Elsevier

The Lancet Oncology

Volume 8, Issue 11, November 2007, Pages 994-1000
The Lancet Oncology

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Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data

https://doi.org/10.1016/S1470-2045(07)70284-XGet rights and content

Summary

Background

Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer.

Methods

We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used.

Findings

The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2·8 years (range 0·0–3·4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0·0001), use of chemotherapy plus estramustine (p=0·008), performance status (p=0·002), and serum PSA concentrations (p=0·04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0·77 [95% CI 0·63–0·93], p=0·008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9·5% (SE 4·0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0·53 [0·38–0·72], p<0·0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0·74 [0·58–0·94], p=0·01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275).

Interpretation

In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Introduction

In 2002, prostate cancer had the highest incidence and was the second leading cause of cancer in the USA, and the third leading cause of cancer in western Europe.1 Although advanced prostate cancer is initially sensitive to androgen deprivation, most deaths occur after the cancer has progressed to castration-refractory status, in which metastatic dissemination usually involves the bones. In patients with castration-refractory prostate cancer, chemotherapy has been shown to improve quality of life,2 progression-free survival,3 and overall survival.4, 5 However, the overall-survival benefit is small, with median survival lasting 18 months in large phase III randomised trials.4, 5

Estramustine phosphate is a nornitrogen mustard-oestradiol conjugate that has been shown to have hormonal and non-hormonal effects in vivo.6 Estramustine mainly inhibits microtubule function by binding to both tubulin7, 8, 9 and microtubule-associated proteins.10 In human beings, estramustine has little antitumour activity as a single drug in the treatment of patients with castration-refractory prostate cancer with responses reported in 20% of patients.11 However, the microtubule-inhibitory properties of estramustine led to the hypothesis that a synergistic antitumour effect could be achieved by combining estramustine with other microtubule inhibitors. This assumption was confirmed in some, but not all, in-vitro models when estramustine was added to vinca-alkaloids12 or taxanes.13, 14

Several phase II and III clinical randomised trials have studied the effect of adding estramustine to chemotherapy, especially to other microtubule inhibitors.6 Although response and progression-free survival were typically higher when estramustine was added to chemotherapy compared with chemotherapy without estramustine, no trial has been powerful enough to detect an improvement in median survival of less than 50%, and the largest of these trials included only 200 patients.15 Therefore, we undertook this meta-analysis of individual patient data from randomised trials that assessed chemotherapy with or without estramustine in patients with castration-refractory prostate cancer. The main aim was to address a controversial clinical question: is overall survival improved when estramustine is added to chemotherapy?

Section snippets

Search strategy and selection criteria

We searched, without language restrictions, Medline and the National Cancer Institute Physician Data Queries clinical trials registry for papers published in 1966–2004. The search strategy used the following search terms: (1) “prostatic neoplasms”; (2) “estramustine”; (3) “randomised controlled trial (“phase III” and “phase II and random”).

We hand-searched the reference lists of review articles for additional publications, and asked participating trialists if they were aware of studies not

Results

Five trials that randomly assessed patients who received a chemotherapy treatment (control group) versus the same chemotherapy plus estramustine were identified in the PSA screening era—ie, when serum PSA became commonly measured in clinics.15, 20, 21, 22, 23 Three additional trials which randomly tested a chemotherapy regimen (namely prednimustine, cisplatin, and vincristine, respectively) with and without estramustine were done by the National Prostate Cancer Project group in the pre-PSA era.

Discussion

To our knowledge, this meta-analysis of individual patient data shows for the first time that overall survival in patients with castration-refractory prostate cancer is significantly improved when estramustine is added to chemotherapy compared with the same chemotherapy without estramustine (adjusted HR 0·77 [0·63–0·93]).

Furthermore, patients who had received chemotherapy plus estramustine had a better PSA response (RR 0·53 [0·38–0·72]) and a better time to PSA progression (HR 0·74

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