Addition of Radiotherapy to Long-Term Androgen Deprivation in Locally Advanced Prostate Cancer: An Open Randomised Phase 3 Trial

doi:10.1016/j.eururo.2012.03.053

European Urology

Volume 62, Issue 2, August 2012, Pages 213-219

https://doi.org/10.1016/j.eururo.2012.03.053 Get rights and content

Abstract

Background

Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited.

Objective

To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients.

Design, setting, and participants

A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3–4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003.

Intervention

ADT (11.25 mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external-beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo.

Outcome measurements and statistical analysis

The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates.

Results and limitations

ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p < 0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p < 0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p < 0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p < 0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period.

Conclusions

Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact.

Introduction

The benefit of the addition of long-term adjuvant androgen-deprivation therapy (ADT) to local radiotherapy in patients with locally advanced prostate cancer was first demonstrated in 1997 [1], [2]. Results from the European Organisation for Research and Treatment of Cancer (EORTC) 22863 and the Radiation Therapy Oncology Group (RTOG) 85-31 trials demonstrated significant improvements in disease control (biochemical, local, and distant) with combination therapy [1], [2]; a benefit in 10-yr overall and disease-specific survival was later confirmed [3], [4]. The RTOG 92-02 study reported improved 10-yr prostate-specific and progression-free survival (PFS) comparing 28-mo androgen suppression with 4 mo [5]; in the EORTC 22961 study, 6-mo androgen suppression was inferior to 3-yr suppression for prostate-specific and overall survival at 5 yr [6]. Two recent meta-analyses confirmed these results [7], [8]. The aim of the current study was to assess the possible benefits of the combined treatment on PFS.

Section snippets

Patients and methods

A prospective open-label randomised multicentre study was conducted in 40 centres in France (239 patients) and Tunisia (25 patients). Enrolment took place between March 2000 and December 2003. Men with histologically confirmed, locally advanced (T3–4N0) or pathologic pT3 prostate adenocarcinoma without documented nodes or metastases were eligible. Patients included had no prior treatment for prostate cancer, were < 80 yr of age, with a Karnofsky performance status of ≥70%, a life expectancy of ≥7

Results

A total of 273 patients were included, 3 of whom withdrew consent before randomisation and 6 were ineligible, leaving 264 randomised patients; 131 patients received ADT alone and 133 combined ADT and radiotherapy. Pretreatment characteristics in the two groups were well balanced with regard to age, performance status, TNM staging, Gleason score, and baseline PSA (Table 1). Twenty-four patients (10 ADT and 14 combined) had undergone pelvic lymphadenectomy, with one in each arm identified as pN1.

Discussion

The 5-yr PFS rates obtained in the current study with combined ADT and radiotherapy (60.9%, ASTRO; 64.7% ASTRO-Phoenix) can be compared with the 76% rate reported in the EORTC 22863 study [11] because the Gleason scores in the current study were higher and evaluation criteria differed. Addition of radiation to hormone therapy led to a significant improvement in 5-yr locoregional control and metastases-free progression, and the data suggest that PFS benefit is due to locoregional control. A

Conclusions

The addition of radiotherapy to 3-yr ADT significantly reduces the risk of progression and improves locoregional control in patients with locally advanced prostate cancer and can be considered a standard treatment option.

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Une revue systématique de la littérature de 2020 à 2022 a été conduite par le CCAFU concernant les éléments de diagnostic et de prise en charge thérapeutique du CaP localisé, en évaluant les références avec leur niveau de preuve.
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To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes.
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Platinum Priority – Prostate CancerEditorial by Michel Bolla on pp. 220–221 of this issueAddition of Radiotherapy to Long-Term Androgen Deprivation in Locally Advanced Prostate Cancer: An Open Randomised Phase 3 Trial

Abstract

Background

Objective

Design, setting, and participants

Intervention

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Introduction

Section snippets

Patients and methods

Results

Discussion

Conclusions

Lancet Oncol

Int J Radiat Oncol Biol Phys

Cancer Treat Rev

Int J Radiat Oncol Biol Phys

Eur Urol

Int J Radiat Oncol Biol Phys

Eur Urol

Lancet

Platinum Priority – Prostate Cancer
Editorial by Michel Bolla on pp. 220–221 of this issue
Addition of Radiotherapy to Long-Term Androgen Deprivation in Locally Advanced Prostate Cancer: An Open Randomised Phase 3 Trial