ArticlesShort-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial
Introduction
Androgen suppression can improve outcomes after radiotherapy for men with newly diagnosed locally advanced prostate cancer by targeting micro-metastases, which may be present in 20–30% of patients.1, 2 Long-term androgen suppression for 28–36 months is more effective than short-term suppression for 6 months or less.3, 4 However, prolonged androgen suppression can also lead to long-term morbidities including sarcopenia, osteopenia, and fractures.5 During the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial,6 we noted an advantage of neoadjuvant androgen suppression for 6 months before starting radiotherapy when compared with patients who received radiation alone. Would an additional 12 months of androgen suppression after 6 months of neoadjuvant androgen suppression and radiotherapy—ie, an intermediate term of 18 months—achieve the gains in efficacy reported after 2 years or more of adjuvant androgen suppression, but without long-term, adverse patient-reported outcomes such as hormone treatment-related symptoms, diminished sexual activity, fatigue, and social dysfunction?
Use of nitrogen bisphosphonates shows in-vitro efficacy in prostate cancer cell lines.7 Reduced skeletal-related events with little morbidity have been reported with these drugs by researchers studying metastatic, castration-resistant prostate cancer.8 Could addition of 18 months of zoledronic acid as a second adjuvant factor decrease bone metastases and prevent androgen suppression-induced osteopenia?
We designed the Randomised Androgen Deprivation and Radiotherapy (RADAR) trial, for men with locally advanced prostate cancer, to investigate the efficacy of radiotherapy with either short-term or intermediate-term androgen suppression, with or without zoledronic acid. Our study incorporated a 2 × 2 factorial design. 3 years after randomisation, we reported that neither androgen suppression nor zoledronic acid had an adverse effect on radiation-induced rectal and urinary morbidity9 or quality-of-life outcomes (with the exception of symptoms related to hormone treatment).10 Moreover, use of zoledronic acid for 18 months prevented osteopenia, and an additional 12 months of androgen suppression did not increase vertebral fractures.11 Here, we present primary and secondary endpoint data 6·5 years after last randomisation and an update of morbidity outcomes.
Section snippets
Study design and participants
The TROG 03.04 RADAR trial is a randomised, open-label, phase 3 trial with a 2 × 2 factorial design, located at 23 treatment centres across Australia and New Zealand (appendix p 11). We judged men eligible for the trial if they met the following criteria: aged 18 years or older; histologically confirmed adenocarcinoma of the prostate without lymph-node or systemic metastases; either stage T2b–4 primary tumour with any Gleason score and a baseline concentration of prostate-specific antigen
Results
Between Oct 20, 2003, and Aug 15, 2007, 2273 men were screened for the study, and 1071 were randomly allocated to one of the four treatment groups (figure 1). As of Feb 28, 2014—ie, 6·5 years after last randomisation—median follow-up was 7·4 years (IQR 6·5–8·4). Baseline characteristics were balanced evenly across treatment groups (table 1).
Of 243 men who died, 91 deaths were attributable to prostate cancer (table 2). In a further 25 patients, recurrent prostate cancer was present, but death
Discussion
No difference was noted between the four treatment groups in terms of the primary endpoint, prostate cancer-specific mortality. However, secondary endpoint data (including PSA progression, the primary endpoint until 2011) indicated that 18 months of androgen suppression alone could be favourable for tumours with a Gleason score of 7 or lower and that 18 months of androgen suppression in combination with 18 months of zoledronic acid might be a good choice for tumours with a Gleason score of 8–10
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