Impact of disease progression date determination on progression‐free survival estimates in advanced lung cancer

Abstract

PURPOSE Progression-free survival (PFS) based endpoints are controversial; however in advanced lung cancer, overall survival is largely influenced by the progression status. We thus evaluated the impact of progression date (PD) determination approach on PFS estimates. METHODS Individual patient data from 21 trials (14 NCCTG; 7 SWOG) were used. Reported progression date (RPD) was defined as either the scan date or the clinical deterioration date. PD was determined using 4 methods (M): RPD (M1), one day after last progression-free scan (M2), midpoint between last progression-free scan and RPD (M3), and using an interval censoring approach (M4). PFS was estimated using Kaplan-Meier (M1, M2, M3), and maximum likelihood (M4). Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time to progression (TTP) estimates. RESULTS PFS estimates using RPD were the highest, with M2 being the most conservative. M3 and M4 were similar due to majority of progressions occurring during treatment (i.e., frequent disease assessments). M3 was less influenced by the length of the assessment schedules (%difference from true TTP <1.5%) compared to M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. CONCLUSION The magnitude of difference in the PFS estimates is large enough to alter trial conclusions in advanced lung cancer. Standards for PD determination, use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS based endpoints.

Eligibility for Bevacizumab as an Independent Prognostic Factor for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study

“…Progression-free survival (PFS) is generally favorable for evaluating the impact on treatment efficacy, since TTF is affected not only by efficacy, but also by toxic effects. However, we did not use PFS in this retrospective study because intervals between radiographic evaluations varied considerably among patients, which would compromise the accuracy of the results [18]. Our results support the notion that BV eligibility confers a positive impact upon chemotherapeutic outcomes, but this speculation requires validation.…”

The Clinical Viewpoint: Definitions, Limitations of RECIST, Practical Considerations of Measurement

“…In a study conducted by Qi and colleagues, individual patient data from 14 North Central Cancer Treatment Group (NCCTG) clinical trials and 7 Southwest Oncology Group (SWOG) clinical trials were used to determine the date of disease progression based on 4 common methods: the reported disease progression date (M1), 1 day after the last progression-free scan (M2), the midpoint between the last progression-free scan and the date of reported disease progression (M3), or interval censoring (M4; ref. 15). The magnitude of difference in the PFS estimates as determined by these 4 methods was large enough to alter trial conclusions in patients with advanced lung cancer; the midpoint method was the least influenced by the assessment schedule.…”

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

“…Issues with PFS as an endpoint are well documented and discussed elsewhere. 12–18 Despite the many issues with PFS, it is considered a possible surrogate endpoint for OS, as it is unaffected by subsequent therapies and could shorten the time to drug approval. Given preliminary promising evidence of PFS as a candidate surrogate endpoint for OS, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 7 additional first-line randomized phase II/III trials (2259 patients).…”