Consensus Statements for Clinical Practice in Advanced/Metastatic Colorectal Cancers in India Using a Modified Delphi Method

Abstract

Background

Colorectal cancer (CRC) is one of the most common malignancies across the world and is the fourth most common cancer among men in India as per the Global Cancer Observatory (GLOBOCAN) data 2020. Available data suggest that approximately 30% of patients present with advanced/metastatic CRC (mCRC). This publication summarizes the latest evidence with cognizance of the unique challenges faced in India by medical oncologists treating mCRC.

Methods

A panel of 38 medical oncologists held a meeting in February 2023 and reviewed the evidence available for the management of mCRC. The meeting concentrated on the recognition and management of mCRC with a focus on systemic therapeutic approaches. A literature review of these aspects of management leads to the formation of consensus statements with the level of evidence and grades of recommendation. Statements were evaluated by the modified Delphi method.

Key Content and Findings

The panel comprising 38 experts formulated 51 consensus statements with regard to the management of mCRC, including oligometastatic CRC, unresectable CRC, as well as various systemic therapeutic options. Resource-constrained scenarios, specifically with regard to the economic constraints and availability of drugs in India, were evaluated as part of the statements.

Conclusion

Our consensus statements offer practical, yet evidence-based management guidelines for treating mCRC in the Indian context. Stratifying and recommending treatment options in a resource-constrained scenario is an important aspect of these statements.

Keywords

India specific - metastatic colorectal cancer - modified Delphi consensus

Anant Ramaswamy

Introduction

Colorectal cancer (CRC) is the third most common malignancy across the world, accounting for approximately 10% of newly diagnosed cancer patients based on the 2020 GLOBOCAN data.[1] In India, CRCs account for approximately 4.9% of all new cancer patients and are responsible for about 4.5% of all cancer-related deaths in the country.[2] [3] Data from Indian cancer registries also suggest that this incidence is increasing. Although information is limited to small cohort studies, evidence also suggests that a greater proportion of CRCs present as advanced/metastatic CRCs (mCRC) (28%) in India as compared to the United States and Europe (15–20%).[4]

Besides increasing systemic therapeutic options, there is an increasing integration of liver-directed therapies in patients with liver-limited metastases as well as cytoreductive surgeries in patients with metastases limited to the peritoneum. This has resulted in multiple questions and options with regard to sequencing and timings of surgical/radiotherapeutic/radiological interventions while maintaining the backbone of systemic therapy. Further nuances include duration of mandated treatment in the metastatic and oligometastatic scenarios as well as dealing with the remarkable improvements and responses seen with immunotherapy in microsatellite-instability—high (MSI-H) CRC.

Data from India are scarce, with small single-institution data showing survivals of approximately 18 months.[5] [6] This is a reflection of diverse reasons, of which one of the most important is the logistic and financial constraints patients and clinicians face when treatment is being considered. A significant proportion of patients in India pay for treatment “‘out of pocket,” though there is increasing penetration of personal and state insurances. Therefore, it is incumbent on treating clinicians to use appropriate options which may not the “best” standard of care as defined by wealthier nations, but an “acceptable” standard of care where resources are at a premium. There are a number of exhaustive guidelines from organizations such as ESMO, ASCO, and the previously published Indian Council of Medical Research (ICMR) guidelines which offer detailed treatment options for mCRC—the aim of the current consensus guidelines is not to recapitulate or repeat the statements from these guidelines.[7] [8] [9] The current guidelines aim at offering medical oncologists practicing in India a primer on how to treat these cancers according to the varying scenarios noted in India. This entails accepting that there are logistic constraints for the management of mCRC patients in India and certain options of treatment are not always based on available phase III randomized control trials, but based on parameters which are practical and pragmatic.

Methods

In an online meeting held in December 2022, sixteen medical oncologists conducted and went through a series of presentations on the management of mCRC. The presented evidence was then further reviewed and condensed into a set of consensus statements. The statements were primarily prepared by two of the authors, while two authors provided additional inputs on the same. All the prepared consensus statements were then reviewed in an in-person meeting in February 2023 by a group of 38 medical oncologists. Attempts were made to involve clinicians from publicly funded hospitals and private healthcare institutions which were high-volume centers for the management of CRC. Each statement was assessed as Agree or Disagree with voting being performed anonymously. A statement was considered as “Accepted” if greater than 70% of the group voted to agree with the statement. In cases where a consensus was not met, statements were revised and voted on again till a consensus was reached. The group evaluated each statement's level of evidence and grade of recommendation as per IDSA-US Public Health Service Grading System (USPHS). As per this system, the letters A to E signify the strength of the recommendation for or against a preventive or therapeutic measure, while the Roman numerals I to III indicate the quality of evidence supporting the recommendation.[10] All recommendations were graded as per this classification excepting those with regard to radiological studies, which was voted upon as “recommended” or “not recommended” only. Aspects with regard to radiological staging and radiotherapy were independently assessed and separately modified based on inputs from a dedicated gastrointestinal radiologist and radiation oncologist from Tata Memorial Hospital, Mumbai.

Consensus Statements

• 1. Radiological assessment

  • Statement 1.1: The baseline imaging for a suspected mCRC includes:

    • Contrast-enhanced computed tomography (CECT) (thorax, abdomen, and pelvis)—recommended.

    • PET CECT—recommended.

  • Statement 1.2: The baseline imaging for a suspected mCRC patient in a resource-constrained setting will be:

    • CECT TAP—recommended.

    • PET CECT—can be considered if a good quality CECT (TAP) has already not been done.

  • Statement 1.3: The additional role of a PET CT scan beyond a well-conducted CECT (thorax, abdomen, and pelvis) in advanced unresectable CRC for staging purposes is:

    • Not recommended as there is limited additional benefit for doing a PET CT scan in this scenario.

  • Statement 1.4: MRI (with contrast) of the abdomen as an investigation for the evaluation of the liver beyond the information available in a well-conducted CECT (e.g., triple phase) of the abdomen in a patient with unresectable liver metastases and CRC:

    • Not recommended.

  • Statement 1.5: MRI (with contrast) of the abdomen as an investigation for evaluation of the liver beyond the information available in a well-conducted CECT of the abdomen (e.g., triple-phase CT) in a patient with potentially resectable or addressable liver/lung metastases and CRC.

    • Can be considered if required after multidisciplinary discussion for planning for surgery, radiotherapy, interventional procedures like radiofrequency ablation (RFA)/TACE/TARE, though not mandatory.

  • Statement 1.6: MRI of the pelvis as an investigation for the evaluation of the rectum beyond the information available in a well-conducted CECT of the abdomen and pelvis in a patient with mCRC.

    • Not routinely recommended in patients not planned for local radiotherapy or surgery.

    • Can be considered if being planned for radiotherapy to rectum.

    • Should be considered if being planned for surgery of the rectal primary.

  • Statement 1.7: MRI of the pelvis as an investigation for evaluation of the rectum beyond the information available in a well-conducted CECT of the abdomen and pelvis (or whole-body PET CT) in a patient with oligometastatic CRC (limited metastases with the potential for resection) being treated with possibly curative intent.

    • Recommended if being planned for radiotherapy and/or surgery of the primary rectal tumor.

Accurate radiological assessment at baseline in suspected mCRC assumes utmost importance, especially in patients with limited and potentially resectable metastases. Ruling out the presence of multiple unresectable metastases in the liver or other organs at baseline is the first step in planning for resection of colorectal liver metastases (CRLMs). This step is crucial to avoid unnecessary resections in patients who otherwise have widely disseminated multiorgan metastases. However, at the same time, accurate baseline staging would justify major, curative liver resections as the 10-year survival rate of mCRC patients with resectable liver metastases who undergo curative liver resections approximately 40 to 50%.[11]

A well-conducted triphasic CECT of the thorax, abdomen, and pelvis as baseline imaging has an accuracy of about 95% in the detection of distant metastases.[12] [13] [14] Its low cost (with the caveat of decreasing costs associated with the performance of PET-CT as opposed to the CT scan of the thorax, abdomen, and pelvis), widespread availability, and high anatomic resolution make it the imaging of choice.[15] However, a CT cannot accurately discriminate neoplastic disease from nonmalignant changes like scars and inflammation (especially with coexisting liver parenchymal disease) and may miss small tumours.[16]

The major advantages of a PET scan over and above a well-conducted triphasic CECT TAP include total body coverage, including bone and a higher sensitivity in the detection of hepatic and lung metastases.[17] [18] FDG PET has an accuracy of 99% in the detection of liver metastases with a sensitivity close to 100% and a specificity of 98%.[18] There are many studies that have shown that FDG PET changes the stage and alters the management in up to one-third of the patients.[19]

The disadvantages of a PET scan include high background activity of liver, which may make detection of very small liver metastases difficult as well as poor spatial resolution of FDG PET, which occasionally makes surgical planning difficult.

