Laila A Gharzai1, Ralph Jiang2, David Wallington3, Gavin Jones4, Samuel Birer1, Neil Jairath1, Elizabeth M Jaworski1, Matthew R McFarlane1, Brandon A Mahal5, Paul L Nguyen6, Howard Sandler7, Todd M Morgan8, Zachery R Reichert9, Joshi J Alumkal9, Rohit Mehra10, Amar U Kishan11, Karim Fizazi12, Susan Halabi13, Edward M Schaeffer14, Felix Y Feng15, David Elliott1, Robert T Dess1, William C Jackson1, Matthew J Schipper16, Daniel E Spratt17. 1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. 2. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. 3. Department of Radiation Oncology, Western Michigan University, Kalamazoo, MI, USA. 4. Department of Radiation Oncology, University of Kentucky, Lexington, KY, USA. 5. Department of Radiation Oncology, University of Miami, Miami, FL, USA. 6. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 7. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 8. Department of Urology, University of Michigan, Ann Arbor, MI, USA. 9. Department of Medical Oncology, University of Michigan, Ann Arbor, MI, USA. 10. Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 11. Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. 12. Department of Cancer Medicine, Institut Gustave-Roussy, Villejuif, France. 13. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. 14. Department of Urology, Northwestern University, Chicago, IL, USA. 15. Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. 16. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. 17. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address: sprattda@med.umich.edu.
Abstract
BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.
BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.
Authors: Christopher U Jones; Stephanie L Pugh; Howard M Sandler; Michael P Chetner; Mahul B Amin; Deborah W Bruner; Anthony L Zietman; Robert B Den; Mark H Leibenhaut; John M Longo; Jean-Paul Bahary; Seth A Rosenthal; Luis Souhami; Jeff M Michalski; Alan C Hartford; Pradip P Amin; Mack Roach; Don Yee; Jason A Efstathiou; Joseph P Rodgers; Felix Y Feng; William U Shipley Journal: Int J Radiat Oncol Biol Phys Date: 2021-09-01 Impact factor: 7.038
Authors: David Guy; Rachel Glicksman; Roger Buckley; Patrick Cheung; Hans Chung; Stanley Flax; David Hajek; Andrew Loblaw; Gerard Morton; Jeffery Noakes; Les Spevack; Joseph L K Chin; George Rodrigues Journal: Can Urol Assoc J Date: 2022-04 Impact factor: 2.052
Authors: Gaëtan Devos; Wout Devlies; Gert De Meerleer; Marcella Baldewijns; Thomas Gevaert; Lisa Moris; Daimantas Milonas; Hendrik Van Poppel; Charlien Berghen; Wouter Everaerts; Frank Claessens; Steven Joniau Journal: Nat Rev Urol Date: 2021-09-15 Impact factor: 14.432
Authors: Kai Yun Ooi; Ian Pereira; Himanshu Nagar; Richard Simcock; Matthew S Katz; Christopher C Parker; Colleen Lawton; Hina Saeed Journal: Clin Transl Radiat Oncol Date: 2021-08-06