Elsevier

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 787-794
The Lancet Oncology

Articles
Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial

https://doi.org/10.1016/S1470-2045(15)00011-XGet rights and content

Summary

Background

Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.

Methods

We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3–T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m2 and estramustine 10 mg/kg per day on days 1–5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.

Findings

We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1–9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55–69) in the ADT plus docetaxel and estramustine group versus 50% (44–57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54–0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.

Interpretation

Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.

Funding

Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Introduction

Although death from prostate cancer is almost always caused by metastatic spread, most patients in high-income countries have localised disease at presentation.1 Within this patient population, a group with a higher risk of relapse and death from prostate cancer has been identified: classification systems are almost entirely based on local extension according to the TNM system, a high Gleason score (≥8), or high serum prostate-specific antigen (PSA) concentration (>20 ng/mL).2 Pathological nodal status, when available, is also an independent prognostic parameter.3 Roughly 15% of patients are diagnosed with high-risk disease and 30–50% of these patients die from the cancer.4, 5, 6, 7, 8, 9

There is strong evidence that combining androgen deprivation therapy (ADT) with radiotherapy improves outcomes, including survival, of patients with high-risk localised prostate cancer compared with radiotherapy alone.4, 5, 6 Furthermore, a combination of ADT and radiotherapy is superior to ADT alone,7, 8 and 3 years of ADT was shown to be superior to 6 months of ADT.9 By contrast, the roles of pelvic radiotherapy10, 11 and prostatectomy12 are debated. Although prolonged ADT is usually recommended in patients with pathological node-positive disease,13 whether these patients should receive local treatment as well has not been fully established.

Research in context

Evidence before this study

When this trial began in 2002, the best treatment for patients with high-risk localised prostate cancer was debated, as it is now, although some evidence supports the use of prolonged ADT combined with radiotherapy. Docetaxel improves survival in patients with metastatic prostate cancer. In September, 2002, we searched PubMed and the proceedings of American Society of Clinical Oncology and European Society for Medical Oncology congresses for randomised phase 3 trials testing docetaxel-based chemotherapy for patients with localised prostate cancer and found none. We repeated the search on March 1, 2015 and found the same results.

Added value of this study

To our knowledge, GETUG 12 shows for the first time that integrating docetaxel and estramustine into the standard care of patients with high-risk localised prostate cancer is associated with a significant improvement of relapse-free survival, with no apparent long-term toxic effects related to chemotherapy.

Implications of all of the available evidence

After a decade when chemotherapy was restricted to patients with metastatic castrate-resistant prostate cancer, the early use of docetaxel-based chemotherapy is becoming an important option for patients who have not developed castration-resistant disease. Longer follow-up of this trial and results of other ongoing studies are needed to establish whether the benefit in relapse-free survival translates into improved metastasis-free survival and overall survival.

For other cancers, chemotherapy regimens that are active against metastatic disease have yielded a higher benefit when used for localised disease. Docetaxel, with or without estramustine, enhanced survival compared with mitoxantrone, the former standard, in metastatic castration-resistant prostate cancer.14 In another study, responses were more common with docetaxel and estramustine and a meta-analysis showed better survival with chemotherapy plus estramustine versus chemotherapy alone.15 This finding prompted the French Groupe d'Etude des Tumeurs Uro-Génitales to assess whether docetaxel and estramustine could improve outcomes in patients with high-risk localised prostate cancer. The preliminary results indicated a better PSA response at 3 months and no negative effect on quality of life at 1 year in the ADT and docetaxel and estramustine group.16 Here we report results for the primary endpoint, relapse-free survival.

Section snippets

Study design and participants

We did this randomised controlled trial at 26 hospitals in France (appendix). We included men with histologically proven adenocarcinoma of the prostate with at least one of the following high-risk features: Gleason score of 8 or greater, stage T3 or T4 disease, serum PSA concentration of 20 ng/mL or more, or pathological node-positive disease. Patients had to have no evidence of metastases on bone scan and abdominopelvic CT scan (or MRI) within the past 6 months (we recommended that these

Results

From Nov 14, 2002, to Dec 21, 2006, we enrolled 413 patients; 206 in the ADT only group and 207 in the ADT plus docetaxel and estramustine group (table 1). Median age was 63 years (IQR 47–77). One patient in the ADT alone group had evidence of bone metastases but was treated and included in the analysis. Three patients with a history of thrombosis (one in the ADT plus docetaxel and estramustine group and two in the ADT alone group) and one with moderately increased aspartate aminotransferase

Discussion

To our knowledge, this is the first randomised phase 3 trial testing docetaxel-based chemotherapy for patients with high-risk localised prostate cancer. The preliminary results suggested more responses (PSA ≤0·2 ng/mL: 34% vs 15%; p<0·0001), acceptable immediate toxic effect (with no toxic effects-related deaths, neutropenic fever and grade 3–4 thromboembolic events in only 2% of patients), and no negative effect on quality of life at 1 year in the ADT plus docetaxel and estramustine group.16

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