In resource-constrained settings where a PET scan may not be available, a well-conducted triphasic CECT of the abdomen is sufficient as a baseline scan to take surgical decisions regarding metastasectomy. In scenarios where CT scans are of inadequate quality or available CT plates do not convey the requisite information (despite a well-conducted CECT), efforts must be made to obtain Digital Imaging and Communications in Medicine (DICOM) images before considering an FDG PET CECT scan. However, if efforts to procure adequate images are unlikely, an FDG PET CECT scan may be offered in light of its superior sensitivity in picking up smaller metastases.

The general preference for a triphasic CECT scan of the abdomen as the imaging modality of choice for evaluation of liver metastases from mCRC is not wholly necessary unless a hyper vascular lesion suggestive of a neuroendocrine tumor (wherein a biphasic scan comprising arterial and venous phases is adequate) or a cholangiocarcinoma/hepatocellular carcinoma (wherein a triphasic scan comprising arterial, venous, and portal phases is required) is suspected. A single-phase CT scan is adequate for staging of the liver in patients with mCRC with liver metastases; however, surgeons may require mapping of the arterial anatomy post-induction/neoadjuvant therapy and hence may consider triphasic scans. CT scans are also widely available and cheaper than MRI in resource-constrained settings. However, for detection and characterization of smaller lesions, MRI may be superior to CECT and FDG PET scans.[20] Evidence is accumulating to show that MRI provides superior anatomic delineation, leading to better localization of hepatic and vascular invasion.[21] [22] MRI scans can be considered as an additional imaging modality (pre- or/and post-neoadjuvant intent therapy) in patients with potentially resectable/addressable liver metastases who are planned for local liver-directed therapies (LDT). Although this is not mandatory, it may help provide better anatomical information regarding the liver lesions that may be therapeutically relevant, may resolve diagnostic dilemmas with respect to some indeterminate liver lesions, and also may help definitively rule out disseminated, small metastatic lesions in the liver that would preclude local treatments (the authors recognize the results of the CAMINO trial which clearly suggest an almost mandatory role of an MRI of the liver in patients with CRLM, though the current recommendations were formed prior to the publication of the complete results of the trial).[23]

MRI is an important pelvic imaging modality in carcinoma rectum due to the excellent soft tissue contrast that it provides between the tumor and other soft tissues on T2-weighted images, which is superior to that provided by a CECT.[24] [25] The sensitivity and specificity of MRI in rectal cancer are heavily operator dependent.[26] Parameters like level of the tumor from the anal verge, T staging, and N staging need to be assessed for planning the type of surgery, and requirement of preoperative chemoradiation. Assessment of risk of peritoneal perforation, feasibility of a total mesorectal excision (TME) in middle rectal, and relationship of the tumor to puborectalis muscle to understand the feasibility of a sphincter-preserving surgery are usually done with an MRI of the pelvis. The high signal intensity of mesorectal fat and the low signal intensity tumor provide a natural, intrinsic contrast in assessing the tumor extent on T2-weighted images on MRI.[27] [28] [29] The excellent soft tissue resolution that MRI provides with intrinsic contrast helps in accurate T staging that ranges anywhere between 60 and 95%, depending on the section thickness, use of appropriate coils, and the expertise of the reporting radiologist.[28] [29] [30] Accurate preoperative assessment of early-stage tumors with clear distal and radial margins helps obviate the need for irradiating the sphincter that leads to better postoperative sphincter function and lower rates of anastomotic site breakdown.[31] In view of superior anatomical delineation, MRI of the pelvis in addition to a well-conducted CECT of the abdomen and pelvis is recommended in those patients with either metastatic or oligometastatic rectal cancer who are being considered for a local radiation or a curative surgical resection of the rectal primary along with metastasectomy (in case of oligometastatic rectal cancer).

• 2. Assessment of biomarkers

  • Statement 2.1: All patients with mCRC (without resource constraints) should have at least the following biomarkers performed at diagnosis:

    • ALL-RAS (KRAS and NRAS) by polymerase chain reaction (PCR)—1A.

    • BRAF by PCR—1A.

    • MSI (by PCR) or MMR (by immunohistochemistry [IHC])—1A.

    • HER2 (by IHC or FISH)—2B.

  • Statement 2.2: Patients with mCRC with significant resource constraints can be considered for the following biomarkers (if validated, testing facility exists in the institution/vicinity):

    • ALL-RAS (KRAS and NRAS) by PCR—1A.

    • BRAF by PCR—1A.

    • MSI (by PCR) or MMR (by IHC)—1A.

  • Statement 2.3: The use of next-generation sequencing (NGS) as an initial investigation for the establishment of RAS/RAF/MMR/HER2 status in a patient without resource constraints:

    • IIIB.

  • Statement 2.4: The use of NGS as an initial investigation for the establishment of RAS/RAF/MMR/HER2 status in a patient with resource constraints:

    • IIID.

Identification of RAS mutations forms one of the cornerstones of biomarker analysis in the management of mCRC. Retrospective analysis and prospective trials have clearly suggested that cetuximab (anti-EGFR-directed monoclonal antibody) had activity in RAS wild type (RAS-WT) tumors only.[32] Similar observations were made for the use of another anti-EGFR monoclonal immunoglobulin G2 antibody, panitumumab.[33] KRAS exon 2 activating mutations occur in approximately 37 to 45% of CRCs.[34] [35] [36] In addition to the ∼40 to 45% of patients with exon 2 KRAS mutations, an additional 9 to 10% of CRC patients carry alternative RAS mutations. These include 4 to 5% NRAS mutations (codons 12 or 13 on exon 2 and codons 59 or 61 on exon 3) and another 5% with a non-exon 2 KRAS mutation (codons 59 or 61 on exon 3 and codons 117 or 146 on exon 4).[37] The predictive value of these “non-KRAS exon 2” RAS mutations has been evaluated across several of the phase III cetuximab or panitumumab-based clinical trials. No benefit was noted with the addition of either cetuximab or panitumumab to either irinotecan or oxaliplatin-based chemotherapy across first, second, and refractory lines of therapy.[38] [39] These results have triggered a change in practice that mandates treatment with anti-EGFR agents to patients with extended left-sided RAS wild-type tumors only (absence of exon 2, 3, or 4 KRAS or NRAS mutations).

BRAF mutations are an independent poor prognostic marker for metastatic colorectal carcinoma.[40] [41] These mutations occur in 5 to 12% of mCRC (with an increased prevalence in right-sided mCRC), and the most common mutation is the single substitution missense mutation V600E.[42] While the negative prognostic impact of BRAF mutation has been confirmed across various studies, debate continues regarding its value as a predictive marker of response to anti-EGFR therapy. It has been postulated that treatment with anti-EGFR therapy may be of limited value in these patients in view of alterations in MAPK pathway.[43] In a retrospective analysis of 113 patients treated with cetuximab or panitumumab, 11/79 (∼14%) patients of KRAS WT were found to have BRAF V600E mutations, and none of them responded.[44] In the second-line treatment of mCRC, the PICCOLO trial reported on a subgroup of 131 patients with BRAF mutant mCRC randomized to second-line panitumumab plus irinotecan or irinotecan alone. Patients with BRAF mutation had a trend toward a worse overall survival with the addition of panitumumab (HR = 1.4; [0.82–2.39]).[45] On the other hand, a combined analysis of the CRYSTAL and OPUS studies showed a nonsignificant trend in RR, progression-free survival (PFS), and overall survival (OS) with the addition of cetuximab to FOLFIRI in BRAF mutant patients.[46] While these data are limited by the small portion of patients with BRAF mutation in each of the above studies, they suggest a lack of a clinically meaningful improvement in OS with the integration of anti-EGFR therapy with chemotherapy or as monotherapy in mCRC with BRAF mutations. This makes BRAF testing essential before starting any targeted therapy for patients with mCRC.

