Background: Because of prolonged screening requirements, patient and time-dependent selection have been proposed as potential biases in clinical trials. The screening process may exclude patients with a need for emergent treatment (and a short period from diagnosis to treatment initiation [DTI]). We explored the impact of DTI on overall survival (OS) in a population-based cohort of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Using population-based administrative databases in Ontario, Canada, we identified adults aged ≥18 years with DLBCL treated with rituximab-based chemotherapy for curative intent between January 2005 and December 2015. Cox regression and multivariable analyses were presented to evaluate the impact of time from DTI on OS, controlling for relevant covariates. Results: We identified 9,441 patients with DLBCL in Ontario; median age was 66 years, 53.6% were male, median number of comorbidities (Johns Hopkins aggregated diagnosis groups) was 10 (interquartile range [IQR], 8–13), and median DTI was 37 days (IQR, 22–61). Between treatment initiation and study end, 43% of patients died (median OS, 1 year; IQR, 0.4–2.8 years). Shorter DTI was a significant predictor of mortality (P<.001). Compared with the shortest DTI period of 0–18 days, those who commenced therapy at 19–29 days (hazard ratio [HR], 0.75; 95% CI, 0.68–0.84), 30–41 days (HR, 0.70; 95% CI, 0.63–0.78), 42–57 days (HR, 0.52; 95% CI, 0.46–0.58), and 58–180 days (HR, 0.52; 95% CI, 0.47–0.58) had improved survival. Increasing age (HR, 1.03; 95% CI, 1.03–1.04), male sex (HR, 1.23; 95% CI, 1.14–1.32), and increasing number of comorbidities (HR, 1.12; 95% CI, 1.11–1.13) were associated with inferior survival. Conclusions: Among patients with DLBCL, shorter DTI was associated with inferior OS. Therefore, DTI may represent a surrogate marker for aggressive biology. Clinical trials with lengthy screening periods are likely creating a time-dependent patient selection bias.
Submitted June 18, 2020; final revision received September 13, 2020; accepted for publication September 15, 2020.
Published online March 10, 2021.
Previous presentation: Parts of this study were presented as a poster at the 60th American Society of Hematology Annual Meeting and Exposition; December 1–4, 2018; San Diego, California. Poster 4850.
Author contributions: Study concept and methodology: All authors. Data curation, formal analysis, resources and software and data validation: Nagamuthu, Gatov, Croxford. Project administration: Blunt, Smyth, Nagamuthu, Gatov. Study supervision: Croxford, Mozessohn, Cheung. Writing—original draft: Blunt, Smyth. Writing—review & editing: Nagamuthu, Gatov, Croxford, Mozessohn, Cheung.
Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI), Cancer Care Ontario (CCO), and Service Ontario.
Disclaimer: The analyses, conclusions, opinions, and statements expressed herein are those of the authors, and not necessarily those of CIHI, CCO, or Service Ontario; no endorsement is intended or should be inferred.