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

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.

Reply to S. Sundar et al and S. Höcht et al

“…3 Although we fully agree with the dangers of multiple testing and unplanned subgroup analyses, much of what they have stated are in fact strengths of randomization and limitations of observational research, especially in the context of our paper. 3 Every study design, including meta-analyses, has strengths and limitations. The strength of a metaanalysis is to capture the heterogeneity of study designs, broad inclusion criteria, treatment differences, and other potential biases or confounders, and finally to determine if a consistent treatment effect can be observed by virtue of a large sample size and consequently a greater power to detect differences that might be missed by individual trials.…”

“…An important consideration of any meta-analysis is the credibility of the results. 3 First, we used the randomized designs from both trials, which is critical to minimize unaccounted forms of bias between study arms. In fact, we used the entire Ottawa 0101 trial and the entire prostate-only randomized cohort in RTOG 9413.…”

A Review on the Current Treatment Paradigm in High-Risk Prostate Cancer

“…Findings from both these studies raised a possibility of superior biochemical relapse-free survival or progression-free survival with adjuvant ADT with prostate directed radiotherapy, respectively [29,36]. An individual patient databased meta-analysis of these two studies demonstrated that the sequencing of ADT with prostate-directed RT has significant impact on long-term oncologic outcomes in patients with localized prostate cancer [37]. Up to a 15-year truncation point in follow-up, restricted mean survival time for progression was significantly higher with adjuvant ADT with an absolute difference of 10.8 months (95% CI: 2.7-18.8), favoring the adjuvant approach.…”

Influence of Timing Between Androgen Deprivation Therapy and External Beam Radiation Therapy in Patients With Localized, High-Risk Prostate Cancer

“…Given that this analysis excluded patients receiving pelvic nodal irradiation, the discrepancy with our findings may be related ot the impact of treatment volumes on the optimal timing of ADT initiation as, suggested by RTOG 9413 (9). Further, ADT duration among all patients in this meta-analysis was six months, making these data less generalizable to a modern HR-PC cohort (18). patients treated with <60 Gy to prevent the inclusion of patients who treated with palliative intent.…”

“…In the RTOG 9413 trial, neoadjuvant ADT initiation benefited patients treated with whole-pelvic RT but not prostate-only RT (9). A recent meta-analysis of the patients treated with prostate-only RT from the RTOG 9413 and Ottawa 0101 trials found improved metastasis-free survival with concurrent ADT initiation as compared to neoadjuvant ADT initiation (18). Given that this analysis excluded patients receiving pelvic nodal irradiation, the discrepancy with our findings may be related ot the impact of treatment volumes on the optimal timing of ADT initiation as, suggested by RTOG 9413 (9).…”