The landmark study by Le and colleagues, evaluating pembrolizumab (anti-PD1 antibody) for patients with deficient mismatch repair protein (dMMR) status, showed excellent, durable overall response rates (ORRs) in the cohort of patients with mCRC.[47] The MMR system helps heal the DNA breaks during replication; a deficiency in this machinery causes microsatellite instability.[48] Testing for mismatch repair-deficient CRC can be conducted using IHC, PCR, or NGS. While PCR is typically regarded as the gold standard, the concordance between PCR and IHC exceeds 97%.[49] In practical application, IHC is commonly utilized as the standard approach. dMMR tumors (or MSI-H) are known to have increased neoantigen load and upregulation of tumor-infiltrating lymphocytes, thus increasing their responsiveness to immune checkpoint blockade.[50] dMMR (or MSI-H) occurs in approximately 5% of all mCRCs. Patients with mCRC and dMMR status have been shown to have less than expected survival with traditional chemotherapy in comparison to patients with proficient MMR tumors.[51] Based on the landmark study, pembrolizumab initially (November 2015) received U.S. FDA breakthrough therapy designation for the treatment of pretreated MSI-H mCRC, and has recently shown efficacy as first-line therapy as well.[52]

One of the mechanisms by which anti-EGFR therapy fails in RAS wild-type mCRC patients is the development of HER2 alterations (amplification or mutation) and facilitating bypass signaling.[53] HER2 amplification is associated with poor response to anti-EGFR therapy and shorter PFS, suggesting inherent resistance.[54] HER2 alterations occur in 4 to 5% of all mCRC patients, predominantly left-sided tumors and are mutually exclusive with RAS mutations. The first real proof-of-concept study was HERACLES phase II trial, which showed excellent clinical activity for dual HER2 blockade with trastuzumab and lapatinib.[55] It is important to note that the study included strong HER2-positive tumors by taking into consideration a higher cutoff of >50% as compared to a 10% cutoff usually taken in breast cancers. Multiple other anti-HER2 targeting strategies have been studied with more or less similar positive outcomes.[56] [57] Although currently testing for HER2 in newly diagnosed mCRC is not standard of care, with more availability of broad NGS-based testing, identifying this small definite subgroup may be beneficial if treated with the novel targeted therapies.

Major benefits of performing NGS or CGP (comprehensive genomic profiling) over single-gene techniques are beyond classical hotspots; we can find additional rare RAS alterations which can directly impact our selection of anti-EGFR therapy. It also allows us to identify non-V600E BRAF mutations, some of which might also impact our treatment decisions.[58] A very small but intriguing subset of mCRC patients have fusion genes resulting from complex rearrangements of protein kinase.[59]

Liquid biopsy, specifically ctDNA analysis, overcomes the limitations of inadequate tissue availability in pretreated settings, by capturing the overall genomic mutational landscape of the disease from blood samples. ctDNA demonstrates high sensitivity (≥93%) for detecting mutations like RAS in treatment-naive patients, even at low variant allele frequencies (≥0.18%).[60] This is an emerging diagnostic modality which will be increasingly used in the near future.

• 3. mCRC—unresectable setting

  • 3.1: First-line systemic therapy—chemotherapy

    • 3.1.1: The following chemotherapeutic regimens can be considered as first-line therapy in patients reasonably fit for chemotherapy (non-frail, non-elderly, limited or controlled comorbidities).

      • FOLFOX/CAPOX—1A.

      • FOLFIRI—1A.

      • CAPIRI—2B.

      • FOLFIRINOX/mFOLFIRINOX/FOLFOXIRI (ECOG PS 0-1)—1A.

    • 3.1.2: The IROX regimen can be considered in patients intolerant to 5-fluorouracil (5-FU)-based regimens or those with a pharmacologically relevant dihydropyrimidine dehydrogenase (DPD) enzyme mutation as per the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for DPD genotype and fluoropyrimidine dosing.

      • IIB

    • 3.1.3: Tegafur–uracil can be used as a substitute for 5-FU in combination with irinotecan or oxaliplatin as part of doublet chemotherapeutic regimens in mCRC.

      • IIB

    • 3.1.4: S1 can be used as a substitute for 5-FU or capecitabine in combination with irinotecan or oxaliplatin as part of doublet chemotherapeutic regimens in mCRC.

      • IIB

    • 3.1.5: S1 can be used as a substitute for 5-FU in combination with irinotecan or oxaliplatin as part of doublet chemotherapeutic regimens in patients who have had significant cardiotoxicity with 5-FU.

      • IVB

    • 3.1.6: In elderly and/or frail (unfit for full-dose chemotherapy) patients, the following options may be considered (with or without targeted therapy):

      • 5-FU (1A).

      • Capecitabine (1A).

      • FOLFOX (1B).

      • CAPOX (1B).

      • FOLFIRI (2B).

      • TAS plus bevacizumab (3B).

Cytotoxic chemotherapy remains the cornerstone of first-line systemic therapy for the majority of patients with mCRC.

Deciding upon the chemotherapy backbone and the regimen's intensity (mono, doublet, or triplet) involves a comprehensive evaluation of patient-related factors, including age, performance status, comorbidities, frailty, organ function, and individual preferences (intravenous vs. oral administration). Subsequent considerations involve disease-related factors such as tumor sidedness, disease burden, and the rate of tumor growth, which may impact the general condition of the patient. Additionally, treatment-related factors such as the risk of cardiotoxicity, incidence of peripheral neuropathy, tolerance to previous regimens, and prior exposure to adjuvant chemotherapy must be carefully taken into account.

For nearly four decades until the late 1990s, the fluoropyrimidine drug 5-FU stood as the sole therapeutic agent for treating mCRC. The emergence of oxaliplatin and irinotecan, used in combination with each other and 5-FU analogs, has further increased options and survival in this group of cancers.

Monotherapy

FOCUS4, CAIRO5, and FFCD 2000-056 were the three Phase III randomized studies that aimed to address the question of whether sequential treatment strategies were better than combination chemotherapies in terms of minimizing adverse events without compromising survival.[61] [62] [63] Overall, these studies indicated that the sequential approach, starting with first-line 5-FU alone, is noninferior in outcomes compared to combination chemotherapy. However, they need to be interpreted with caution as the response rates and PFS were superior with the combination approach in all three studies, and also there was a relatively lower exposure of patients to all three cytotoxic drugs in these studies (ranging from 16 to 55%). Therefore, adopting a sequential strategy might result in lower disease control, posing a risk of fewer patients being exposed to all three drugs and, consequently, potentially lower survival rates.

In our opinion, monotherapy should be reserved for patients who are not suitable for doublet chemotherapy due to factors such as elderly age, comorbidities, frailty, and/or contraindications to cytotoxic agents. Addition of targeted therapy agents like bevacizumab and anti-EGFR therapies to the single-agent chemotherapy backbone further improves the efficacy modestly and is dealt with later.

Doublet Chemotherapy

The primary backbone for systemic chemotherapy in patients with mCRC continues to be doublet chemotherapy. There are two main categories of regimens: those based on oxaliplatin and those based on irinotecan, with further distinctions based on the administration of 5-FU, either orally (via 5-FU analogs such as capecitabine, S1, or UFT) or intravenously. Two randomized phase 3 studies have been published comparing the FOLFOX and FOLFIRI regimens, revealing similar efficacy in terms of response rates (around 55%), PFS (approximately 8 months), and overall survival (approximately 21 months).[64] [65] As expected, both regimens have a differential safety and adverse event profile. For patients who opt to avoid central venous line access or desire a longer interval between chemotherapy, oral 5-FU analog-based chemotherapy regimens featuring capecitabine, S1, or UFT can be considered. Numerous randomized phase 3 studies, along with a meta-analysis, have demonstrated the comparable effectiveness and safety of capecitabine and oxaliplatin (CAPOX/XELOX) when compared to infusional 5-FU/folinic acid plus oxaliplatin (FOLFOX). Notably, while the FOLFOX regimen exhibited a higher incidence of neutropenia, CAPOX/XELOX was associated with higher incidences of thrombocytopenia, diarrhea, and hand–foot syndrome.[66] [67] [68] [69]

Triplet Chemotherapy

Several studies have demonstrated the synergistic clinical activity achieved by combining all three cytotoxic agents—fluoropyrimidine, oxaliplatin, and irinotecan.[70] [71] The exposure of mCRC patients to this trio of agents during the course of their treatment has been shown to provide the best chances of survival.[72] These findings prompted the development of the FOLFOXIRI regimen (folinic acid, 5-FU, oxaliplatin, and irinotecan) for the initial treatment of mCRC patients.

