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Meta-Analysis
. 2021 Jan 10;39(2):136-144.
doi: 10.1200/JCO.20.02438. Epub 2020 Dec 4.

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis

Daniel E Spratt  1 , Shawn Malone  2 , Soumyajit Roy  2   3 , Scott Grimes  2 , Libni Eapen  2   4 , Scott C Morgan  2 , Julia Malone  2 , Julia Craig  2 , Robert T Dess  1 , William C Jackson  1 , Holly E Hartman  1   5 , Amar U Kishan  6 , Rohit Mehra  7 , Samuel Kaffenberger  8 , Todd M Morgan  8 , Zachery R Reichert  9 , Joshi J Alumkal  9 , Jeff Michalski  10 , W Robert Lee  11 , Thomas M Pisansky  4 , Felix Y Feng  12 , William Shipley  13 , Howard M Sandler  14 , Mathew J Schipper  1 , Mack Roach 3rd  12 , Yilun Sun  1 , Colleen A F Lawton  15
Affiliations
Meta-Analysis

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis

Daniel E Spratt et al. J Clin Oncol. .

Abstract

Purpose: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa.

Methods: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS).

Results: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups.

Conclusion: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Trial registration: ClinicalTrials.gov NCT00769548.

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Figures

FIG 1.
FIG 1.
Consolidated Standards of Reporting Trials (CONSORT) Diagram. ADT, androgen deprivation therapy; RT, radiotherapy.
FIG 2.
FIG 2.
Forest plot of oncologic outcomes comparing neoadjuvant versus adjuvant ADT. ADT, androgen deprivation therapy; HR, hazard ratio; RMST, restricted mean survival time.
FIG 3.
FIG 3.
Kaplan-Meier of the primary end point of progression-free survival comparing adjuvant versus neoadjuvant ADT with RT. ADT, androgen deprivation therapy; HR, hazard ratio; RT, radiotherapy.
FIG 4.
FIG 4.
Comparison of adjuvant versus neoadjuvant ADT with RT. (A) Cumulative incidence of biochemical failure, (B) distant metastasis, and (C) prostate cancer–specific mortality. ADT, androgen deprivation therapy; RT, radiotherapy.
FIG A1.
FIG A1.
PRISMA diagram.
FIG A2.
FIG A2.
Subgroup analyses by end point.
FIG A3.
FIG A3.
Oncologic outcomes after adjustment for clinical trial. ADT, androgen deprivation therapy; HR, hazard ratio.
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