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Gastrointestinal Cancer

End Points for Adjuvant Therapy Trials: Has the Time Come to Accept Disease-Free Survival as a Surrogate End Point for Overall Survival?

^a British Columbia Cancer Agency, Vancouver, British Columbia, Canada; ^b Mayo Clinic Cancer Center, Rochester, Minnesota, USA

Key Words. Adjuvant therapy • Overall survival • Disease-free survival

Correspondence: Daniel J. Sargent, Ph.D., Cancer Center Statistics, Mayo Clinic Cancer Center, 200 First Street SW, Rochester, Minnesota 55905, USA. Telephone: 507-284-5380; Fax: 507-266-2477; e-mail: sargent.daniel{at}mayo.edu

The intent of adjuvant therapy is to eradicate micro-metastatic residual disease following curative resection with the goal of preventing or delaying recurrence. The time-honored standard for demonstrating efficacy of new adjuvant therapies is an improvement in overall survival (OS). This typically requires phase III trials of large sample size with lengthy follow-up. With the intent of reducing the cost and time of completing such trials, there is considerable interest in developing alternative or surrogate end points. A surrogate end point may be employed as a substitute to directly assess the effects of an intervention on an already accepted clinical end point such as mortality. When used judiciously, surrogate end points can accelerate the evaluation of new therapies, resulting in the more timely dissemination of effective therapies to patients.

The current review provides a perspective on the suitability and validity of disease-free survival (DFS) as an alternative end point for OS. Criteria for establishing surrogacy and the advantages and limitations associated with the use of DFS as a primary end point in adjuvant clinical trials and as the basis for approval of new adjuvant therapies are discussed.

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