ArticlesQuality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial
Introduction
Androgen suppression improves outcomes after radiotherapy in patients with prostate cancer.1, 2, 3, 4, 5, 6 Efficacy is greater with 2 years or more of androgen suppression than with 6 months or less.7, 8 However, longer durations of androgen suppression increase long-term morbidity.9, 10, 11, 12, 13 These concerns led us to take a conservative approach after the results of our first trial, TROG 96.01,14 showed an advantage of adding neoadjuvant androgen suppression for 6 months to radiotherapy for men with locally advanced prostate cancer. In its successor, the RADAR trial, we aim to determine whether an additional 12 months of androgen suppression after 6 months of neoadjuvant androgen suppression and radiotherapy would achieve gains in efficacy that 2 years or more of adjuvant androgen suppression can produce, without long-term adverse patient-reported outcomes (PROs). Nitrogen bisphosphonates showed in-vitro efficacy in prostate cancer cell lines15, 16, 17 and reduced skeletal-related events in a trial of patients with advanced castrate-resistant metastatic prostate cancer.18 We therefore incorporated 18 months of zoledronic acid into RADAR to assess whether it would reduce the frequency of bone metastases and androgen suppression-induced osteopenia.
Because the major limitation of the TROG 96.01 trial was the low-dose, non-conformal radiotherapy, we took advantage of the better radiotherapy delivery systems available in Australia and New Zealand in 2003 to incorporate a dose-escalation programme into the RADAR trial.19, 20 Addressing this limitation gave us the opportunity to ascertain not only whether higher radiation doses reduce the need for androgen suppression, but whether these doses can be delivered without long-term detrimental effects on PRO scores. Since a high-dose rate brachytherapy (HDRB) boost was one of the dose-escalation options, the RADAR trial is one of the first in which the value of this treatment was tested in a randomised setting. We report the effect of the study drugs and radiation dose escalation on PROs in the RADAR trial up to 36 months after randomisation.
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Study design and patients
The TROG 03.04 RADAR trial is a randomised, open-label, phase 3 trial with a 2×2 factorial design. It was undertaken at 23 centres in Australia (n=17) and New Zealand (n=6). Eligible men had histologically confirmed adenocarcinoma of the prostate without lymph node or systemic metastases, and with stage T2b–4 primary tumours, or stage T2a primary tumours with a Gleason score of 7 or greater and baseline prostate-specific-antigen (PSA) levels of 10 μg/L or more immediately before randomisation.
Results
Between Oct 20, 2003, and Aug 15, 2007, 1071 patients were randomly assigned to four treatment groups (figure 1). Table 1 shows the baseline tumour characteristics and details of the radiotherapy dose and technique. 1067 (99·6%) of 1071 patients completed the EORTC QLQ C-30 and PR-25 questionnaires at randomisation, 1026 (97·3%) of 1055 after radiotherapy, 1009 (97·4%) of 1036 at 18 months after randomisation, and 940 (95·6%) of 983 at 36 months.
At baseline, testosterone concentrations were
Discussion
In this study, 18 months of androgen suppression worsened the adverse changes in PRO scores caused by 6 months of androgen suppression and radiotherapy. However, these increases were restricted to only a few PRO domains: sexual activity, HTRS, fatigue, and financial problems at 18 months after randomisation. The increases were also restricted in time. With the exception of HTRS (particularly hot flushes, gynaecomastia, and weight gain), when marginal differences persisted, the adverse PRO
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