Weekly vs. Bolus Cisplatin Concurrent with Definitive Radiotherapy for Squamous Carcinoma of the Head and Neck: A Systematic Review and Network Meta-Analysis

Abstract

The optimal schedule for cisplatin delivered concurrently with definitive radiation for squamous carcinoma of the head and neck remains controversial. Randomized data in the postoperative setting is mixed, and definitive studies are ongoing. Meanwhile, multiple trials have already compared cetuximab to cisplatin in the definitive setting. Across these trials, the cetuximab dosing was identical, but cisplatin dosing was variable and can be categorized as weekly (40 mg/m2 q1 week) or bolus (100 mg/m2 q3 weeks). We indirectly compared these two cisplatin schedules by performing a network meta-analysis of cetuximab trials. We performed a PRISMA-concordant systematic review to identify randomized controlled trials comparing cisplatin to cetuximab for patients with non-metastatic squamous carcinoma of the head and neck treated with definitive radiation therapy. Trials of primary surgery, incorporating induction therapy, or mixing other therapeutics were excluded. The analysis was pre-registered with the Open Science Foundation. Individual patient survival data was extracted from the published overall survival curves using a digitizer, and outcomes were validated against published point-estimates and hazard ratios. A random effects Cox regression was used to perform the individual-patient analysis using a one-step approach under a frequentist framework. Random effects were applied to model heterogeneity in the baseline hazard function and treatment effect. Models were adjusted by HPV and smoking status, which were trial-level covariates. Alternative endpoints (DFS, LRF, DM, etc.) were analyzed qualitatively. IRB approval was not required. Five randomized trials were identified, including 1,678 patients. Bolus cisplatin was delivered to 572 patients in 2 trials, and weekly to 271 in 3 trials. The risk of bias was low. Relative to cetuximab, both bolus and weekly cisplatin reduced the risk of death (adjusted HR 0.63, 95% CI 0.46-0.87, p = 0.004 & HR 0.56, 95% CI 0.37-0.86, p = 0.008 respectively). No interaction was identified between regimen and HPV or smoking status. Between-study heterogeneity (δ2) was 0.148 and treatment effect heterogeneity (τ2) was small (<0.0002). There was no statistical difference in OS between bolus vs. weekly regimens (weekly vs. bolus HR 0.90, 95% CI 0.53-1.52, p = 0.345). This Cox model therefore suggested that on average, the absolute difference in 5-year OS is <1.5% between the two regimens, which was not statistically significant. Secondary endpoints and toxicity were not obviously different by regimen, qualitatively. Using cetuximab as a common reference, there was no significant difference in survival between weekly and bolus cisplatin schedules.