent therapy (60.8 versus 52.1 percent, median PFS 17.1 versus 13.1 months). The intermittent strategy yielded lower rates of grade ≥3 skin toxicity (13 versus 27 percent), and fewer patients discontinuing therapy for toxicity. The results of this study do have the caveat of a relatively small sample size.
●A lack of benefit for maintenance bevacizumab versus no treatment until progression following six months of induction FOLFIRI plus bevacizumab was shown in the randomized phase III PRODIGE 9 trial [112].
Complete break in therapy — The data on maintenance therapy described above have led to the general conclusion that some form of maintenance therapy is preferred rather than a complete break in therapy in patients who are responding to or have stable disease after induction chemotherapy therapy. However, while maintenance therapy prolongs PFS compared with no maintenance therapy, none of the trials described above have shown that this approach is associated with better overall survival compared with a complete break in therapy.
At least two meta-analyses and a more recent trial have specifically addressed the role of observation (ie, a complete break in therapy) versus maintenance treatment in patients initially treated with either oxaliplatin or irinotecan-based initial systemic therapy for mCRC, all of which have concluded that overall survival is not adversely impacted by a complete break in treatment:
●A network meta-analysis included 12 randomized trials comparing the different treatment strategies of continued chemotherapy, observation, and maintenance therapy (including fluoropyrimidine alone, bevacizumab alone, or fluoropyrimidine plus bevacizumab) [113]. Different induction regimens were used in the different trials, including an oxaliplatin-based regimen in nine [81,100-106,114,115], an irinotecan-based regimen in two [112,116], and mixed regimens in one trial [106].
Comparisons of any maintenance therapy versus observation demonstrated that maintenance therapy was associated with improved PFS in both direct (HR 0.63, 95% CI 0.45-0.86) and indirect analyses (HR 0.58, 95% CI 0.43-0.77), but the effect on overall survival was not significant (HR for the indirect analysis 0.91, 95% CI 0.83-1.01). Analyses of each specific maintenance strategy (fluoropyrimidine alone, bevacizumab alone, fluoropyrimidine plus bevacizumab) versus observation alone also found improved PFS but not overall survival for all comparisons.
●Similarly, an individual patient data meta-analysis of more than 4000 patients enrolled on nine trials evaluating intermittent therapy after successful completion of induction therapy (six with planned stopping of all therapy, the other three discontinuing oxaliplatin with continuation of the other regimen components as maintenance therapy) also concluded that a complete break in therapy did not adversely impact survival [117]. The overall analysis of intermittent versus continuous therapy showed no significant overall survival detriment from intermittent therapy (HR 1.03, 95% CI 0.93-1.14), whether from complete break (HR 1.04, 95% CI 0.87-1.26) or maintenance (HR 0.99, 95% CI 0.87-1.13). PFS results were broadly consistent with the overall survival results. In a preplanned analysis, thrombocytosis was confirmed as a poor prognostic factor, but it did not predict for inferior survival from a complete treatment break compared with continuous therapy (interaction HR 0.97, 95% CI 0.66-1.40).
●Additional data are available from the randomized FOCUS4-N trial, in which 254 patients with stable or responding disease after 16 weeks of induction therapy with a variety of regimens were randomly assigned to a complete break in therapy with active monitoring versus single-agent capecitabine (1250 mg/m2 twice daily on days 1 through 14 of each 21-day cycle), until progression [118]. Maintenance therapy with capecitabine doubled the time to progression and return to full-dose chemotherapy (median PFS 3.88 versus 1.87 months, HR 0.40, 95% CI 0.21-0.75), but had no impact on median overall survival (14.8 versus 15.2 months, adjusted HR 0.93, 95% CI 0.69-1.27). Furthermore, those assigned to maintenance capecitabine had significant higher rates of cumulative toxicity, especially diarrhea, fatigue, nausea, and palmar plantar erythrodysesthesia, although these were primarily low grade.
ASSESSING TREATMENT RESPONSE — During chemotherapy, response is typically assessed by periodic assay (every one to three months) of serum carcinoembryonic antigen (CEA) levels, if initially elevated, and interval radiographic evaluation (typically every 8 to 12 weeks, or as prompted by a rising CEA level). Although persistently rising CEA levels are highly correlated with disease progression, confirmatory radiologic confirmatory studies should be obtained prior to a change in therapeutic strategy, with the notable exception of confirmed peritoneal carcinomatosis that is not radiographically measurable.
Radiographic response — Radiographic tumor response is usually quantified using Response Evaluation Criteria In Solid Tumors (RECIST) (table 3) [119,120].
Immunotherapy using immune checkpoint inhibitors is increasingly being integrated into the care of patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) mCRC. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors'.)
Individuals treated with immune checkpoint inhibitors for dMMR/MSI-H mCRC can have pseudoprogression [121], and objective response criteria specifically developed for these drugs should be used (eg, immune-modified RECIST [imRECIST] (table 4)). (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)
Serum tumor markers — If initially elevated, a 50 percent or greater declines in CEA from baseline to first restaging can predict disease nonprogression and correlate with favorable long-term outcomes [122]. On the other hand, persistently rising CEA levels (particularly rapidly rising levels [123]) are highly correlated with disease progression [124,125]. However, confirmatory radiologic studies are generally recommended in both settings, particularly if a change in therapeutic strategy is being considered because of a rising CEA. Caution should be used when interpreting a rising CEA level during the first four to six weeks of a new therapy, since spurious early elevation in serum CEA may occur, especially after oxaliplatin [126-128].
