Letters COMMENT & RESPONSE In Reply We would like to thank Jain et al and Garfinkle et al for their thoughtful comments on our recent Original Investigation.1 Jain et al inquired about those who received higher doses of radiation (54-59 Gy). We report a protective association between higher dose of radiation and lower all-cause death (adjusted hazard ratio [aHR], 0.75; 95% CI, 0.56-1.01). Data are unavailable to explore grade 4 hematologic and nonhematologic toxic effects. We did attempt to determine outcomes based on hospital volume with hierarchical models, but the sample size in the lowestvolume hospitals affected convergence. We therefore reported a descriptive analysis of regional variation in treatment patterns and outcomes. Finally, Jain et al inquired about the use of capecitabine in combination with mitomycin C or cisplatin. In the cohort, only 17 patients received capecitabine in combination with mitomycin C, while none received capecitabine with cisplatin. Because capecitabine is an oral medication, we could not determine interruptions or discontinuation. Therefore, these patients were excluded from analyses evaluating the association between chemoradiation interruption or noncompletion and survival outcomes. Garfinkle et al raised the important concern of immortal time bias. In designing the study, we initially considered using time zero as the date of last radiation dose; with this time zero, patients who did not complete radiotherapy and those who completed radiotherapy had no survival requirement inherent in the exposure definition. Using this approach, the estimated aHR of 5-year all-cause death in those who did not complete radiotherapy vs those who did was 1.54 (95% CI, 1.122.12). This estimate is nearly identical to that we report in our article (aHR, 1.55; 95% CI, 1.13-2.14), in which the date of first radiation dose was used. We chose to use date of first radiation dose as time zero because of concerns of potential con-

founding (eg, from difference in cancer progression or greater comorbidity) by radiotherapy completion status when using date of last radiation dose as time zero. As suggested, we conducted Cox regression with radiotherapy modeled as a timedependent exposure whereby patients who underwent radiotherapy were classified as noncompleters until they received at least 45 Gy and 25 fractions, from which point they were classified as completers. Using this approach, the estimated aHR was 1.55 (95% CI, 1.13-2.14)—a result again nearly identical to our original analysis. Our final study design preferentially addressed potential confounding bias over immortal time bias. Based on the 3 aHRs reported above, these biases, if present, appear to have a similar effect on the study result, with the bias toward higher mortality in noncompleters relative to completers. Sunil Patel, MD, MSc Susan Brogly, PhD Michael Raphael, MD Author Affiliations: Queen’s University, Kingston, Ontario, Canada (Patel); Department of Surgery, Queen’s University, Kingston, Ontario, Canada (Brogly); University of Toronto, Toronto, Ontario, Canada (Raphael). Corresponding Author: Sunil Patel, MD, MSc, Queen’s University, 76 Stuart St, Kingston, Ontario K7L2V7, Canada ([email protected]). Published Online: October 1, 2020. doi:10.1001/jamaoncol.2020.3963 Conflict of Interest Disclosures: Dr Brogly reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development outside the submitted work. No other disclosures were reported. Additional Contributions: We would like to acknowledge Wenbin Li, PhD (ICES Queen’s, Kingston, Ontario, Canada), for his analytical support. Salary reimbursement was provided to ICES Queens for his analytic time. 1. Raphael MJ, Ko G, Booth CM, et al. Factors associated with chemoradiation therapy interruption and noncompletion among patients with squamous cell anal carcinoma. JAMA Oncol. 2020;6(6):881-887. doi:10.1001/jamaoncol.2020. 0809

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