Off-Protocol Radiation Therapy in Phase 3 Metastatic Solid Tumor Trials.

Purpose: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes.

Methods And Materials: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression.

Results: A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04).

Conclusions: Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials.