Elsevier

The Lancet Oncology

Volume 14, Issue 2, February 2013, Pages 117-124
The Lancet Oncology

Articles
2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(12)70537-5Get rights and content

Summary

Background

Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety.

Methods

Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0–2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0–1 vs 2. Patients were assigned 75 mg/m2 docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m2 docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606.

Findings

177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0–6·2 vs 4·9 months, 4·5–5·4; hazard ratio 1·3, 95% CI 1·1–1·6, p=0·014). Grade 3–4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002).

Interpretation

Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated.

Funding

Sanofi.

Introduction

Androgen deprivation is a standard treatment for advanced prostate cancer and leads to reductions in symptoms in 70–80% of patients.1 Nevertheless, this treatment is not curative, and most patients develop castration-resistant disease within a median of 2 years.1, 2 Several treatment options are available for patients with hormone-refractory prostate cancer, including docetaxel plus prednisone,3 docetaxel plus estramustine,4 cabazitaxel plus prednisone,5 abiraterone,6 sipuleucel-T,7 enzalutamide (formerly MDV3100),8, 9 and 223radium.10 Besides docetaxel and cabazitaxel, a few other chemotherapy agents, such as mitoxantrone, estramustine, and vinblastine, have some activity in patients with advanced prostate cancer.11

Docetaxel was approved for the treatment of metastatic, androgen-refractory prostate cancer by the US Food and Drug Administration in 2004. Approval was based mainly on two randomised trials that showed longer median survival of around 2 months in patients assigned docetaxel than in those who received mitoxantrone plus prednisone.3, 4 In the TAX 327 study,3 1006 patients with advanced prostate cancer received 5 mg prednisone twice daily plus 12 mg/m2 mitoxantrone every 3 weeks, 75 mg/m2 docetaxel every 3 weeks, or 30 mg/m2 docetaxel once weekly for 5 of every 6 weeks. Median survival favoured the two docetaxel arms, being 18·9 months and 17·4 months, respectively, versus 16·5 months in the mitoxantrone group.3 An updated analysis based on a longer follow-up time confirmed these results.12 In the Southwest Oncology Group (SWOG) 9916 trial,4 patients received 60 mg/m2 docetaxel plus estramustine every 3 weeks or mitoxantrone plus prednisone. Median survival was significantly longer in the docetaxel group than in the mitoxantrone group (17·5 vs 15·6 months p=0·02). The docetaxel regimen was associated with more adverse events than was mitoxantrone plus prednisone, including neutropenic fever, fatigue, diarrhoea, nail changes, sensory neuropathy, and alopecia.3, 4

3-weekly intravenous administration of docetaxel in combination with oral prednisone has become the standard first-line chemotherapy for castration-resistant advanced prostate cancer.13 Various doses (from 20 mg/m2 to 40 mg/m2) have been assessed. We hypothesised that 2-weekly administration of docetaxel might be better tolerated than 3-weekly docetaxel in patients with prostate cancer, and might lead to longer times on treatment and better treatment outcomes with fewer adverse events. As, to our knowledge, a 2-weekly regimen has not been compared with 3-weekly docetaxel as first-line cytotoxic therapy for advanced prostate cancer in a randomised trial, we did an open-label, parallel-group, prospective, multicentre, phase 3, randomised trial to test this hypothesis.

Section snippets

Patients

We screened and treated all eligible patients referred to 11 study centres in Finland, Ireland, and Sweden between March 1, 2004, and May 31, 2009. Inclusion criteria were histologically or cytologically confirmed prostate cancer that had progressed during endocrine treatment; surgical castration or treatment with a luteinising-hormone-releasing hormone analogue; no previous cancer chemotherapy except with estramustine; WHO performance status score 0–2; age older than 18 years; presence of

Results

361 patients were screened. Two patients in the 3-weekly group and one in the 2-weekly group withdrew consent, and six patients in each group had major protocol violations or a medical disorder that precluded docetaxel administration (figure 1). The remaining 346 patients (176 assigned 3-weekly docetaxel, 170 assigned 2-weekly docetaxel) comprise the per-protocol population. The baseline characteristics of the patients were similar in the two treatment groups (table 1).

We administered 1249

Discussion

Docetaxel administered every 2 weeks was associated with longer TTTF and fewer occurrences of neutropenia and neutropenic infections than was 3-weekly administration in patients with castration-resistant advanced prostate cancer. Although the difference in TTTF was significant, the absolute difference between median TTTFs in the two groups was small (0·7 months). Somewhat unexpectedly, median overall survival was longer by 2·5 months in the 2-weekly docetaxel group than in the 3-weekly group.

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