VA Offers Pathway through First-Line Treatment Options for mCRC

by | Mar 25, 2025

Illustration: Colon cancer, Cancer attacking cell Source: Mohammed Haneefa Nizamudeen, iStock

WASHINGTON, DC — The VA diagnoses approximately 4,000 new CRC cases annually. More than half of people with CRC either have metastatic disease at diagnosis or will develop it, making understanding the tests and treatments available to match therapy to each patient essential to achieving the best outcomes possible for these patients.1,2

This goal has been made both easier and more difficult to achieve as the number of therapies available for metastatic CRC (mCRC) has exploded over the last decade, making treatment selection far more complex than when chemotherapy was the only option, while simultaneously extending survival for many patients who receive appropriately matched targeted therapies.

To simplify the selection process, the VA Oncology Clinical Pathway–Colon Cancer provides guidance for physicians to help ensure veterans receive the care most likely to optimize their outcomes.3

Because of the breadth of therapy options and the variety of molecular profiles that present in mCRC, this article focuses on treatment for stage IV unresectable proficient mismatch repair or microsatellite stable CRC based on the VA’s step-wise, evidence-based approach.

The first step in managing stage IV CRC is evaluating whether the disease is potentially resectable. For a minority of patients with limited metastatic spread, surgical resection may be an option and could offer the potential for long-term disease control, when combined with chemotherapy with or without oxaliplatin.

Some patients may be candidates for resection following chemotherapy. For these veterans, the Clinical Pathway recommends chemo, with oxaliplatin if the patient can withstand an aggressive approach, and reevaluation after up to four months.

Surgery is not feasible in most stage IV CRC cases, however, necessitating a systemic therapy-only course. In these cases, treatment focuses on extending survival, slowing disease progression, and maintaining functional well-being.

Prior to selecting a treatment regimen, patients should undergo comprehensive molecular testing to ensure proper matching with a therapy. The following biomarkers should be assessed in unresectable mCRC: mismatch repair (MMR) status, RAS and BRAF mutation status, and tumor sidedness.

Approximately 15% of metastatic CRC cases exhibit deficient mismatch repair (dMMR), making them highly responsive to immune checkpoint inhibitors rather than chemotherapy.4

For the majority of veterans with proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumors, chemotherapy remains the standard first-line treatment. The presence of RAS or BRAF mutations determines eligibility for specific targeted therapies and informs drug selection, while tumor sidedness has been shown to impact treatment response, as left-sided tumors generally respond better to EGFR inhibitors, whereas right-sided tumors tend to show greater benefit from VEGF inhibition.5

Veterans with left-sided primary, defined as originating in the splenic flexure and the colon distal to that, with RAS wild-type (RASwt) and BRAF wild-type (BRAFwt) tumors who are eligible for chemotherapy have a clear pathway. Patients with this type of CRC receive panitumumab with chemotherapy as standard therapy, although capecitabine may be substituted if a patient has severe renal impairment, is unable to self-report toxicity or is likely to have adherence issues.

A fluoropyrimidine-based doublet regimen serves as the cornerstone of systemic therapy for left-sided, RASwt/BRAFwt patients. The VA recommends mFOLFOX6 (5-FU, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin). For veterans who cannot tolerate oxaliplatin, FOLFIRI (5-FU, leucovorin, irinotecan) is an alternative. Contraindications for oxaplatin include adjuvant treatment in the prior 12 months, pre-existing grade 2 or higher neuropathy or patient preference to avoid neuropathy.

For right-sided tumors or those with RAS or BRAF mutations, EGFR inhibitors do not provide significant benefit. Instead, the VA Clinical Pathway recommends VEGF inhibition with bevacizumab.

For these veterans, the VA recommends that who can tolerate oxaliplatin receive mFOLFOX6 or CAPOX, while those unable to receive oxaliplatin may be treated with FOLFIRI (5-FU, leucovorin, irinotecan). Bevacizumab is added for eligible patients. Among the requirements for eligibility for bevacizumab in this context, an individual must have received fluoropyrimidine and platinum agent in the first-line setting and does not have a non-healing wound/fracture, has not undergone major surgery in the prior four weeks, does not have a bleeding disorder or coagulopathy or recent history of GI perforation. Patients also should not have uncontrolled hypertension, arterial thromboembolism, symptomatic heart failure or arrhythmia, or active cocaine use.

For veterans ineligible for targeted therapy, chemotherapy alone remains the primary option. A biomarker-driven treatment plan ensures optimal outcomes while minimizing unnecessary toxicity.

Once therapy is initiated, regular imaging and biomarker assessments help gauge treatment response. If disease progression occurs, second-line options—including alternative chemotherapy regimens, additional targeted therapies, or participation in clinical trials—are considered. The overarching goal remains disease control while maintaining quality of life.

 

  1. U.S. Department of Veterans Affairs. VHA 2024 Annual Report: VA Health Care: A Strong Foundation. A Healthy Future.
  2. Cervantes A, Adam R, Roselló S, Arnold D, et al; ESMO Guidelines Committee. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Jan;34(1):10-32. doi: 10.1016/j.annonc.2022.10.003. Epub 2022 Oct 25.
  3. U.S. Department of Veterans Affairs. Oncology Clinical Pathways: Colon Cancer. August 2024. V4.2024.
  4. Williams CJM, Peddle AM, Kasi PM, et al. Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response. Nat Rev Clin Oncol. 2024 Dec;21(12):839-851. doi: 10.1038/s41571-024-00943-6. Epub 2024 Sep 24.
  5. Svec J, Onhajzer J, Korinek V. Origin, development and therapy of colorectal cancer from the perspective of a biologist and an oncologist. Crit Rev Oncol Hematol. 2024 Dec;204:104544. doi: 10.1016/j.critrevonc.2024.104544. Epub 2024 Oct 25.