The Value of Progression-Free Survival as a Treatment End Point Among Patients With Advanced Cancer

Abstract

IMPORTANCEIt is unclear whether patients with advanced cancer value surrogate end points, particularly progression-free survival (PFS). Despite this uncertainty, surrogate end points form the basis of regulatory approval for the majority of new cancer treatments.OBJECTIVE To summarize and qualitatively assess studies evaluating whether patients with advanced cancer understand and value PFS.EVIDENCE REVIEW MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature databases were searched from database inception to November 12, 2018. Articles eligible for inclusion investigated patient understanding, preference, or perceived value of disease progression or PFS in the setting of advanced cancer. Three authors independently reviewed and extracted data from all studies eligible for inclusion. FINDINGS In total, 17 studies representing 3646 patients were included. Of these studies, 15 specifically aimed to assess patients' values toward, and their willingness to trade off toxic effects for gains or losses in the end point of PFS. All studies examined used widely disparate definitions when attempting to describe the meaning of PFS to patients. Ten studies specifically presented patients with the term progression-free survival as an attribute choice. In the words used to define the attribute of PFS, 6 studies used the term survival. Five studies clarified that PFS may not translate into better overall survival, and 5 studies explained that improvements in PFS may not reflect how well the patient may feel. No study clarified that a PFS event could represent either progression or death, and no study defined for the patient what constituted progression. The studies assessed herein underrepresented ethnic and racial minorities (mean percentage of white patients, 88%; range, 77%-96%). Values and preferences may vary across cultural backgrounds given that different relative preferences were assigned to cost and efficacy outcomes in North American vs Asian studies, although only a few studies were evaluated. CONCLUSIONS AND RELEVANCEThe existing literature evaluating patients' understanding, preferences, and values toward the end point of PFS was severely limited by the heterogeneity of methods, attribute selection, and descriptions used to define PFS to patients. High-quality studies are needed that clearly define PFS for patients and that systematically document their understanding of the term. Only then can it be assessed whether PFS is an end point of value to patients with advanced cancer.

<p>Analysis of Patient Preferences in Lung Cancer – Estimating Acceptable Tradeoffs Between Treatment Benefit and Side Effects</p>

“…Therefore, PFS, which is also often used as an endpoint in clinical trials, was chosen as a benefit attribute. How to best explain PFS to patients requires further exploration, 51 but in our survey development process, the definition of PFS was tested with lung cancer patients and was found to be acceptable.…”

Association of progression-free or event-free survival with overall survival in diffuse large B-cell lymphoma after immunochemotherapy: a systematic review

“…However, OS as the primary endpoint requires a large sample size and long follow-up time to observe the survival benefit, leading to high clinical development costs and delays in introducing novel drugs. When used as the primary endpoints in clinical trials, early efficacy endpoints such as progression-free survival (PFS) and event-free survival (EFS) may require a smaller sample size and shorter evaluation time than OS, and have been established in some malignancies [ 6 – 8 ]. Trial- and individual-level studies have demonstrated that 24-month PFS and EFS may be considered the early efficacy endpoints for OS in DLBCL [ 9 – 12 ].…”

Inappropriate use of progression-free survival in cancer drug approvals

“…Regulators point to patient demand as justification. However, a recent systematic review questions whether patients value this endpoint 13. Studies examining this question differed in how they defined progression-free survival to patients, reflecting the inherent complexity of this endpoint and the challenge in interpreting changes, even for clinicians and researchers.…”