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Prostate Radiotherapy With Adjuvant ADT Improves Metastasis-Free Survival Over Neoadjuvant ADT
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This meta-analysis used individual patient data from two randomized phase III trials to evaluate the optimal sequencing of androgen deprivation therapy and radiotherapy in patients with localized prostate cancer. An adjuvant approach was associated with superior clinical outcomes, including improvement in biochemical failure rates as well as progression-free and metastasis-free survival compared with a neoadjuvant approach. No significant increase in long-term toxicity was observed.
- According to this study, sequencing of androgen deprivation therapy and radiotherapy greatly improves long-term progression-free survival in patients with localized prostate cancer.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
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.
Additional Info
Disclosure statements are available on the authors' profiles:
Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis
J. Clin. Oncol 2020 Dec 04;[EPub Ahead of Print], DE Spratt, S Malone, S Roy, S Grimes, L Eapen, SC Morgan, J Malone, J Craig, RT Dess, WC Jackson, HE Hartman, AU Kishan, R Mehra, S Kaffenberger, TM Morgan, ZR Reichert, JJ Alumkal, J Michalski, WR Lee, TM Pisansky, FY Feng, W Shipley, HM Sandler, MJ Schipper, M Roach, Y Sun, CAF LawtonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Urology
This paper is an individual patient meta-analysis of two trials that compared different sequencing of short-course (4–6 months) androgen deprivation therapy (ADT) and radiotherapy (RT) in localized (mostly intermediate-risk) prostate cancer. Although treatments were heterogeneous, a simplified summary of the study design is that, in one arm of the meta-analysis, men received radiation toward the beginning of a short course of ADT (early RT), and, in the other arm, men received radiation toward the end of the short course of ADT (late RT). Those who received early RT (and thus had a more extended period of ADT after the end of radiation) appeared to have fared better with respect to clinically meaningful endpoints, including distant metastases-free survival.
This meta-analysis is an important contribution to the discussion and should reassure clinicians that there is no need to wait for an extended neoadjuvant ADT phase before starting prostate-only radiation. However, the study is likely not the final word on sequencing. One of the trials upon which this meta-analyses was based, RTOG 9413, suggests that there is an interaction between sequencing and the target volume of radiation. RTOG 9413 hints that neoadjuvant ADT might improve outcomes when pelvic lymph nodes are intentionally targeted. Until this interaction is better understood, some uncertainty about the optimal sequencing of RT and ADT will linger.
Advanced Prostate Cancer
Adjuvant was better than neoadjuvant. The clear difference is that radiation has already occurred, and the DNA damage has been initiated. So, giving ADT after radiation creates the possibility for synergy. However, likely the neoadjuvant situation creates less interaction between the hormonal therapies and radiation. Thus, synergy is likely lost. That's how I would interpret that.