Sara M Tolaney1,2, Elizabeth Garrett-Mayer3, Julia White4, Victoria S Blinder5, Jared C Foster6, Laleh Amiri-Kordestani7, E Shelley Hwang8, Judith M Bliss9, Eileen Rakovitch10, Jane Perlmutter11, Patricia A Spears12, Elizabeth Frank1, Nadine M Tung13, Anthony D Elias14, David Cameron15, Neelima Denduluri16, Ana F Best6, Angelo DiLeo17, Lawrence Baizer18, Lynn Pearson Butler19, Elena Schwartz18, Eric P Winer1,2, Larissa A Korde20. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 2. Harvard Medical School, Boston, MA. 3. American Society of Clinical Oncology, Alexandria, VA. 4. The Ohio State University Comprehensive Cancer Center, Columbus, OH. 5. Memorial Sloan Kettering Cancer Center, New York, NY. 6. Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD. 7. US Food and Drug Administration, Silver Spring, MD. 8. Department of Surgery, Duke University Comprehensive Cancer Center, Durham, NC. 9. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom. 10. Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. 11. Gemini Group, Ann Arbor, MI. 12. University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC. 13. Beth Israel Deaconess Medical Center, Boston, MA. 14. University of Colorado School of Medicine, Aurora, CO. 15. University of Edinburgh Cancer Research Centre, Edinburgh, United Kingdom. 16. US Oncology Network, Virginia Cancer Specialists, Arlington, VA. 17. Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. 18. Coordinating Center for Clinical Trials, National Cancer Institute, Rockville, MD. 19. The Emmes Corporation, Rockville, MD. 20. Cancer Therapy and Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD.
Abstract
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.
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.
Authors: Christine V Pestana; Chad A Livasy; Erin E Donahue; Brittany Neelands; Antoinette R Tan; Terry Sarantou; Lejla Hadzikadic-Gusic; Richard L White Journal: Ann Surg Oncol Date: 2022-07-09 Impact factor: 4.339
Authors: Wanyuan Cui; Kelly-Anne Phillips; Prudence A Francis; Richard A Anderson; Ann H Partridge; Sherene Loi; Sibylle Loibl; Louise Keogh Journal: Breast Date: 2022-05-16 Impact factor: 4.254