Two randomized studies comparing FOLFOXIRI with FOLFIRI in mCRCs showed contrasting results: the GONO19 study showed statistical improvement in PFS and OS, while the HORG 20 study did not.[73] [74] Despite these discordant results, a systematic review and meta-analysis of randomized controlled trials, comparing triplet chemotherapy to doublet chemotherapy (specifically FOLFOX or FOLFIRI) as the initial treatment for mCRC, have revealed a relevant increase in efficacy with an expected increase in toxicities as well.[75] There was a 25% relative risk reduction of death and a 27% relative risk reduction in disease progression, compared with the doublet regimens. However, this improvement came at the cost of higher rates of grade 3 adverse events.[21]

In the era of targeted therapy, the FOLFOXIRI triplet regimen has been successfully combined with bevacizumab, further strengthening its clinical utility.[76]

Due to its synergistic activity and impressive response rates, the FOLFOXIRI triplet regimen is the preferred choice for patients where conversion therapy is being considered with the intention of resection, or when the disease burden is substantial, accompanied by a rapid growth rate that threatens to deteriorate the patient's general condition. However, it is not recommended for administration in patients older than 75 years or those patients younger than 75 years with an ECOG PS > 0. Preferably, it should be avoided in cases where patients have prior exposure to oxaliplatin in the adjuvant setting.

Older patients with mCRC (> 60 years of age as per Indian criteria) should be considered for a comprehensive geriatric assessment (CGA) if feasible before being planned for systemic therapy. Multiple components of the CGA and the CGA itself have proven to have correlations with adverse events as well as survival outcomes in mCRC.[77] [78] [79] [80] The CGA can be used as an adjunct in planning treatment for older patients with CRC. Additionally, randomized controlled trials in patients ≥70 years (with or without frailty) have shown similar survival outcomes with 5-FU (on analogs) based therapy in comparison to combination therapy, and this needs to be considered while planning for therapy in these patients.[81] [82]

• 3.2: First-line systemic therapy—Targeted therapy and maintenance.

  The rationale for the use of targeted therapy in mCRCs, especially in RAS wild-type tumors, has heavily depended on dividing tumors into right-sided and left-sided CRCs. Right- and left-sided colon cancers have embryologically different origin. While the former arises from the midgut, the latter arises from the hindgut.[83] Left-sided tumors generally have better outcomes as compared to the right-sided ones.[84] Recent meta-analysis of 13 randomized clinical trials showed significantly worse PFS and OS for the right-sided metastatic colon cancers irrespective of the biological therapy.[85] These differences in outcomes can be attributed predominantly to different molecular signatures occurring on each side. Data from The Cancer Genome Atlas (TCGA) database and PETACC-3 adjuvant trial showed predominant epidermal growth factor receptor (EGFR) pathway upregulation in the left-sided cancers. Even when RAS and RAF mutations were excluded, gene signature patterns were considerably different between right and left colon cancers.[86] A retrospective study of ∼ 2,500 CRC specimens showed statistically higher prevalence of BRAF, PIK3CA, CTNNB1, ATM, and PTEN in right-sided colon cancer, while more patients with left-sided primary disease had TP53 and APC gene alterations.[87]

  • 3.2.1: The following targeted therapeutic options in combination with first-line chemotherapy are considered in patients (without resource constraints) with left-sided tumors (ALL RAS WT, BRAF WT):

    • FOLFOX plus anti-EGFR-directed antibody (1A).

    • FOLFIRI plus anti-EGFR-directed antibody (1A).

    • FOLFIRI/FOLFOX plus bevacizumab (1B).

    • FOLFOXIRI/modified FOLFIRINOX plus bevacizumab (2A).

    • CAPOX plus bevacizumab (1B).

    • CAPOX plus weekly cetuximab (3B).

  • 3.2.2: The following targeted therapeutic options in combination with first-line chemotherapy are considered in patients (with resource constraints and not feasible for anti-EGFR-directed antibodies) with left-sided tumors (ALL RAS WT, BRAF WT):

    • FOLFIRI/FOLFOX plus bevacizumab (1A).

    • FOLFOXIRI/modified FOLFIRINOX plus bevacizumab (1A).

    • CAPOX plus bevacizumab (1A).

    • FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI or modified FOLFIRINOX alone (1A).

  • 3.2.3: The following targeted therapeutic options in combination with first-line chemotherapy are considered in patients (without resource constraints) with left-sided tumors (ALL RAS WT, BRAF WT):

    • FOLFOXIRI/modified FOLFIRINOX plus anti-EGFR-directed antibody (no recommendation as consensus not achieved).

  • 3.2.4: The following targeted therapeutic options in combination with first-line chemotherapy are considered in patients (without resource constraints) with right-sided tumors and unresectable metastatic sites (not being considered for downstaging to potential resection) of disease (ALL RAS WT):

    • FOLFIRI/FOLFOX plus bevacizumab (1A).

    • FOLFOXIRI/modified FOLFIRINOX plus bevacizumab (1A).

    • CAPOX plus bevacizumab (1A).

    • FOLFOX plus anti-EGFR-directed antibody (1C).

    • FOLFIRI plus anti-EGFR-directed antibody (1C).

Post hoc analysis of several studies showed primary tumor location to have an important predictive effect on clinical outcomes when treated with EGFR or VEGF inhibitors. In a subgroup analysis in the CRYSTAL and FIRE-3 study, the addition of cetuximab to FOLFIRI had a modest additional benefit in PFS and OS (statistically not significant) if the primary tumor was located on the right side.[88] Similar observations were made in PRIME study evaluating panitumumab with or without FOLFOX chemotherapy. PFS and OS advantage of anti-EGFR therapy was restricted to patients with left-sided mCRC.[89] CALGB/SWOG 80405 studied cetuximab versus bevacizumab along with doublet chemotherapy and found poorer outcomes with cetuximab plus chemotherapy in right-sided tumors. Although all analysis is post hoc in nature, these are clearly consistent among all major first-line clinical trials. NCCN/ASCO recommends against the use of EGFR inhibitors for the first-line treatment in right-sided mCRC irrespective of RAS status.

On the other hand, primary tumor location does not seem to be predictive of benefit from bevacizumab treatment in patients with mCRC. Data from Australian prospective multicenter mCRC registry studying 926 patients showed improved PFS with addition of bevacizumab to chemotherapy irrespective of primary tumor location (right side: 8.5 vs. 4.9 months {HR = 0.46, p < 0.001} in favor of chemotherapy + bevacizumab (left side: 10.5 vs. 7.5 months {HR = 0.71, p = 0.006} in favor of chemotherapy + bevacizumab).[90]

In a recent retrospective exploratory subgroup analysis of two randomized phase III studies with bevacizumab in the first-line treatment of mCRC, Loupakis et al showed that there was no effect of primary tumor location on efficacy of bevacizumab.[91] Therefore, bevacizumab remains targeted therapy of choice in patients with right-sided mCRC irrespective of RAS status.

Individual patient data meta-analysis of six major randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK, and 20050181) has clearly reported a significant improvement in RR (OR: 2.12, 95% CI: 1.77–2.55), PFS (HR: 0.78, 95% CI: 0.70–0.87, p < 0.001), and OS (HR: 0.75, 95% CI: 0.67–0.84, p < 0.001) in the anti-EGFR-containing arms.[92] Addition of bevacizumab to chemotherapy in the treatment of left-sided mCRC also improves all efficacy endpoints; however, the magnitude of benefit is less as compared to anti-EGFR-based therapy. Hence, one may consider using bevacizumab-based first-line treatment for left-sided mCRC especially if the patient has concerns about skin toxicity or costs of the treatment, but clearly anti-EGFR therapy remains the treatment of choice for left-sided mCRC. The paradigm study, a phase III trial comparing panitumumab to bevacizumab-based chemotherapy in predominantly left-sided, all RAS wild-type mCRC, demonstrated a statistically significant OS advantage with panitumumab-based therapy. However, the degree of benefit observed was significantly less compared to prior post hoc analyses.[93]

• 3.2.6: The treatment options as initial therapy in patients with mCRC with RAS mutant and/or BRAF mutant (V600E) status are the following:

  • FOLFOXIRI/mFOLFIRINOX plus bevacizumab (2A).

