Potential biological and clinical benefit of prostate-directed interventions in patients with metastatic prostate cancer.

In a recent issue of the Lancet, Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators, Parker et al.1 reported the updated results of a large prospective randomized control trial (RCT) that attempted to compare the additional radiotherapy with androgen deprivation therapy (ADT) and docetaxel for metastatic prostate cancer (mPCa). In this study, 2,061 men with mPCa were randomly assigned in a 1:1 ratio to receive ADT and docetaxel or ADT and docetaxel with radiotherapy and confirmed that addition of radiotherapy substantially improved failure-free survival [adjusted hazard ratio (HR), 0.76; 95% confidence interval (CI), 0.68–0.84; P<0.0001] but not overall survival (HR, 0.92; 95% CI, 0.80–1.06; P=0.27) in all patients. Subgroup analysis according to metastatic burden at randomization was prespecified in this RCT. High metastatic burden was defined as ≥4 bone metastases with at least one metastatic lesion outside the vertebral bodies, pelvis, or viscera. All other patients who were evaluable by imaging exams were considered to have low metastatic burden2. In a subgroup of patients with low metastatic burden, additional radiotherapy had improved overall survival (adjusted HR, 0.68; 95% CI, 0.52–0.90), whereas a significant benefit of prostate radiotherapy was not observed in patients with high metastatic burden (adjusted HR, 1.07; 95% CI, 0.90–1.28).

Regarding the dose schedule of radiotherapy to prostate, either one of the two hypofractionated dose schedule of external-beam radiotherapy was selected before randomization: 36 Gy in 6 fractions or 55 Gy in 20 fractions. These hypofractionated schedules were unique to this RCT because recommended dose schedules of radical radiotherapy for localized PCa involves 74–80 Gy. In a prior RCT evaluated benefit of additional radiotherapy to mPCa with bone metastasis, namely HORRAD trial (n=432), the prescribed dose was either conventional schedule (70 Gy in 35 fractions) or hypofractionated schedule (57.76 Gy in 19 fractions of 3.04 Gy)3. Radiotherapy group had not significantly improved overall survival compared with androgen deprivation therapy (ADT) alone (control group) (HR, 0.90; 95% CI, 0.70–1.14; P=0.40) in the HORRAD trial. In contrast, additional radiotherapy (15 months; 95% CI, 11.8–18.2) had significantly prolonged median time to prostate-specific antigen progression (crude HR, 0.78; 95% CI, 0.63–0.97; P=0.02) compared with ADT alone (12 months; 95% CI, 10.6–13.4). Differences in prostate radiotherapy regimens should be carefully considered while designing comparisons among this type of clinical trials. Overall, the optimum dose schedule and technique in the setting of additional radiotherapy to the primary prostate tumor for metastatic PCa are still uncertain.

Annals of translational medicine. 2019 Mar [Epub]

Authors: Makito Miyake, Takuya Owari, Nobumich Tanaka, Kiyohide Fujimoto

References:
1. Parker, Christopher C., Nicholas D. James, Christopher D. Brawley, Noel W. Clarke, Alex P. Hoyle, Adnan Ali, Alastair WS Ritchie et al. "Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial." The Lancet 392, no. 10162 (2018): 2353-2366.

2. Sweeney, Christopher J., Yu-Hui Chen, Michael Carducci, Glenn Liu, David F. Jarrard, Mario Eisenberger, Yu-Ning Wong et al. "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer." New England Journal of Medicine 373, no. 8 (2015): 737-746.

3. Boevé, Liselotte MS, Maarten CCM Hulshof, André N. Vis, Aeilko H. Zwinderman, Jos WR Twisk, Wim PJ Witjes, Karl PJ Delaere, R. Jeroen A. van Moorselaar, Paul CMS Verhagen, and George van Andel. "Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial." European urology 75, no. 3 (2019): 410-418.

Department of Urology, Nara Medical University, Nara, Japan.

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