乳腺癌术后疗效终点标准化定义更新( 二 )

Sara M. Tolaney, Elizabeth Garrett-Mayer, Julia White, Victoria S. Blinder, Jared C. Foster, Laleh Amiri-Kordestani, E. Shelley Hwang, Judith M. Bliss, Eileen Rakovitch, Jane Perlmutter, Patricia A. Spears, Elizabeth Frank, Nadine M. Tung, Anthony D. Elias, David Cameron, Neelima Denduluri, Ana F. Best, Angelo DiLeo, Lawrence Baizer, Lynn Pearson Butler, Elena Schwartz, Eric P. Winer, Larissa A. Korde.
Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; American Society of Clinical Oncology, Alexandria, VA; US Oncology Network, Virginia Cancer Specialists, Arlington, VA; The Ohio State University Comprehensive Cancer Center, Columbus, OH; Memorial Sloan Kettering Cancer Center, New York, NY; National Cancer Institute, Rockville, MD; US Food and Drug Administration, Silver Spring, MD; The Emmes Corporation, Rockville, MD; Duke University Comprehensive Cancer Center, Durham, NC; University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Gemini Group, Ann Arbor, MI; University of Colorado School of Medicine, Aurora, CO; The Institute of Cancer Research, London, United Kingdom; University of Edinburgh Cancer Research Centre, Edinburgh, United Kingdom; University of Toronto, Toronto, ON, Canada; Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.
METHODS: We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point.
RESULTS: Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.
CONCLUSION: We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.