  • FOLFOX/FOLFIRI/CAPOX plus bevacizumab (2A).

  • mFOLFIRINOX/FOLFOXIRI (2B).

  • FOLFOX/FOLFIRI/CAPOX (2B).

As previously discussed in the RAS biomarkers section, anti-EGFR therapy's role in the first-line treatment for RAS mutant mCRC is generally limited and not recommended. However, two exceptions are currently under investigation. Firstly, the potential of sotorasib with panitumumab is being explored for mCRC patients with the KRAS G12C mutation, showing promise in initial case reports and phase I studies.[94] Secondly, for those with a BRAF mutation, the combination of cetuximab with encorafenib has gained FDA approval for second-line treatment and beyond. However, its recommendation for first-line use awaits completion of the BREAKWATER study.[95]

Bevacizumab is a recombinant humanized monoclonal antibody specifically binding and blocking all human vascular-endothelial growth factor (VEGF)-A isoforms. In the landmark trial AVF2107, Hurwitz and colleagues compared irinotecan, bolus fluorouracil, and leucovorin (IFL) with or without bevacizumab in the first-line treatment of mCRC and found significant improvement in ORR, PFS, and OS.[96] Several subsequent phase III randomized clinical trials showed consistent improvement in PFS; however, OS was most pronounced in the setting of fluoropyrimidines monotherapy.[97] [98] [99] In the individual patient data meta-analysis of seven RCTs (AVF2107, NO16966, ARTIST, AVF0780, AVF2192, AGITG MAX, and E3200), KRAS mutational status was available in 530 patients (14.1% of the total study population), which showed benefit of addition of bevacizumab irrespective of KRAS status.[100] Therefore, bevacizumab remains targeted therapy of choice in patients with RAS mutant mCRC.

• 3.2.7: The use of anti-HER2-directed therapy is considered as follows.

  • Addition of trastuzumab alone to chemotherapy (2C).

  • Addition of trastuzumab and tucatinib in chemotherapy-refractory HER2-positive mCRC (2A).

  • Pertuzumab (with trastuzumab) and T-DM1 (2C).

  • Trastuzumab deruxtecan in chemotherapy-refractory HER2-positive mCRC (2A).

For all practical purposes, HER2 positivity is considered for those patients who are scored as 3+ by IHC, show HER2 amplification by fluorescent in situ hybridization (FISH) or HER2 amplifications as detected by NGS. A majority of the treatment options for patients with HER2-positive mCRCs have been explored in the pretreated scenario, though upfront testing for HER2 status is encouraged by the guidelines. Trastuzumab and deruxtecan, pertuzumab and T-DM1, and trastuzumab and tucatinib are options that can be considered in this scenario.[55] [57] [101] [102]

• 3.2.8: In patients with mCRC (RAS mutant), patients who have achieved at least stable disease after 4 to 6 months of chemotherapy (with or without bevacizumab) can be considered for the following:

  • Observation (1A).

  • Capecitabine or infusional 5-FU monotherapy (1A).

  • Combination of infusional 5-FU/capecitabine plus bevacizumab (1A).

  • Bevacizumab alone (1D).

• 3.2.9: In patients with mCRC (RAS wild type), patients who have achieved at least stable disease after 4 to 6 months of chemotherapy (with or without cetuximab/panitumumab) can be considered for the following:

  • Observation (1A).

  • Capecitabine or 5-FU monotherapy (1A).

  • Combination of 5 FU plus cetuximab/panitumumab(1A).

  • Cetuximab (1C).

  • Panitumumab monotherapy (1D).

Continuation of first-line chemotherapy until disease progression is an issue, especially in the setting of oxaliplatin-based treatment in view of cumulative neurotoxicity. Several studies have analyzed treatment breaks (also known as “treatment holidays”) versus maintenance strategies in first-line treatment of mCRC, especially in the setting of oxaliplatin-based doublet chemotherapy. Early indications of the feasibility of intermittent treatment came from OPTIMOX trials, suggesting complete treatment breaks may have inferior outcomes and the patients receiving maintenance therapy had longer PFS.[103] [104] In the era of biological therapy, first indications of continued maintenance therapy came from NO16966 trial, with conflicting results from later studies.[105] [106] [107] In the CAIRO-3 study, patients were randomized if they had at least stable disease after six cycles of CAPOX plus bevacizumab (CAPOX-B) to the continuation of capecitabine with bevacizumab versus observation with the primary endpoint being PFS2 (defined as progressive disease after re-introduction of CAPOX-B). The study achieved its primary endpoint of improved PFS2 (8.5 months in the observation group and 11.7 months in the maintenance group [HR: 0.67, 95% CI: 0.56–0·81, p < 0·0001]), though overall survival was only numerically improved with the maintenance strategy.[105] The SAKK 41/06 phase III trial also suggested that observation was not noninferior to a maintenance strategy using bevacizumab (time to tumor progression: 2.9 vs. 4.1 months, HR: 0.74 [95% CI: 0.58–0.96] in favor of maintenance therapy). The German AIO 0207 study, another noninferior study design, evaluated three follow-up strategies after 24 weeks of oxaliplatin-based doublet induction chemotherapy (observation, bevacizumab alone, and bevacizumab + fluoropyrimidine) with a primary endpoint of time to failure of strategy. Though only a small number of patients (36%) went on for re-induction chemotherapy as compared to CAIRO 3 study (∼60%), PFS was better when both the maintenance arms were compared to observation alone.[106]

A meta-analysis of 14 prospective studies done between 2009 and 2017 showed a small but definite and statistically significant PFS benefit for use of maintenance therapy versus observation, although no overall survival benefit was seen.[108]

The role of anti-EGFR therapies in the maintenance setting for mCRC has recently evolved after retrospective studies and the results of the recently published PANAMA study.[109] [110] The PANAMA phase II study evaluated the question of panitumumab with 5-FU versus 5-FU alone in a maintenance setting and showed an improvement in PFS, though without significant differences in OS.[69] In conclusion, data supporting maintenance strategy in mCRC is strong for fluoropyrimidine with or without bevacizumab or panitumumab. All patients receiving oxaliplatin-based induction chemotherapy should be considered for maintenance therapy, although individualization and discussion with the patient is essential, considering that “treatment holidays” for a limited time can be acceptable for any patient with indolent and asymptomatic.

• C.3.3: First-line systemic therapy—Immunotherapy.

  • 3.3.1: In patients (without resource constraints) with mCRC with dMMR (MSI-H) status, the following options are considered:

    • Pembrolizumab (1A).

    • Nivolumab plus low-dose ipilimumab (3A).

    • Nivolumab alone (3B).

  • 3.3.2: In patients with mCRC with dMMR (MSI-H) status and nonfeasibility of immunotherapy due to resource constraints, chemotherapy with or without targeted therapy as for pMMR (MSI-S) will be considered.

    • 1B

  • 3.3.3: In patients with mCRC with dMMR (MSI-H) status (with resource constraints), based on extrapolation from other tumor sites and expert consensus, low-dose immunotherapy (possibly weight-based and other options) can be considered.

    • VC

The KEYNOTE-177 trial has established pembrolizumab as the standard of care in patients with MSI-H or dMMR mCRCs. The study met one of its primary endpoints (improvement in PFS), though a coprimary endpoint of improved OS was not met. The lack of improvement in OS is likely due to the high proportion of patients crossing over to the pembrolizumab arm (60%), among other possible reasons.[111] The first results of the CheckMate 8HW study have suggested that the combination of nivolumab plus ipilimumab also improves PFS compared to chemotherapy. Within the confines of the early results of the CheckMate 8HW trial as well as the flaws of a cross-trial comparison, the combination of nivolumab plus ipilimumab can be considered as an option for the treatment of MSI-H mCRCs.[112]

Despite the available patient assistance programs for pembrolizumab and nivolumab, these options are out of reach of the majority of Indian patients. In such a scenario, most patients with MSI-H mCRC are started on chemotherapy with or without targeted therapy. Based on the mechanism of action of immune checkpoint inhibitors (ICIs) and the dosing considerations noted in early-phase studies, it is postulated that low-dose ICIs may also have efficacy. The use of low-dose nivolumab has shown efficacy in a randomized phase III trial in advanced head and neck cancers. Keeping the above factors in mind, the recommendations suggest that low-dose ICIs can be considered in the Indian scenario in MSI-H mCRCs, though there are limited data and publications with regard to this usage.[113]

• 4. mCRC—Conversion therapy and oligometastatic disease (OMD).

