Cancer Trials: Is Progression-Free Survival Enough?

October 8, 2018

A new study questions the use of progression-free survival as a surrogate endpoint in cancer clinical trials after finding it overlooks quality of life issues.

Progression-free survival (PFS) has become a frequent outcome used to evaluate new cancer drug efficacy.

But Canadian researchers failed to find a substantial link between PFS and health-related quality of life (HRQoL) in cancer trials, casting doubt on its role as a surrogate endpoint.

Lead investigators Sean Alexander Kennedy, Bruno Kovic and Xuejing Jin analyzed the results of 38 randomized oncology trials to try to pin down the connection between patients’ length of survival and quality of life.

They evaluated trials that focused on intravenous, oral, intraperitoneal or intrapleural chemotherapy or biological treatments and reported progression-free survival or health-related quality of life.

Their findings, published in JAMA Internal Medicine, suggest PFS benefits are unrelated to improved quality-of-life scores reported by patients — and don’t always translate into an overall survival (OS) benefit, an objective endpoint representing the duration of survival that’s viewed as the most important cancer trial outcome.

The report says there are only two possible reasons to use progression-free survival as an endpoint in oncology — the belief that it’s a valid surrogate marker for overall survival and the assumption that patients who live longer without disease progression — even without longer survival — will experience a higher quality of life.

But according to current evidence, progression-free survival is too unpredictable and inconsistent to serve as a viable surrogate for overall survival.

“[PFS’] association with improved [health-related quality of life] is far from self-evident,” the study says, “because HRQoL is likely to be impaired by adverse events resulting from the treatments responsible for prolonged” progression-free survival.

Oncological experts have questioned whether it’s appropriate to use PFS to evaluate treatments given the uncertainties, the investigators say.

They note that progression-free survival is a frequent surrogate because shorter and smaller trials can be used to measure it, making it more convenient.

It’s also a popular measure in FDA drug approvals. At least a dozen drugs approved by the agency over a five-year period used PFS as a primary endpoint.

Its use as a surrogate outcome has also been popular in clinical trials due to limitations associated with overall survival that include higher costs, larger sample sizes, longer follow-up and confounding effects that come from crossover designs and post-progression therapies.

Researchers say their findings indicate clinical trials must be “adequately powered” for overall survival and/or designed for strict and accurate quality of life measurements to meet the needs of cancer patients.  


-By James Miessler