New study below [1].
We know that early use of Docetaxel [Taxotere] may benefit men with extensive metastases, but what about high-risk men without mets?
"A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years."
"Six-year rate of distant metastasis was 14% for AS {Androgen Suppression} + RT {Radiotherapy} and 9.1% for AS + RT + CT {Chemotherapy} ..."
"Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT ..."
-Patrick
[1] [full text] ascopubs.org/doi/full/10.12...
Discussion section"
This phase III clinical trial was designed to test the hypothesis that docetaxel CT, known to improve OS for men with metastatic castration-sensitive prostate cancer, could improve OS among men with high-risk localized prostate cancer when used in an adjuvant fashion after standard RT and AS. An improvement in OS was observed with adjuvant CT in this setting. The CT was generally well tolerated. In addition, the cumulative incidence of DM was reduced, and there were improvements in DFS, although not DSS, using blinded central review of cause of death. The NRG Oncology RTOG 0521 study followed a previous adjuvant CT study, RTOG 9902, which was terminated early because of thromboembolic toxicity associated with estramustine.16,17 Lack of unanticipated toxicity and better-tolerated CT led to timely completion of this protocol.
RT doses were standard at the time of study accrual.18 Although the radiation doses in NRG Oncology RTOG 0521 (72 to 75.6 Gy) were modestly lower than contemporary RT doses (eg, 79.2 Gy), the hypothesized benefit of docetaxel was to be primarily in the reduction of DM. The study findings showed that the 6-year rate of DM was significantly lower at 9.1% in the AS + RT + CT arm versus 14.0% in the AS + RT arm (P = .044).
Since NRG Oncology RTOG 0521 was designed, there have been other studies examining the role of docetaxel CT earlier in the clinical course of prostate cancer. GETUG-12 (Groupe d’Étude des Tumeurs Urogénitales)19 randomly assigned 413 patients with high-risk clinically localized disease treated with local therapy to AS (36 months) plus four cycles of adjuvant CT with docetaxel and estramustine or AS alone. Although the addition of CT increased relapse-free survival, a recent update of GETUG-12 demonstrated no statistically significant improvement in a prespecified end point of metastasis-free survival.20 In addition, the Scandinavian trial SPCG-13 (Scandinavian Prostate Cancer Group) demonstrated no benefit in biochemical DFS in a cohort of 378 men with intermediate- or high-risk disease randomly assigned to AS (12 months) plus adjuvant CT with six cycles of docetaxel CT versus AS alone.21 Similarly, the SPCG-12 study showed no benefit in biochemical DFS for 459 high-risk patients randomly assigned to radical prostatectomy plus adjuvant CT with six cycles of docetaxel chemotherapy versus radical prostatectomy alone.22 The discordance in results between RTOG 0521, which showed benefits in OS, DM, and DFS, and GETUG-12, SPCG-13, and SPCG-12 may stem from differences in patient populations among the studies. The RTOG 0521 cohort included patients with more aggressive disease; 84% of patients in RTOG 0521 had a Gleason score 8 to 10 disease, whereas a majority of patients in GETUG-12, SPCG-13, and SPCG-12 had a Gleason score less than or equal to 7 disease. These differences underscore the need to select high-risk patients with the most aggressive disease when considering treatment with adjuvant docetaxel.
Docetaxel-based CT has been used in castration-sensitive metastatic prostate cancer. In the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study,7 790 patients were randomly assigned to AS or AS + CT with six cycles of docetaxel. Median OS was improved with CT from 44 to 58 months. The survival benefit seemed to be restricted to those with higher-volume metastatic disease. In addition, the GETUG-15 study, with a smaller sample size than CHAARTED, did not show an OS benefit,23 although an update24 showed a trend toward OS benefit among the subset with high-volume disease as defined in CHAARTED. In the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial, which included patients with metastatic and nonmetastatic disease, docetaxel improved survival for men with castration-sensitive prostate cancer, with the primary benefit seen in patients with metastatic disease.8 Taken together, these studies suggest that there is a positive effect of docetaxel CT in subsets of men with castration-sensitive prostate cancer but reinforce the need for improved patient selection to better define these subsets. Studies in both nonmetastatic and metastatic castration-sensitive disease suggest a greater benefit of docetaxel in the subsets of patients with more aggressive disease features. In this study, PSA failure rates were not significantly different between the arms. It is possible that docetaxel, when used in combination with long-term AS + RT, may be focused on the androgen-insensitive clones that produce less PSA. This underlines the need for future investigation of the molecular profiles of patient samples from clinical trials to identify the biologic drivers of tumors in patients who benefit from docetaxel-based CT.
NRG Oncology RTOG 0521 was designed to detect an improvement in OS at 4 years. This early time point was derived from previous trials performed by RTOG in consideration of the practical issues related to trial accrual and the long natural history. Accordingly, a one-sided hypothesis was proposed, and the trial was designed with a one-sided P value along with a strong power of 90% to detect a positive effect with relative certainty. Although the magnitude of reduction in hazard (HR, 0.69) was not as large as the prestated HR goal of 0.49, in part because of higher-than-expected survival in the control group, the study was positive as hypothesized, and the clinically significant reduction in deaths is summarized in Table 2. There was not only improvement in OS but also improvement in DFS and reduction in 6-year rate of DM (Table 3). Sensitivity analysis of the patients treated per protocol (Table 4) confirmed the benefit noted in OS (HR, 0.59). Improvement in DFS and reduction in 6-year rate of DM were also confirmed with this analysis. Longer follow-up may better define the results, although competing risks are always a concern. Improved methods of risk stratification, including the emerging use of molecular profiling, may help to better identify patients who will benefit from intensification of treatment with CT in the future.
Although there are multiple management options, on the basis of the results of this trial, adjuvant CT with docetaxel can be reasonably discussed with selected men with high-risk localized prostate cancer who are fit for CT.
Radiotherapy (Radiation) To The Primary Tumor Benefits Men With Prostate Cancer Who Have Distant Metastasis at Diagnosis 
Comparative Effectiveness of Radical Prostatectomy vs EBRT Plus Brachytherapy in High-Risk Localized Prostate Cancer
