Adams, Richard

Purpose In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. Patients and Methods Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). Results BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m 2 , and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m 2 had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. Conclusion Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.

PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.