@article{2f1cee03058947df8808104594319273,
title = "Simulation modeling of cancer clinical trials: Application to omitting radiotherapy in low-risk breast cancer",
abstract = "Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.",
author = "{CISNET-BOLD Collaborative Group} and Yisheng Li and Schechter, {Clyde B.} and Reshma Jagsi and Juhee Song and Julia White and George Luta and Chapman, {Judith Anne W.} and Feuer, {Eric J.} and Zellars, {Richard C.} and Natasha Stout and Julian, {Thomas B.} and Timothy Whelan and Xuelin Huang and Hwang, {E. Shelley} and Hopkins, {Judith O.} and Sparano, {Joseph A.} and Anderson, {Stewart J.} and Fyles, {Anthony W.} and Robert Gray and Willi Sauerbrei and Jeanne Mandelblatt and Berry, {Donald A.} and Jinani Jayasekera",
note = "Funding Information: This work was supported by the National Institutes of Health under National Cancer Institute (NCI) Grant U01CA12958, U10CA180868, UG1CA189867, and U10CA180822. The research was also supported in part by supplemental funding provided by the NCI{\textquoteright}s Coordinating Center For Clinical Trials, a Lombardi Comprehensive Cancer Center American Cancer Society Young Investigator Award (ACS IRG 92-152-20), and the Cancer Prevention Research Fellowship sponsored by the American Society of Preventive Oncology and Breast Cancer Research Foundation (ASPO-17-001) to Dr. Jayasekera. Funding Information: Jinani Jayasekera, Yisheng Li, Clyde Schechter, Reshma Jagsi, Juhee Song, Julia White, George Luta, Judith-Anne Chapman, Eric Feuer, Richard Zellars, Natasha Stout, Thomas B. Julian, Tim Whelan, Xuelin Huang, E. Shelley Hwang, Judith Hopkins, Stewart Anderson, Anthony Fyles, Willi Sauerbrei, and Jeanne Mandelblatt have nothing to disclose. Julia White received honoraria from Qfix. Joseph A. Sparano owns stock in Metastat, has served in an advisory role for Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack, and has received research funding from Presceint Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Robert Gray has received research funding from Abbott Molecular, Agios, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, ImClone Systems, Janssen-Ortho, Kanisa, Millennium, Nodality, Onyx, OSI Pharmaceuticals, Pfizer, Sanofi, Sequenta, Syndax, and Novartis. Donald Berry is co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutical and medical device companies, National Institutes of Health cooperative groups, international consortia, and patient advocacy groups.",
year = "2018",
doi = "10.1093/jnci/djy059",
language = "English (US)",
volume = "110",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "12",
}