Average cumulative relative dose of adjuvant chemotherapy is more important than average relative dose intensity for colorectal cancer survival, with implications for treating obese patients: The OCTOPUS consortium

Abstract

Background:After curative surgery for colorectal cancer (CRC), some studies indicatepoorer survival in obese patients. Adjuvant chemotherapy (ACT) for CRC is commonlycapped at a body surface area (BSA) 2.2m2, potentially reducing chemotherapyaverage cumulative relative dose (ACRD) and average relative dose intensity (ARDI) inobese patients.Methods:Individual participant-level data from MOSAIC, SCOT, PROCTORSCRIPT, andCHRONICLE (CRC-ACT) randomised-trials, with derivable BMI, BSA, and chemotherapydoses, were included from the OCTOPUS consortium. ARDI and ACRD were calculatedas percentages of actual to expected (full BSA-based) dose intensity (cumulativedose/treatment duration in weeks) or cumulative dose, respectively, averaged acrossthe drugs in the regimen. Two-stage random-effects meta-analyses of linear or Coxproportional hazards regression models were performed to explore BMI-ARDI/-ACRDand ARDI-/ACRD-survival relationships, respectively. The primary outcome was dis-ease-free survival (DFS), and secondary outcomes were overall (OS) and cancer-specific (CSS) survival, in addition to ARDI and ACRD. All models where adjusted for age, sex, performance status, t-stage and n-stage (in addition to BMI in the survivalmodels).Results:7269 patients were eligible. BMI 5kg/m2 increments were associated with a2.04% reduction in cycle 1 dose (95% CI:-2.45,-1.64; p ACRD 5% increments wereassociated with improved DFS (HR 0.953 (0.926, 0.980); p¼0.001), OS (HR0.931(0.908, 0.955); p<0.001) and CSS (HR 0.941(0.924, 0.959); p<0.001) survival.However, no significant relationship was demonstrated for ARDI (DFS HR 1.015 (0.967,1.065); p¼0.552; OS HR 1.035 (0.990, 1.081); p 0.134; CSS HR 1.022 (0.982, 1.064); p¼0.282), nor for sex-interactions for both ACRD and ARDI.Conclusions:ACRD is more important than ARDI in determining survival. Elevated BMIis associated with a reduced cycle 1 dose and a modest ACRD reduction. These in-direct effects through under-treatment might explain poorer survival in obese pa-tients, rather than direct effects of obesity resulting from, for example, tumour biology.