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The addition of bevacizumab (a monoclonal antibody against vascular endothelial growth factor, VEGF) to 5-fluorouracil-based chemotherapy has a proven overall survival benefit in metastatic colorectal cancer. Nevertheless, the cost of antibody therapies and increasing evidence that the efficacy of targeted agents may be predicted by patient and tumour characteristics have prompted the investigation of biomarkers that may predict benefit from bevacizumab. Guiu et al examined the impact of body mass index, visceral fat area and subcutaneous fat area on the clinical outcome of patients with metastatic colorectal cancer treated with chemotherapy alone or chemotherapy plus bevacizumab.1 The authors claim that a visceral fat area greater than the median was significantly associated with a reduced response, shorter time to progression and shorter overall survival in patients who received chemotherapy plus bevacizumab but not those who received chemotherapy alone.
However, it has been demonstrated that the objective response rate in patients with colorectal cancer receiving chemotherapy plus bevacizumab is not predictive of the survival benefit conferred by the addition of bevacizumab to chemotherapy.2 Observational data suggest that patients with colorectal cancer who progress on bevacizumab plus chemotherapy show a prolonged survival if subsequent treatment regimens include bevacizumab.3 These data cast doubt on the applicability of response and time to progression as useful measures of the efficacy of bevacizumab. The cohorts of the chemotherapy alone and bevacizumab plus chemotherapy patients are small in size, have few events and are highly heterogeneous in regard to the type of cytotoxic chemotherapy received. No interaction analyses are provided for the survival data. Therefore, it is not possible to reliably determine from these data whether visceral fat area has a general prognostic effect for patients receiving 5-fluorouracil-based chemotherapy or whether it has specific predictive value as regards bevacizumab. There has been no attempt to control for false statistical significance due to multiple testing. It is likely that the borderline statistical significance seen for the effect of visceral fat area on overall survival (p=0.049) will not be statistically significant following correction for multiple testing.
Finally, Guiu et al propose that the biological mechanism for the alleged effect of visceral fat area on reduced responsiveness to bevacizumab may be due, in part, to upregulation of VEGF by leptin and/or differences in the volume of distribution of bevacizumab. Yet, pre-treatment tumour,4 stromal4 and circulating5 VEGF levels have all been shown to be non-predictive of the survival benefit afforded by bevacizumab in colorectal cancer. Pharmacokinetic data on bevacizumab in colorectal cancer suggest that >98% of circulating VEGF is bound by bevacizumab when dosed at 2.5 or 5.0 mg/kg per week.6 Therefore, slight variations in the volume of distribution of bevacizumab (20% to 30%)6 associated with a patient's weight will be unlikely to have a meaningful clinical impact.
In summary, the study presented by Guiu et al has significant limitations in design, patient heterogeneity, statistical analysis and interpretation. These data do not support the overstated conclusion that ‘VFA [visceral fat area] measured before starting first-line bevacizumab-based therapy is likely to be a useful predictive biomarker in metastatic colorectal cancer’.1
Competing interests None.
Provenance and peer review Not commissioned; not externally peer reviewed.
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