Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.
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Roy Soumyajit, Romero Tahmineh, Michalski Jeff M, Feng Felix Y, Efstathiou Jason A, Lawton Colleen A F, Bolla Michel, Maingon Philippe, de Reijke Theo, Joseph David, Ong Wee Loon, Sydes Matthew R, Dearnaley David P, Tree Alison C, Carrier Nathalie, Nabid Abdenour, Souhami Luis, Incrocci Luca, Heemsbergen Wilma D, Pos Floris J, Zapatero Almudena, Guerrero Araceli, Alvarez Ana, San-Segundo Carmen Gonzalez, Maldonado Xavier, Reiter Robert E, Rettig Matthew B, Nickols Nicholas G, Steinberg Michael L, Valle Luca F, Ma T Martin, Farrell Matthew J, Neilsen Beth K, Juarez Jesus E, Deng Jie, Vangala Sitaram, Avril Norbert, Jia Angela Y, Zaorsky Nicholas G, Sun Yilun, Spratt Daniel, Kishan Amar U, Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium Investigators
Аннотация
MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.
RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.
CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.