  • 4.1: Patients with synchronous or metachronous mCRC which is considered for potentially curative intent treatment and intent should be discussed in a multidisciplinary clinic before embarking on treatment.

    • 1A

  • 4.2: In patients with clearly resectable primary tumor (nonrectal colonic) and limited metastases which is resectable, the first option of therapy can be radical surgery at both sites followed by an adjuvant chemotherapy-like approach.

    • 1B

  • 4.3: In patients with clearly resectable rectal primary tumor and limited metastases which is resectable, radiotherapy (short course or long course) can be considered if the primary tumor is ≥ T3 and/or node positive on local staging.

    • 2B

  • 4.4: In patients with clearly resectable primary rectal tumor and limited metastases, which is resectable, the first option of therapy can be radical surgery (with or without prior local radiotherapy based on local staging of the rectal primary) at both sites, followed by adjuvant chemotherapy-like approach.

    • 2C

  • 4.5: In patients with clearly resectable CRC and limited metastases, which are resectable and in whom R0 resection has been undertaken at both sites, targeted therapeutic options postsurgery are not proven to be useful and should be rarely or not considered.

    • 2B

  • 4.6: In patients where the ability to achieve complete resection at the primary site and metastatic sites is doubtful initially, systemic therapy (chemotherapy with or without targeted therapy) should be attempted before consideration of local therapy (surgery and radiotherapy).

    • 1B

  • 4.7: In patients where the ability to achieve complete resection at the primary site and metastatic sites is doubtful initially, the following chemotherapeutic regimens can be used with neoadjuvant intent for the purposes of conversion:

    • mFOLFIRINOX/FOLFOXIRI (1A).

    • FOLFOX/CAPOX (1A).

    • FOLFIRI (1A).

  • 4.8: In patients with left-sided mCRCs (ALL RAS WT; BRAF WT) and OMD who require “conversion therapy” prior to resection, the rationale for initiation of chemotherapy and monoclonal antibodies should be as for patients with unresectable and widely mCRC with response assessments every 2 to 3 months for evaluation of resection.

    • 2A

  • 4.9: In patients with left-sided mCRCs (RAS mutant) and OMD who require “conversion therapy” prior to resection, the rationale for initiation of chemotherapy with/without bevacizumab should be as for patients with unresectable and widely mCRC, with response assessments every 2 to 3 months for evaluation of resection.

    • 2A

  • 4.10: In patients with right-sided mCRCs (RAS mutant) and OMD who require “conversion therapy” prior to resection, the rationale for initiation of chemotherapy with/without bevacizumab should be as for patients with unresectable and widely mCRC with response assessments every 2 to 3 months for evaluation of resection.

    • 2A

  • 4.11: In patients with right-sided CRCs (ALL RAS wild type) and OMD who require “conversion therapy” prior to resection, chemotherapy and the following targeted therapies can be considered with response assessments every 2 to 3 months for evaluation of resection.

    • Anti EGFR monoclonal antibodies (2B).

    • Anti-VEGF monoclonal antibodies (2B).

  • 4.12: In patients who have undergone R0 resection of primary tumor and metastatic sites after initial conversion therapy, further chemotherapy (without targeted therapy) (for a perioperative period of approximately 6 months) can be considered as part of a “perioperative approach.”

    • 2B

  • 4.13: In patients who have undergone R0 resection of primary tumor and metastatic sites after initial conversion therapy, further targeted therapy (with chemotherapy) should not be considered as part of a “perioperative approach.”

    • 3B

General Principles

There is significant overlap in the treatment options between patients who have synchronous mCRC where there is a possibility of using conversion therapy and proceeding to possible local therapy (LT), and patients with OMD.[7] Hence, for the purposes of these recommendations, both categories have been considered together. It is also important to note that the current recommendations have limited inputs from surgeons, interventional radiologists, radiation oncologists, and other contributors from a potential multidisciplinary board (MTB) setup and primarily concentrates on rationalizing systemic therapeutic options in the management of mCRC. Further updates of these recommendations in the future will include inputs from other members on an MTB approach. The recommendations also recognize that using a combined approach for patients being planned for a “conversion approach” and OMD suffers from the following drawbacks:

1. OMD is emerging as a distinct biological entity with a specific genomic profile and is likely no longer an anatomical entity that can be considered halfway between localized disease and diffuse metastatic disease.[114] [115] [116]

2. OMD is a more well-defined entity predominantly comprising resected primary lesion (usually), and less than five sites of metastases at not more than two different organ sites, all of which are amenable to LT. However, there are other existing definitions and principles according to which OMD is identified and managed.

3. LT has a greater role in OMD than patients in the “conversion” pathway, with LT approaches showing a survival benefit (predominantly DFS or PFS benefits) for using LT with or without systemic therapy compared to systemic therapy alone.

Specific Management

A majority of evidence for the management mCRC with resectable/potentially resectable metastases comes from the management of CRLMs. While older studies attempted to prognosticate patients based on simple biological, anatomical, and serological criteria in patients with liver metastases, most of these studies were conducted in an era where biomarkers like RAS/RAF/MMR were not identified, and there were limited systemic and targeted therapeutic options.[117] Patients with limited lung metastases as well as peritoneal-only metastases have also come under the ambit of resection pre- or post-systemic therapy. Because of the varying criteria used by institutions, the current recommendations suggest that all institutions form their own guidelines for assessing resectability and LT via consensus among treating oncologists, surgeons, radiation oncologists, intervention radiologists, and other members of an MDT. Broadly, the following principles are suggested:

1. In patients with clearly R0-resectable primary and metastatic sites, surgery should be considered upfront followed by systemic therapy using an adjuvant-like approach. While there is limited evidence for using such an approach of “pseudo-adjuvant” chemotherapy, 6 months of systemic chemotherapy (FOLFOX or CAPOX) can be considered based on extrapolation from the management of stage III CRC. The use of targeted therapy after resection is not recommended.[118]

2. In patients where there are doubts on the possibility of R0 resection on an initial staging evaluation, it is preferable to start with systemic chemotherapy with targeted therapy as the initial approach, followed by 2- to 3-monthly assessments for the possibility of resection/LT. The evidence for such an approach comes from the study by Nordlinger et al (EORTC 40983), which compared perioperative FOLFOX4 chemotherapy to surgery alone in patients with CRC and resectable CRLM and achieved its primary endpoint of improved PFS in the perioperative group.[119]

3. The addition of targeted therapy as part of a “conversion” approach with neoadjuvant intent should follow the principles as for unresectable disease, with the following points to be kept in mind:

   • In patients with right-sided mCRC or left-sided RAS mutant/BRAF mutant CRC, using FOLFIRINOX plus bevacizumab might be beneficial in terms of response and downstaging compared to FOLFIRI/FOLFOX plus bevacizumab at the cost of additional treatment-related side effects. In patients who may not be fit for a triple therapy combination, FOLFOX/FOLFIRI plus bevacizumab is an acceptable and preferred option.[120] [121]

   • In patients with left-sided mCRC with RAS WT/BRAF WT status, there appears to be no significant differences in outcomes when comparing FOLFIRI/FOLFOX plus bevacizumab and FOLFOX/FOLFIRI and cetuximab based on the results of the CAIRO5 study.[121] There is controversy with regard to the management of patients in this subset, as previous meta-analyses have suggested increased downstaging and response rates when anti-EGFR-directed therapy was used.[93] [122] However, either of the two approaches (anti-VEGF-directed therapy or anti-EGFR-directed therapy) can be used as part of conversion therapy in mCRC.

   • Assessments for resectability should be conducted by relevant imaging every 8 to 10 weeks to ensure that the window for resection is not lost and to avoid increased duration of exposure to chemotherapeutic agents, especially oxaliplatin, which may cause increased liver toxicity and perioperative complications.

