Surrogate Efficacy Endpoints in Oncology Trials
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CURRENT OPINION
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Surrogate Efficacy Endpoints in Oncology Trials Maurie Markman Department of Gynecologic Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Abstract
There will be little debate with the statement that the single most important goal of anti-neoplastic therapy in the setting of advanced or metastatic disease is to substantially prolong overall survival (or ‘cure’) from the time of initial diagnosis. As a result, this objective has been established as the primary endpoint in the majority of cancer trials conducted in this clinical setting. However, documenting an improvement in overall survival may require waiting until a sufficient number of study participants have died. As a result, there has been interest in developing acceptable surrogates (e.g. progression-free survival [PFS]) that may be employed at an earlier time point to declare whether a particular strategy will, or will not, ultimately be revealed to improve overall survival. In the discussion that follows, the potential utility of, and difficulties with, surrogates for overall survival in cancer trials will be discussed. Further, a rationale for considering the legitimate use of surrogates for defining clinical efficacy, independent of the relationship between the surrogate and overall survival, will be highlighted. It is concluded that in some settings an improvement in PFS is an excellent surrogate for overall survival, and the acceptance of PFS as a valid ‘early’ study endpoint will permit patients to experience the benefits of a new management approach at an earlier point following its initial introduction into clinical evaluation. However, it is also the case that an improvement in PFS may not translate into a subsequently documented superior overall survival. This result may occur due to the administration of increasingly effective ‘second-line’ treatment approaches employed following the completion of study-based therapy. In this setting, to accept PFS as the sole indicator of clinical benefit (without a documented improvement in overall survival), it will be critical to determine if this outcome was achieved with an acceptable treatment-related toxicity profile and a favourable impact on objective measures of quality of life.
The topic of surrogate markers for efficacy in oncology studies is currently one of the most hotly debated issues in the cancer clinical trials arena. Much of the focus of the discussion has been on the requirements for regulatory approval, and concern for the costs associated with newer anti-cancer agents.[1-3] It has been argued by some that with therapeutic regimens for many tumour types now easily exceeding $US100 000 for a ‘standard course’ of treatment, the only acceptable study endpoint for a change in a management paradigm resulting in the substitution of a newer for an older anti-neoplastic is an equivocally documented improvement in overall survival.[1-3] While it is recognized that the cost of cancer care w
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