Circulating tumor DNA (ctDNA) is the fraction of circulating DNA that is derived from a patient's cancer. Colorectal cancers shed DNA into the blood, and interest in using ctDNA as a surrogate indicator of treatment response has grown as techniques to detect and quantify such DNA have improved. A meta-analysis of 24 studies on patients with mCRC reporting on the predictive or prognostic value of ctDNA concluded that a small or no early decrease in ctDNA levels during treatment was associated with short progression-free and overall survival, but the majority of included studies had a high risk of bias [129].
Few large prospective validation studies have been performed on ctDNA-based treatment monitoring. At least in advanced breast cancer, there are some data that suggest that ctDNA responses do not always parallel imaging-based responses [130], and no studies convincingly demonstrate improved patient outcomes or any cost savings when compared with standard of care monitoring approaches.
Thus, in our view, there is not yet enough known about the mechanisms controlling ctDNA change and how well radiologic responses or CEA changes and ctDNA markers correlate with each other to understand whether ctDNA can replace or supplement periodic assay of CEA or radiologic assessment, and the clinical utility of serial assay of ctDNA during remains uncertain. This position is consistent with a year 2018 joint review of the utility of ctDNA analysis in patients with cancer by American Society of Clinical Oncology and the College of American Pathologists, which concluded that there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer [131]. However, this remains an active area of research with a number of ongoing studies that should impact information on the potential future utility of ctDNA analysis in this setting.
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
●Available agents – Many systemic agents are used to treat metastatic colorectal cancer (mCRC), in combination with other drugs and as monotherapy. These include chemotherapy (fluorouracil [FU], oxaliplatin, irinotecan, among others), antiangiogenic agents, molecularly targeted agents, and immune checkpoint inhibitors. (See 'Systemic therapy' above.)
●Predictive biomarkers – Predictive biomarkers (specific targetable molecular alterations found in colorectal cancer) are often used to select therapy for mCRC. (See 'Predictive biomarkers' above.)
•RAS and BRAF wild-type disease – Patients with mCRC whose tumors are RAS and BRAF V600E wild-type are eligible for treatment with EGFR inhibitors (cetuximab or panitumumab). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'RAS/BRAF wild-type tumors'.)
•RAS mutant disease – RAS mutated mCRC is resistant to EGFR inhibitors (cetuximab or panitumumab) and we do not use them in these cancers, either alone or in addition to chemotherapy. (See 'Impact of RAS status on the use of EGFR inhibitors' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'RAS or BRAF mutant tumors'.)
•BRAF V600E mutant disease – BRAF V600E mutated mCRC shows resistance to EGFR inhibitors, and we do not use them as single agents for these cancers, due to limited benefit in randomized trials. (See 'BRAF mutations' above.)
However, for those with treatment-refractory disease, cetuximab or panitumumab can be combined with encorafenib, a BRAF inhibitor, to overcome tumor resistance to EGFR inhibitors. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, BRAF mutated tumors'.)
•Other clinically relevant biomarkers – Other clinically relevant biomarkers include mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), HER2 expression, and molecular alterations in NTRK. (See 'dMMR or MSI-H tumors' above and 'HER2-positive tumors' above and 'TRK-fusion-positive tumors' above.)
●Treatment goals – Some patients with stage IV disease can be surgically cured of their disease, and the goal of initial chemotherapy is maximal reduction in tumor burden. For most, treatment is palliative, and the goals are to prolong overall survival and maintain quality of life (QOL) for as long as possible. (See 'Treatment goals' above.)
●Timing of therapy – For most patients, we suggest early rather than deferred initiation of chemotherapy, and when possible, before patients become symptomatic (Grade 2C). (See 'Timing of systemic therapy' above.)
●Duration of initial therapy – The optimal duration of initial chemotherapy for unresectable mCRC is controversial. The decision to permit treatment breaks for responding patients must be individualized and based upon the regimen being used, tolerance of and response to chemotherapy, disease bulk and location, symptomatology, and patient preference. For many patients with chemotherapy responsive disease who do not have bulky or severely symptomatic disease, intermittent rather than continuous therapy may mitigate treatment-related toxicity, and does not appear to adversely impact overall survival. (See 'Continuous versus intermittent therapy' above.)
•Patients receiving oxaliplatin – For most patients who are responding to an oxaliplatin-based initial regimen, we suggest discontinuing oxaliplatin before the onset of severe neurotoxicity (usually after three to four months of therapy) while continuing the other agents in the regimen (Grade 2C). Continuing oxaliplatin is a reasonable alternative for patients who have an ongoing response and no clinically significant neuropathy. (See 'Patients receiving oxaliplatin' above.)
A complete break in therapy is also a valid option, particularly if a complete clinical response is observed or for those with small-volume metastatic disease who have a partial response or stable disease to the initial course of chemotherapy. Decision-making should also consider patient preference. In such cases, close follow-up with tumor assessment at two-month intervals and early resumption of chemotherapy at the first sign of progression is recommended. (See 'Complete break in therapy' above.)
•Patients receiving irinotecan – The advantages of intermittent treatment with irinotecan-based regimens are less clear, and for most patients, we continue treatment for as long as tolerability and tumor shrinkage continue. Intermittent treatment is an option for responding patients who desire a break in therapy, particularly for those receiving concomitant therapy with an anti-EGFR agent. (See 'Irinotecan' above.)
●Response assessment – Response to chemotherapy is typically assessed by periodic assay of serum carcinoembryonic antigen (CEA) levels, if initially elevated, and interval radiographic evaluation. Although persistently rising CEA levels are highly correlated with disease progression, confirmatory radiologic confirmatory studies should be obtained prior to a change in therapeutic strategy, with the notable exception of confirmed peritoneal carcinomatosis that is not radiographically measurable. (See 'Assessing treatment response' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Axel Grothey, MD, who contributed to an earlier version of this topic review.
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