title: Phase I trials involving radiation therapy, quantifying the risks.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Center for Translational Research in Radiation Oncology, Department of Radiation Oncology, Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Yaacov Richard
authors.initials: YR
authors.lastname: Lawrence
authors.forename: Charles
authors.initials: C
authors.lastname: Glass
authors.forename: Zvi
authors.initials: Z
authors.lastname: Symon
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
mesh_terms: D017677:Age Distribution; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D015897:Comorbidity; D019317:Evidence-Based Medicine; D006801:Humans; D015994:Incidence; D009369:Neoplasms / Q000401:mortality* / Q000532:radiotherapy*; D020266:Radiotherapy, Conformal / Q000401:mortality*; D018570:Risk Assessment; D017678:Sex Distribution; D015996:Survival Rate; D016896:Treatment Outcome
keywords: clinical trial; drug toxicity; neoplasms; phase I; radiation oncology; radiation-sensitizing agents