   • Resection of the metastases should be carried out approximately 5 weeks from the previous administration of chemotherapy–bevacizumab, assuming bevacizumab has not been omitted from the last cycle of therapy.

   • It should be noted that resection post–systemic therapy poses a different challenge compared to upfront resections in patients with mCRC. Use modalities such as RFA, microwave ablation, or stereotactic body radiotherapy (SBRT) prior to resection, or a two-staged resection may be applicable in select scenarios.[7] Portal vein embolization to ensure hypertrophy or remnant liver is also an acceptable option in scenarios where hepatic resections are being planned in the future.

   • It is important to note that there is limited or no role of resection of the primary tumor (barring emergent scenarios) in patients who have unresectable metastatic sites of disease. This is now supported by a small phase III trial from Japan.[123]

A number of studies have shown a benefit for the usage of LT as opposed to systemic therapy alone, though the quantum of benefits is not well quantified.[124] [125] However, a majority of these studies have not accounted for disease biology via the use of biomarkers or used monoclonal antibodies as part of systemic therapeutic approaches. Nevertheless, as approximately 20 to 45% of patients with OMD can have long-term survival, the use of LT should be considered paramount in the management of OMD. A detailed description of the pros and cons of the various LTs is beyond the scope of the current recommendations, but the recommendations do recognize the use of modalities such as TARE, SBRT, and cytoreductive surgery (CRS), with or without HIPEC, in the management of mCRC.[126] [127]

• 5. mCRC—Second-line therapy and chemorefractory mCRC.

  • 5.1: The following chemotherapeutic regimens can be considered as second-line therapy in patients reasonably fit for chemotherapy after progression on oxaliplatin/irinotecan-based first-line regimens, assuming there are no other limitations.

    • FOLFIRI/CAPIRI (post-progression with oxaliplatin-based regimens) 1A.

    • FOLFOX/CAPOX (post-progression with irinotecan-based regimens) 1A.

    • Irinotecan monotherapy (1A).

    • Oxaliplatin monotherapy (3C).

At a juncture where the patient needs to be assessed for second-line chemotherapy in mCRC, the most important factors to be taken into consideration are the ECOG performance status of the patient and prior treatment. For patients who have progressed on oxaliplatin-based regimens (i.e., CAPOX/FOLFOX), single-agent irinotecan has been shown to be superior to single-agent infusional 5-FU or supportive care alone in terms of efficacy with similar quality of life.[128] [129] Evidence shows that addition of 5-FU to irinotecan (FOLFIRI) does not have an overall survival advantage but offers benefit in terms of PFS and ORR with no significant difference in toxicity. FOLFIRI can be thus offered as second-line chemotherapeutic regimen to fit patients with a large disease burden who have previously received oxaliplatin-based chemotherapy for metastatic disease as it gives better ORR and PFS.[130] A phase 3 study in Asian patients also demonstrated the noninferiority of mCAPIRI as compared to FOLFIRI with or without bevacizumab in the second-line treatment of mCRC.[131] Hence, while CAPIRI or mCAPIRI is not commonly recommended as first-line therapy in mCRC, mCAPIRI as a second-line treatment option with reduced dose capecitabine can be considered as an acceptable alternative to FOLFIRI without compromising the efficacy. In patients who have received first-line FOLFIRI, superiority of FOLFOX over single-agent 5-FU or oxaliplatin was seen in phase 3 RCT in mCRC patients, where it offers a clinically relevant and statistically significant PFS advantage.[132] CAPOX and FOLFOX regimens can be used interchangeably based on the clinical scenario and patient profile.[133] Oxaliplatin monotherapy is not commonly used as a second-line agent in mCRC.

• 5.2: The following targeted agents can be considered as second-line therapy in combination with chemotherapy in patients with RAS mutant mCRC:

  • Bevacizumab (whether received bevacizumab prior or not) (2B).

  • Ramucirumab (2B).

In the second-line treatment of mCRC, whether or not bevacizumab has been used in the first-line setting, it may be added to any second-line chemotherapy regimen based on evidence of randomized phase 2 and phase 3 studies as well as their pooled meta-analysis that showed a modest but clinically meaningful and statistically significant survival improvement.[134] [135] [136] [137] Evidence from a randomized controlled trial suggests a bevacizumab dose of 5 mg/kg body weight to be equally efficacious as 10 mg/kg body weight in second-line mCRC patients who have progressed on oxaliplatin-based therapy.[138] This is particularly relevant to resource-constrained settings where ensuring lowered costs helps more patients benefit from these drugs. Although there is no randomized trial comparing single-agent irinotecan with irinotecan plus bevacizumab in second-line mCRC treatment, in light of the evidence from other trials previously quoted, it is a reasonable treatment option.

Based on evidence from a randomized phase III study that showed a statistically significant overall survival benefit, ramucirumab can be combined with second-line FOLFIRI in patients who have progressed in first-line chemotherapy with or without bevacizumab.[139] The risk of arterial and venous thromboembolic events and life-threatening gastrointestinal or nongastrointestinal bleeding is not increased by the addition of ramucirumab, unlike the other antiangiogenic agents, making it a relatively safe drug.[140] Data are lacking regarding the benefit of the addition of ramucirumab to FOLFOX in second-line mCRC treatment. However, we can use the combination of FOLFOX + ramucirumab in the second-line if the patient has received irinotecan-based therapy in the first-line.

• 5.3: The following targeted agents can be considered as second-line therapy in combination with chemotherapy in patients with RAS wild-type mCRC (irrespective of tumor sidedness and assuming they have not received anti-EGFR monoclonal antibodies during initial therapy):

  • Cetuximab (2B).

  • Panitumumab (2B).

• 5.4: The following targeted agents can be considered as second-line therapy in combination with chemotherapy in patients with RAS wild-type mCRC (assuming they have received anti-EGFR monoclonal antibodies during initial therapy):

  • Cetuximab (2C).

  • Panitumumab (2C).

Based on randomized controlled trial data that showed PFS benefit and better ORRs with the addition of panitumumab to FOLFIRI in second-line RAS wild-type mCRC patients, panitumumab or cetuximab can be added to FOLFIRI/irinotecan in second-line mCRC therapy in patients who have not received EGFR-targeted therapy in the first line. These combinations have shown limited benefits in PFS without improvements in OS.[45] [141] [142] Data are lacking regarding the benefit of the addition of panitumumab or cetuximab to FOLFOX in second-line mCRC treatment. However, we can use the combination of FOLFOX + panitumumab in the second line if the patient has received irinotecan-based therapy in the first line. In patients who have already received EGFR-targeted therapy in the first line, there are limited data to support the continuation of the EGFR-targeted agent along with a change in the chemotherapy backbone.[143] Under the selection pressure of anti-EGFR therapies, CRCs that are RAS wild type may become resistant to EGFR-targeted therapies by altering the RAS mutation status. Additionally, due to tumor heterogeneity, both RAS wild-type and RAS mutated clones may co-exist from the baseline. Once the RAS WT tumor cell population reduces due to the effect of EGFR-targeted therapies, the RAS mutated cells proliferate and repopulate the tumor, making the tumor resistant to EGFR-targeted therapies. Also, RAS mutations can develop de novo in previously RAS WT tumors, especially mutations in the extracellular domain of the EGFR.[55] Both these mechanisms contribute to the development of resistance to EGFR-targeted therapies when used in the first line. Hence, the belief that patients with RAS WT mCRC who have had progression on first-line treatment, which includes EGFR-targeted agents, will become permanently resistant to further EGFR-targeted therapy may not be completely true.

Sometimes, sensitivity to EGFR-targeted therapies may be restored by a treatment break. This forms the rationale for continuing the EGFR-targeted therapy and changing the chemotherapy backbone alone.[144] [145] [146] [147] [148] However, in view of the small sample sizes of these studies, this is usually not a recommended approach.

• 5.5: The following treatment options can be considered in patients with mCRC (irrespective of RAS status), refractory to oxaliplatin and irinotecan-based therapy.

  • Regorafenib full dose (1A).

  • Regorafenib via dose escalation approach (2A).

  • TAS-102 (1B).

  • TAS-102 plus bevacizumab (1A).

