Elsevier

European Urology

Volume 75, Issue 3, March 2019, Pages 410-418
European Urology

Platinum Priority – Prostate Cancer
Editorial by Alan Dal Pra, Matthew Abramowitz and Alan Pollack on pp. 419–422 of this issue
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

https://doi.org/10.1016/j.eururo.2018.09.008Get rights and content

Abstract

Background

The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue.

Objective

To determine whether overall survival is prolonged by adding local treatment of the primary prostatic tumour with external beam radiation therapy (EBRT) to ADT.

Design, setting, and participants

The HORRAD trial is a multicentre RCT recruiting 432 patients with prostate-specific antigen (PSA) >20 ng/ml and primary bone mPCa on bone scan between 2004 and 2014.

Intervention

Patients were randomised to either ADT with EBRT (radiotherapy group) or ADT alone (control group).

Outcome measurements and statistical analysis

Primary endpoint was overall survival. Secondary endpoint was time to PSA progression. Crude and adjusted analyses were applied to evaluate treatment effect.

Results and limitations

Median PSA level was 142 ng/ml and 67% of patients had more than five osseous metastases. Median follow up was 47 mo. Median overall survival was 45 mo (95% confidence interval [CI], 40.4–49.6) in the radiotherapy group and 43 mo (95% CI: 32.6–53.4) in the control group (p = 0.4). No significant difference was found in overall survival (hazard ratio [HR]: 0.90; 95% CI: 0.70–1.14; p = 0.4). Median time to PSA progression in the radiotherapy group was 15 mo (95% CI: 11.8–18.2), compared with 12 mo (95% CI: 10.6–13.4) in the control group. The crude HR (0.78; 95% CI: 0.63–0.97) was statistically significant (p = 0.02).

Conclusions

The current RCT comparing ADT to ADT with EBRT to the prostate in patients with primary bone mPCa did not show a significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings.

Patient summary

This study investigated the effect of adding radiation therapy to the prostate to hormonal therapy in prostate cancer patients with metastasis to the bone at diagnosis. In our patient group, additional radiotherapy did not improve overall survival. Further research is needed to confirm our findings.

Twitter summary

Adding radiotherapy to the prostate in patients with bone metastatic prostate cancer does not improve overall survival.

Introduction

In western countries, prostate cancer (PCa) is the most common form of cancer among men of 50 yr and older, with a mortality-to-incidence ratio of 20% [1]. Worldwide, an estimated 1.1 million cases were diagnosed in 2012 [2]. Although the widespread use of prostate-specific antigen (PSA) testing has led to earlier detection of PCa, in 2015 still 16% of patients with PCa in The Netherlands presented with bone metastatic disease at first diagnosis. The current standard treatment for metastatic disease is systemic therapy with androgen deprivation therapy (ADT) that, at present, is frequently combined with docetaxel or abiraterone [3], [4], [5].

Treatment of the primary prostatic tumour is not standard practice in those with metastatic disease, although local therapy has been proven to prolong overall survival in other primary metastasised malignancies [6], [7], [8], [9]. During the Advanced Prostate Cancer Consensus Conference 2017, however, 69% of panellists suggested that radical local treatment should be regarded as the appropriate type of treatment for patients with newly diagnosed oligometastatic prostate cancer [10]. In addition, 48% of panellists considered radical local treatment in men with de novo asymptomatic high-volume metastatic prostate cancer. To date, no randomised controlled trials (RCTs) have been published to address the potential benefits of simultaneous local treatment of the prostate complementary to ADT.

The current RCT was based on the hypothesis that in patients with primary bone metastatic PCa (mPCa), the oncological outcome might be improved by administrating radical radiotherapy (RT) to the primary tumour in addition to standard ADT. The HORRAD trial is a multicentre prospective RCT that studies the efficacy of external beam radiation therapy (EBRT) to the prostate in addition to standard ADT in patients with mPCa, with overall survival as the primary outcome.

Section snippets

Trial design and participants

The HORRAD trial is a multicentre prospective RCT. Patients were recruited in 28 centres across The Netherlands. Patients were eligible if they had a previously untreated, histologically confirmed diagnosis of adenocarcinoma of the prostate with any number of bone metastases on bone scintigraphy. Tumours could be of any grade (Gleason score 6–10) and T stage (cT1-cT4; cN0-cN1; M1) [11].

Exclusion criteria were age >80 yr; PSA <20 ng/ml; previous treatment for prostate cancer; insufficient

Patients characteristics

Between November 2004 and September 2014, 446 patients diagnosed with mPCa were assessed for eligibility in 28 participating centres. Six patients were excluded because of either a second malignancy (n = 2), absence of osseous metastases (n = 2), or unknown screening failure (n = 2). Eight patients declined to participate, despite having previously given informed consent. The remaining 432 patients were randomly assigned to either ADT with EBRT (RT group, n = 216) or ADT alone (control group, n = 216).

Discussion

This is the first RCT in patients with mPCa evaluating local treatment of the primary tumour along with ADT compared to ADT alone, with overall survival as the primary endpoint. No overall survival benefit was shown for concurrent local treatment after a median follow-up time of 47 mo. Median overall survival was 45 mo (95% CI: 40.4–49.6) in the RT group and 43 mo (95% CI: 32.6–53.4) in the control group (p = 0.4).

The results of our RCT differ from those in the recent literature, where various

Conclusions

The current randomised trial comparing ADT to ADT with EBRT to the prostate in patients with primary mPCa showed no significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings.

Author contributions: Liselotte M.S. Boevé had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hulshof,

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