Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology

Abstract

IMPORTANCE Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit. OBJECTIVE To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life. DATA SOURCES For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016. STUDY SELECTION Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies. DATA EXTRACTION AND SYNTHESIS We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions. MAIN OUTCOME AND MEASURE The association between PFS duration and HRQoL. RESULTS Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were −0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, −0.27 to 0.52); for physical HRQoL (n = 20 trials) it was −0.20 (95% CI, −0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, −0.05 to 1.60). CONCLUSIONS AND RELEVANCE We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Association between progression‐free survival and patients’ quality of life in cancer clinical trials

“…To our knowledge, this is the largest study of the association between PFS and quality of life, with quality of life data available for 147 clinical trials from 2010 to 2015. Our results are consistent with a recent systematic review, which included 38 trials from 2000 to 2016 and reported no association between PFS and quality of life 23 ; the inclusion of a larger number of studies may strengthen the robustness of the findings of our study. We focused on Phase 3 clinical trials, because they provide the highest level of evidence on the safety and efficacy of an intervention and are therefore most likely to affect clinical practice.…”

Health‐related quality of life in oncology drug reimbursement submissions in Canada: A review of submissions to the pan‐Canadian Oncology Drug Review

“…9,11 Because these trials are used to inform submissions in other jurisdictions as well, similar issues have been reported. 12 Simultaneously, trials for cancer drugs are increasingly using surrogate outcomes such as progression-free survival (PFS) as their endpoint, but recent evidence reported by Kovic et al 13 has suggested that there is no association between PFS and HRQOL. These authors found the assumed link between PFS and HRQOL to be effectively false, and this questions the appropriateness of PFS as a measure of benefit in cancer drug trials.…”

“…These authors found the assumed link between PFS and HRQOL to be effectively false, and this questions the appropriateness of PFS as a measure of benefit in cancer drug trials. 13 Recently, there has been a growing skepticism about the additional benefit conferred by some high-cost cancer drugs. 6,7 The evidence provided by manufacturers in their submissions is becoming increasingly based on earlier stage trials.…”

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs

“…3,4 In recent years, PFS and response rates have become increasingly popular surrogate measures used in cancer trials. 5 Nevertheless, evidence shows that such surrogate measures may be an unpredictable marker of OS 6 and QoL benefit. 7 A systematic review in 2018 failed to find a significant association between PFS and QoL in cancer trials.…”