University of Texas MD Anderson Cancer Center Houston, TX
A. D. Sherry1, T. A. Lin2, Z. R. McCaw3,4, E. J. Beck1, R. Kouzy1, J. Abi Jaoude5, A. H. Passy1, A. M. Miller1, G. S. Kupferman1, C. D. Fuller6, C. R. Thomas Jr7, E. J. Koay8, C. Tang9,10, P. Msaouel11,12, and E. B. Ludmir8,13; 1Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 3Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 4Insitro, South San Francisco, CA, 5Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 6Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 7Department of Radiation Oncology and Applied Sciences, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, NH, 8Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 9Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 10Department of Genitourinary Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 11Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 12Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 13Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): Increasing data suggest that radiotherapy, particularly ablative radiotherapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled on prospective trials testing systemic therapy, the use of off-protocol radiotherapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiotherapy was permitted among systemic therapy phase III trials, how often off-protocol radiotherapy is utilized, and whether off-protocol radiotherapy correlated with study outcomes. We hypothesized that off-protocol radiotherapy is routinely utilized during the protocol systemic therapy of phase III trials. Materials/
Methods: Two-arm, superiority-design, published phase III randomized trials testing systemic therapy with available protocols were screened from ClinicalTrials.gov. Off-protocol radiotherapy was defined as radiotherapy that was not required by the protocol, that did not require permanent discontinuation of the protocol’s systemic therapy, and that did not result in a change in progression status. Adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) for trial-level covariate associations were computed by logistic regressions with Firth’s penalized likelihood correction. Results: After screening 1,877 trials, a total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiotherapy 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 radiotherapy utilization rates. No data were reported on the use of ablative off-protocol radiotherapy. No trials evaluated or adjusted for the potential influence from off-protocol radiotherapy on study endpoints. Among the subset of open-label studies, trials permissive towards off-protocol radiotherapy were more likely to meet their primary endpoint (aOR 4.50, 95% CI 1.23 to 20.23, P = 0.04). Conclusion: In a large-scale analysis of phase III randomized controlled trials, most trials allowed off-protocol radiotherapy during the protocol systemic therapy. Although off-protocol radiotherapy may influence study endpoints, the rates of off-protocol radiotherapy were rarely reported, and no trial accounted for the effects of off-protocol radiotherapy on trial outcomes. These findings argue for standardized approaches, reporting, and sensitivity analyses regarding off-protocol radiotherapy, particularly ablative radiotherapy, among phase III systemic therapy trials.
