Immortal Time Bias in National Cancer Database Studies

Purpose: In studies evaluating the benefit of adjuvant therapies, immortal time bias (ITB) can affect the results by incorrectly reporting a survival advantage. It does so by including all deceased patients who may have been planned to receive adjuvant therapy within the observation cohort. Given the increase in National Cancer Database (NCDB) analyses evaluating postoperative radiation therapy (PORT) as an adjuvant therapy, we sought to examine how often such studies accounted and adjusted for ITB.

Methods and materials: A systematic review was undertaken to search MEDLINE and EMBASE from January 2014 until May 2019 for NCDB studies evaluating PORT. After appropriate exclusion criteria were applied, 60 peer-reviewed manuscripts in which PORT was compared with postoperative observation or maintenance therapy were reviewed. The manuscripts were reviewed to evaluate whether ITB was accounted for, the method with which it was adjusted for, impact factor, year of publication, and whether PORT was beneficial.

Results: Of the 60 publications reviewed, 23 studies (38.3%) did not include an adjustment for ITB. Most studies that did adjust for ITB employed a single landmark (LM) time (n = 31), 4 used a sequential landmark analyses, and 2 used a time-dependent Cox model. In 23 of 31 studies (74.2%) that did adjust for ITB via a single LM time, the rationale behind why the specified LM time was chosen was not clearly explained. There was no relationship between adjusting for ITB and year of publication (P = .074) or whether the study was published in a high-impact journal (P = .55).

Conclusions: Studies assessing adjuvant radiation therapy by analyzing the NCDB are susceptible to ITB, which overestimates the effect size of adjuvant therapies and can provide misleading results. Adjusting for this bias is essential for accurate data representation and to better quantify the impact of adjuvant therapies such as PORT.