Role of biological agents in first-line treatment of metastatic colorectal cancer
Biological agents are generally indicated for the first-line treatment of patients with metastatic colorectal cancer unless contraindicated due to, for example, reduced organ function, poor performance status or cardiovascular insufficiency.
Biological agents reimbursed for use in the treatment of patients with metastatic colorectal cancer in Australia include:
- Anti-VEGF therapy: bevacizumab – a humanised monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A), a member of a family of VEGF receptor-activating ligands.
- Anti EGFR therapy: cetuximab and panitumumab – monoclonal antibodies that target epidermal growth factor receptor (EGFR).
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected reviews, primary studies, and other clinical practice guidelines (see Guideline development process).
Anti-VEGF therapy – bevacizumab[edit source]
In a pivotal early randomised controlled trial (RCT), the addition of bevacizumab to the bolus irinotecan, leucovorin (folinic acid), and fluorouracil (IFL) regimen significantly improved response rates (45% versus 35%), increased time to tumour progression (11 versus 6 months), and prolonged overall survival (20 versus 16 months).
Since then, benefit for adding bevacizumab to a variety of fluoropyrimidine, irinotecan, and oxaliplatin-containing regimens used for first-line therapy has been confirmed, although the magnitude of both the overall and progression-free survival benefits are relatively modest. To date, there are still only limited data on the benefit of adding bevacizumab to an oxaliplatin-based regimen although this has been a standard first-line treatment in many patients, and no RCT comparing FOLFIRI versus FOLFIRI plus bevacizumab has been published.
XELOX [CAPOX] can also be combined with bevacizumab. The evidence supporting this and FOLFOX4 combined with bevacizumab in the first line comes from the randomised phase III, NO16966 trial by Saltz et al. Patients were randomly assigned in a 2 X 2 factorial design to FOLFOX 4 or XELOX followed by bevacizumab or placebo. After a median follow-up of 27.6 months, PFS was significantly increased with bevacizumab compared with placebo when combined with oxaliplatin-based chemotherapy (HR=0.83; p=0.0023), the median PFS duration being 9.4 months with bevacizumab plus chemotherapy versus 8.0 months with placebo plus chemotherapy.
However, the overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. The lack of continuation of either bevacizumab or flluoropyrimidine until disease progression may have blunted the contribution of bevacizumab, thereby diminishing its impact on OS and PFS.
An open-label, phase 3 trial (the TRIBE study) reported that the combination of leucovorin calcium (folinic acid), 5FU, oxaliplatin and irinotecan hydrochloride (FOLFOXIRI) in combination with bevacizumab enhanced response rate and progression-free survival, compared with FOLFIRI plus bevacizumab and reported a median overall survival of 29.8 months. The use of FOLFOXIRI–bevacizumab treatment is limited to select patients with excellent performance status and minimal comorbidities. The contribution bevacizumab makes to the triplet regimen is uncertain.
Bevacizumab can be associated with a number of potentially serious side effects, including proteinuria, hypertension, bleeding, bowel perforation, impaired wound healing, arterial (but not venous) thromboembolic events (such as transient ischemic attack, stroke, angina, myocardial infarction), and reversible posterior multifocal leukoencephalopathy.
For patients with RAS and BRAF wild-type tumours, an important question is whether a bevacizumab-containing regimen provides superior outcomes as compared with an initial regimen that contains an anti-EGFR agent. Emerging data suggest that first-line cetuximab-containing regimens may provide superior outcomes for patients with RAS/BRAF wild-type metastatic colorectal cancer with a primary tumour site in the left colon (see Left-sided versus right-sided tumours).
Currently there is no validated predictive biomarker for bevacizumab.
See eviQ protocols:
Anti-EGFR therapy[edit source]
The EGFR antibodies cetuximab and panitumumab are active in various combinations, either alone or with cytotoxic chemotherapy agents.
The activity of EGFR antibodies is limited to patients with RAS wild-type tumours. Thus, knowledge of the RAS mutational status of the patient is a prerequisite to treatment with EGFR antibodies.
Unlike cetuximab (a chimeric monoclonal antibody produced in a murine culture), panitumumab is a fully human monoclonal antibody, and has a lower incidence of infusion reactions. The available evidence suggests that antitumor efficacy is similar to that of cetuximab, and that the two drugs might be interchangeable.
The addition of cetuximab to FOLFIRI has been shown to improve response rate, median progression-free survival rate and overall survival rate in first-line use, compared with FOLFIRI alone in metastatic colorectal cancer patients with RAS wild-type tumours. Both cetuximab and panitumumab also increase the activity of the cytotoxic doublet FOLFOX in metastatic colorectal cancer patients with RAS wild-type tumours. In contrast, benefits have not been shown for the addition of EGFR antibodies to oxaliplatin-based regimens where non-infusional fluoropyrimidines were used, such as bolus administration, the combination of 5-flourouracil (5FU), calcium leucovorin (folinic acid) and oxaliplatin (FLOX), capecitabine, or capecitabine plus oxaliplatin (CAPOX). Capecitabine-based therapy should not be used in combination with EGFR antibody therapies.
Combinations of cetuximab or panitumumab plus an irinotecan or oxaliplatin-based cytotoxic regimen that contains infusional 5FU (i.e, FOLFIRI and FOLFOX) are safe and effective. These are a reasonable first-line option for patients with RAS and BRAF wild-type tumours, especially for patients with a primary tumour on the left side.
See eviQ protocols for cetuximab:
See eviQ protocols for panitumumab:
Biological agents targeting EGFR or VEGF in combination with chemotherapy are recommended in the first-line treatment of most patients unless contraindicated.
EGFR antibodies should:
Patients with left sided colorectal cancer should be considered for initial doublet chemotherapy and anti-EGFR therapy where appropriate. Alternate options remain appropriate based on patient preference and comorbidity.See left vs. right section
EGFR antibodies may be less efficacious in patients with BRAF mutations.
Patients with right sided colorectal cancer should be considered for initial doublet chemotherapy plus or minus anti-VEGF. See left vs. right section
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