• 5.6: The following treatment options can be considered in patients (without resource constraints) and with mCRC (RAS WT) refractory to oxaliplatin- and irinotecan-based therapy.

  • Panitumumab monotherapy (1B).

  • Cetuximab monotherapy (1B).

• 5.7: The following treatment options can be considered in patients (with resource constraints) and with mCRC (RAS WT) refractory to oxaliplatin- and irinotecan-based therapy.

  • Panitumumab monotherapy (1C).

  • Cetuximab monotherapy (1C).

• 5.8: Rechallenge with chemotherapy can be considered post two lines of chemotherapy (oxaliplatin and irinotecan based) in a select group of patients in mCRC.

  • IIIB

Regorafenib is an oral, small molecule inhibitor of multiple kinases. Two large, randomized phase III trials in mCRC patients who have progressed on two or more lines of therapy including 5-fluoropyrimidines, oxaliplatin, irinotecan, and monoclonal antibodies have demonstrated the benefit of regorafenib as compared to placebo in terms of PFS and OS. The benefit was modest but statistically significant.[149] [150] The phase II REDOS trial explored the approach of dose escalation strategy for regorafenib by starting at a lower dose of 80 mg per day and gradually increasing the dose.[151] This approach was associated with lower incidence of toxicity, especially the HFSR, without compromising the efficacy of regorafenib. Hence, this dose escalation approach may be used as a reasonable alternative to standard dosing of regorafenib, among other approaches.[152] [153]

TAS-102 is an oral fixed drug combination of the thymidine analog trifluridine and a thymidine phosphorylase inhibitor tipiracil. Tipiracil prevents the quick degradation of trifluridine. TAS-102 as monotherapy or in combination with bevacizumab has shown modestly improved survival compared to placebo alone.[154] [155] [156] Like regorafenib, TAS-102 (with or without bevacizumab) can be considered as an option in chemotherapy-refractory mCRC.

In patients refractory to irinotecan- and oxaliplatin-based therapies, both panitumumab and cetuximab can be used as monotherapy in patients with RAS WT tumors based on modest benefits in survival in this setting in prospective trials.[157] [158] [159] Both the EGFR-targeted agents cetuximab and panitumumab provide superior PFS and OS as compared to best supportive care alone in chemotherapy-refractory mCRC patients and can be considered, especially in patients who have never received any EGFR-targeted therapies in the earlier lines and have a good performance status. However, in resource-constrained settings, the quantum of benefits seen with using anti-EGFR agents as monotherapy is not preferred. In such a resource-constrained scenario, re-challenge with the initial chemotherapy regimen that was used is an option, though backed only by weak evidence.[160] [161] Assessment of residual toxicity from previous chemotherapy drugs must be done before rechallenging, especially with issues like neuropathy due to oxaliplatin.

• 5.9: In patients with chemotherapy-refractory BRAF mutant tumors, options of therapy include:

  • Encorafenib plus cetuximab (2A).

  • Second-line chemotherapy as for other subsets of CRC(2B).

In patients with chemotherapy-refractory BRAF-mutant tumors, a combination of the BRAF inhibitor encorafenib and cetuximab leads to superior OS and ORR as compared to cetuximab with irinotecan or FOLFIRI.[162] Hence, this regimen is strongly recommended for this subset of mCRC patients, though procurement of encorafenib in India is difficult.

• 6. Follow-up protocols

  There are no firm guidelines for the frequency of follow-up evaluations and examinations of patients during the course of their treatment for mCRCs. While patients on active therapeutic interventions will be on frequent evaluation, assessment of radiological and serological disease status using carcinoembryonic antigen (CEA) antigen levels with or without cancer antigen (19.9 (CA 19.9) can be considered every 8 to 12 weeks, though there are no fixed criteria for the same. While CEA is a useful tool for monitoring on follow-up, there are a number of nonmalignant causes for rise in CEA and these should be kept in mind before acting on minor perturbations in these values.[163] [164] A majority of clinical trials consider 6 to 8 weekly tumor-related assessments including CEA and radiology, though such frequent assessments may not be required in clinical practice unless there are particular patient-specific scenarios.

• 7. Principles of management not covered in the statements

  Certain important aspects of the management of mCRCs were not covered in the discussions during the consensus statements. These will be taken up in future versions of the statements, but have now been mentioned in brief.

  • 7.1: The sensitivity and specificity of CEA and CA 19.9 levels during diagnosis and monitoring in patients with mCRC had not been discussed during the formulation of the consensus statements. A detailed review will be considered in future revisions of these statements.

  • 7.2: DPD genotype testing was not specifically discussed during the development of the consensus statements. However, based on the FDA guidelines as well as guidelines detailed by the Clinical Pharmacogenetics Implementation Consortium (CPIC), the discussants broadly agreed that the pros and cons of testing for DPD genotypes should be discussed with patients being planned for 5-FU-based (or analogs of 5-FU) systemic therapy while being counseled for treatment. Capecitabine or fluorouracil should not be recommended for use in patients known to have clinically relevant and proven homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. With regard to partial DPD deficiency in those genotypes known to cause 5-FU (or analogs of 5-FU) related adverse events, dose modifications can be considered, though there is limited consensus on the same.[165] [166] Available Indian data across cancers have shown significant variability in the prevalence of heterozygous and homozygous DPD genotypes and needs further systematic evaluation.[167] [168]

  • 7.3: The appropriate duration for follow-up of patients not on active cancer-directed therapy is a matter that requires further evaluation in the Indian context. CT scans or PET scans are commonly used every 8 to 12 weeks, though there is limited evidence to support for or against this practice. This topic will be considered for evaluation in subsequent revisions of the guidelines.

Discussion

The current set of recommendations and guidelines for the management of mCRC, with a specific focus on the context of Indian patients, offers a primer for practicing Indian medical oncologists on how to manage their patients across scenarios. It represents the consensus opinion of a group of representative medical oncologists from various parts of the country, including community oncologists and oncologists from academic institutions, to prepare a document that can offer practical management guidelines without solely relying on evidence generated in other parts of the world. It recognizes that resource constraints play a major role in determining the management of patients in India, despite improving access to healthcare across the country.

While multiple comprehensive and better-elucidated guidelines exist for the management of mCRC across the world, a number of these guidelines offer “all or none” scenario in terms of treatment options due to various reasons. Among the strongest examples of such scenarios would be the use of low-dose ICIs in MSI-H mCRCs, or for that matter any MSI-H cancer. While clinical trials using low-dose ICIs are few in number, pharmacokinetic and pharmacodynamic studies do suggest that lower doses may be as efficacious as standard dosing.[169] [170] It is likely that prospective randomized trials using low-dose ICIs will be conducted with difficulty or not at all. In such a setting, the current guidelines recognize such difficulties and have included low-dose ICIs as an option, albeit with a very low degree of recommendation. The recommendations also offer treating oncologists a rationale for lower consideration of some options as opposed to others based on availability and resource constraints. An example would be recognizing that rechallenge with chemotherapy would be a fair option, despite the lack of large-scale prospective evidence, as opposed to monotherapy with anti-EGFR-directed therapy (where phase III trials provide evidence for limited survival benefits), which would be prohibitively expensive in areas with logistic/resource constraints. Despite repeated references to the Indian scenario and resource constraints, the recommendations unequivocally also offer evidences and practice guidelines for scenarios where all treatment options are available and feasible.

Though this is one of the first such attempts at rationalizing the use of systemic therapeutic options using a collaborative approach, there is a definite lacuna in terms of treatment recommendations for conversion therapy in mCRC and OMD. The lack of detailed input from other members of a multidisciplinary team, specifically molecular pathologists, intervention radiologists, and surgeons, is reflected in the absence of detailed recommendations on various aspects of these topics. Inclusion of experts from the aforementioned fields among others is strongly recommended by the guidelines in the management of mCRC and updates of these recommendations will include them in the preparation of guidelines.

To summarize, the current consensus statements offer practical, yet evidence-based management guidelines for treating mCRC in the Indian context. Stratifying and recommending treatment options in a resource-constrained scenario is an important aspect of these statements.

Conflict of Interest

None declared.

Authors’ Contributions

All authors contributed equally and approved the manuscript.

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Publication History

Received: 28 September 2024

Accepted: 02 May 2025

Article published online:
26 May 2025