Letters COMMENT & RESPONSE

Survival and Outcomes After Noncompletion of Treatment for Anal Cancer To the Editor We have read with great interest the Original Investigation by Raphael and colleagues1 evaluating factors associated with radiotherapy completion in the treatment of squamous cell anal carcinoma. As a secondary outcome, the authors estimated the association of treatment noncompletion with all-cause death, cancer-specific death, and the combined outcome of colostomy or death. They reported a higher cancer-specific death (hazard ratio [HR], 1.90; 95% CI, 1.322.75) and overall death (HR, 1.47; 95% CI, 1.14-1.89) among patients who did not complete radiotherapy. In the Methods, the authors stated that for all time-toevent analyses, time zero was the first dose of radiation. While such an approach best emulates a randomized clinical trial setting, it may introduce immortal time bias. Immortal time is a period of cohort follow-up whereby, because of the exposure definition, it is impossible for the outcome to occur.2 It frequently occurs with time-varying exposures that require multiple doses/measurements to meet the exposure definition and is thus particularly relevant in observational studies of cancer therapies. In the current study,1 the time between the first and last radiation fraction (minimum of 5 weeks to complete 25 fractions) was classified as completed, when, in fact, it was immortal person-time. While 5 weeks (approximately 0.1 years) of immortal time may seem trivial, 82% of the entire cohort, or 926 patients, were assigned to the radiotherapy completion group; thus, 92.6 person-years were potentially misclassified. Indeed, patients would have been considered as not completing the treatment if an outcome had occurred during this time period. This bias is suggested in the Kaplan-Meier survival curves, which rapidly diverged early in follow-up and then became parallel; such early treatment effects are characteristic of immortal time bias.3

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There are several methods to avoid immortal time bias when studying a time-varying exposure. One approach is to advance time zero of follow-up to the end of exposure completion for all patients in the cohort (ie, all patients would have the same opportunity of experiencing an event). Another approach is to perform a time-varying analysis, whereby patients would be able to contribute person-time in both exposure groups (ie, radiotherapy noncompletion and completion).2 While we cannot deduce the exact magnitude or clinical significance of this bias, we would encourage the authors to reanalyze their cohort using a time-varying approach to further substantiate their positive findings. The authors addressed an important clinical question for which additional research is much needed, and we congratulate them on their work. Richard Garfinkle, MD, MSc Laurent Azoulay, PhD Marylise Boutros, MD Author Affiliations: Division of Colon and Rectal Surgery, Jewish General Hospital, Montreal, Quebec, Canada (Garfinkle, Boutros); Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada (Azoulay). Corresponding Author: Marylise Boutros, MD, Division of Colon and Rectal Surgery, Jewish General Hospital, 3755 Cote Ste Catherine, G-317, Montreal, Quebec, H3T 1E2, Canada ([email protected]). Published Online: October 1, 2020. doi:10.1001/jamaoncol.2020.3949 Conflict of Interest Disclosures: Dr Azoulay reported serving as a consultant for Janssen and Pfizer outside the submitted work. No other disclosures were reported. 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 2. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008; 167(4):492-499. doi:10.1093/aje/kwm324 3. Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care. 2012;35(12):2665-2673. doi:10.2337/dc120788

(Reprinted) JAMA Oncology Published online October 1, 2020

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