Cancer endpoints-Overall Survival

Overall survival (OS)

Overall Survival (OS) is despite it's disadvantages, still considered the most important endpoint in cancer studies but often compete with Progression-free survival (PFS) as the primary endpoint. Scientific, risk and cost considerations have to be taken into account.

Definition: Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population.
The FDA document "Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics" gives advice concerning this important endpoint.

Overall survival is by FDA considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint. This endpoint is precise and easy to measure, documented by the date of death.

The FDA document discusses some advantages and disadvantages of OS:
Regulatory evidence: Clinical benefit for regular approval
Study design: • Randomiomized studies essential • Blinding not essential
Advantages: • Universally accepted direct measure of benefit • Easily measured • Precisely measured
Disadvantages: • May involve larger studies • May be affected by cross-over therapy and sequential therapy • Includes non-cancer deaths.

Overall survival should be evaluated in randomized controlled studies. Data derived from historical trials are seldom reliable for time-dependent endpoints as OS and PFS. Apparent differences in outcome between historical controls and current treatment groups can arise from differences other than drug treatment, including patient selection, improved imaging techniques, or improved supportive care. Randomized studies minimize the effect of these differences by providing a direct outcome comparison. Demonstration of a statistically significant improvement in overall survival can be considered to be clinically significant if the toxicity profile is acceptable, and has often supported new drug approval.

A summary of the FDA document on cancer endpoints including some discussions around them can be found here: Oncology endpoints in a changing landscape.

Main challenge: Non-responders to study treatment (lack of efficacy, adverse events, other reasons) may result in the patient leaving the main schedule of the study and only survival will be recorded. Another treatment is often tried, leading to cross-over treatment. The cross-over issue is a disadvantage for the Overall survival endpoint. How to deal with it?

Hans Fagertun can assist you in the discussion whether to use OS or another survival-related endpoint as the primary endpoint.