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