Phase I trials involving radiation therapy, quantifying the risks

Over one third of cancer patients receive radiation therapy ( RT ) at some point. Our purpose was to quantify the risks to patients associated with enrolment onto RT ‐based phase I trials. Methods All phase I and phase I / II clinical trials involving RT published in English between 2001 and 2010 were identified via a PubMed search. For pragmatic reasons, we focused on trials from 2001, 2005 and 2009. For each trial we calculated a ‘toxicity ratio’ equal to the number of grade 3/4/5 toxic events divided by the number of patients in the trial. Linear regression was used to determine which variables were associated with higher toxicity ratios. Results There were a total of 33 treatment‐related deaths, and 1812 acute grade 3/4 toxicities among the 2994 subjects in 98 trials. The median toxicity ratio over 98 trials was 0.46 (95% confidence interval ( CI ) 0.34 to 0.58). Multivariate regression analysis showed that toxicity ratios were significantly higher in trials with chemotherapy ( P  = 0.002) and in trials for cancers of the head‐and‐neck ( P  < 0.001). The median toxicity ratio in chemotherapy trials was 0.60 (95% CI : 0.48 to 0.72) compared with trials without chemotherapy 0.08 (95% CI : 0.03 to 0.13). Conclusions Although the risk of grade 5 toxicity is low, the risk of major toxicity is significant in phase I RT trials. These values are comparable to published risk estimates for phase I non‐ RT trials.