The U.S. Food and Drug Administration (FDA) recently granted bevacizumab (Avastin) accelerated approval for use in combination with paclitaxel (Taxol) to treat some patients with metastatic breast cancer. The decision cast a spotlight on a somewhat controversial clinical trial endpoint that the agency used to support its decision. Though the combined therapy improved progression-free survival (PFS) by 5 months compared with the control group, which received only paclitaxel, there was no significant improvement in patients' overall survival (OS).

The difference between PFS and OS is that PFS measures the time from a patient's random assignment to one treatment arm or another until the patient's cancer begins to grow again or the patient dies from their cancer; whereas OS measures the time from randomization until death from any cause.

Central to the controversy over the use of PFS as an endpoint in cancer clinical trials is whether delaying disease progression matters if a cancer treatment doesn't also lengthen patients' lives. Put another way, which matters more: longer life or better quality of life?

FDA considers OS the most reliable cancer endpoint. It is a universally accepted direct measure of the benefit of an experimental drug or other treatment, and it is unequivocal and easy to measure. Demonstrating in a clinical trial that a drug improves OS, however, is no easy feat. It often requires trials with hundreds of patients that take years to complete.

Furthermore, with multiple treatment options now available for many types of cancer, patients can switch to other therapies if the treatment they are receiving in a clinical trial stops working. That's good for patients, but it creates a conundrum for those who must interpret trial results: If a patient's OS improved, how much of that improvement was due to the study drug and how much was due to subsequent treatments?

In this respect, explains Dr. Daniel J. Sargent, a biostatistician with the North Central Cancer Treatment Group (an NCI-sponsored clinical trials cooperative group) who has authored numerous articles about endpoints in cancer clinical trials, PFS offers an advantage over OS because it requires patients to be followed only until their disease progresses. PFS, therefore, measures only the effect of the study drug and is not diluted by subsequent treatments patients receive, as OS may be.

"Most patients stop taking the study drug when their disease begins to progress," he says, "so the PFS clock stops at that point." This also means that trials using PFS as an endpoint can be completed more quickly than trials using OS, and they generally require fewer patients.

A key advantage of PFS as a clinical trial endpoint, says Dr. Sargent, is that "it captures both a tumor-shrinkage and a tumor-stabilization effect." This is important because, unlike conventional chemotherapeutic drugs that kill cancer cells, causing tumors to shrink, many new targeted drugs (including bevacizumab) work by other mechanisms, which may stop tumors from growing but don't always cause them to shrink.

A concern with using PFS as a trial endpoint, says Dr. Sargent, is that it's more subjective than OS and can be influenced by outside factors, including how disease progression is defined and measured, which may vary from one trial to another. For example, because progression is measured by X-rays or computerized tomography (CT) scans, measures of PFS can differ depending on how frequently those assessments are performed.

Other questions surrounding PFS include: What magnitude of improvement in PFS is clinically meaningful? And is an improvement in PFS beneficial to patients in and of itself, regardless of whether OS is also improved?

Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis, is emphatic that, at least in advanced breast cancer, an improvement in PFS is beneficial to patients in and of itself. "In advanced breast cancer, disease progression is often symptomatic and uncomfortable, so if we can delay that, it's a benefit to the patient," she says.

However, Dr. Zujewski adds two caveats: "The magnitude of the benefit must be sufficient to be confident that it's not biased. An increase of a month or two would not provide that confidence and would probably not be clinically meaningful. Second, patients must not endure a lot of toxicity as a price for keeping their disease in control longer. If an oral agent had very few side effects and delayed progression for 4 months, most patients with advanced breast cancer would take it."

Dr. Richard Pazdur, director of the FDA Office of Oncology Drug Products, agrees. "I have no problem accepting that, in a lethal disease such as metastatic cancer, delaying progression is a clinical benefit in itself, provided that the magnitude of the benefit is sufficient and the side-effect profile acceptable."

FDA has recently approved several other new anticancer drugs based on an improvement in PFS, notes Dr. Pazdur, including sorafenib (Nexavar) for renal cell cancer, gemcitabine (Gemzar) for ovarian cancer, and ixabepilone (Ixempra) for breast cancer.

The agency still asks clinical trial sponsors to enroll a sufficient number of patients to detect an effect on OS, adds Dr. Pazdur. "We always want to be sure a drug isn't reducing OS," he explains. "But a dogmatic approach that we will accept only an improvement in OS for drug approval doesn't serve anyone well, certainly not patients. I know there are people who think granting approvals based on an improvement in PFS amounts to lowering the standard, but I view it as having greater flexibility."

—Eleanor Mayfield