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Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.
Gharzai, Laila A; Jiang, Ralph; Wallington, David; Jones, Gavin; Birer, Samuel; Jairath, Neil; Jaworski, Elizabeth M; McFarlane, Matthew R; Mahal, Brandon A; Nguyen, Paul L; Sandler, Howard; Morgan, Todd M; Reichert, Zachery R; Alumkal, Joshi J; Mehra, Rohit; Kishan, Amar U; Fizazi, Karim; Halabi, Susan; Schaeffer, Edward M; Feng, Felix Y; Elliott, David; Dess, Robert T; Jackson, William C; Schipper, Matthew J; Spratt, Daniel E.
Affiliation
  • Gharzai LA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Jiang R; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Wallington D; Department of Radiation Oncology, Western Michigan University, Kalamazoo, MI, USA.
  • Jones G; Department of Radiation Oncology, University of Kentucky, Lexington, KY, USA.
  • Birer S; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Jairath N; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Jaworski EM; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • McFarlane MR; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Mahal BA; Department of Radiation Oncology, University of Miami, Miami, FL, USA.
  • Nguyen PL; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sandler H; Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Morgan TM; Department of Urology, University of Michigan, Ann Arbor, MI, USA.
  • Reichert ZR; Department of Medical Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Alumkal JJ; Department of Medical Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Mehra R; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Kishan AU; Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Fizazi K; Department of Cancer Medicine, Institut Gustave-Roussy, Villejuif, France.
  • Halabi S; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
  • Schaeffer EM; Department of Urology, Northwestern University, Chicago, IL, USA.
  • Feng FY; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Elliott D; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Dess RT; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Jackson WC; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • Schipper MJ; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Spratt DE; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address: sprattda@med.umich.edu.
Lancet Oncol ; 22(3): 402-410, 2021 03.
Article in En | MEDLINE | ID: mdl-33662287
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Biomarkers / Neoplasm Recurrence, Local Type of study: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Aged / Humans / Male Language: En Journal: Lancet Oncol Journal subject: NEOPLASIAS Year: 2021 Document type: Article Affiliation country: United States
Fulltext
Add to My VHL
Print
XML
PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Biomarkers / Neoplasm Recurrence, Local Type of study: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Aged / Humans / Male Language: En Journal: Lancet Oncol Journal subject: NEOPLASIAS Year: 2021 Document type: Article Affiliation country: United States