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Estramustine Phosphate Sodium

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Prostate Cancer

  • Drug Evaluation
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Summary

Synopsis

Estramustine phosphate sodium (estramustine phosphate), a unique antitumour agent, is selectively taken up by prostate cells and exerts antineoplastic effects by interfering with microtubule dynamics and by reducing plasma levels of testosterone.

In noncomparative studies of estramustine phosphate in patients with hormone-refractory disease, objective response rates ranging from 19 to 69% have been reported. Preliminary clinical investigations indicate that combining estramustine phosphate with vinblastine, etoposide or paclitaxel improves objective response rates over single-agent treatment, although no survival benefit over single-agent treatment has been demonstrated to date.

In comparative studies, estramustine phosphate produces similar objective response rates to conventional antineoplastic agents in patients with hormone-refractory prostate cancer.

In previously untreated patients with advanced metastatic hormone-responsive prostate cancer, objective responses are achieved in approximately 80% of patients. Estramustine phosphate appears to be at least as effective as estrogen or flutamide therapy in these patients.

Nausea and vomiting are the most frequently observed adverse effects of treatment with estramustine phosphate. While these symptoms are usually mild to moderate in nature, they may occasionally be more troublesome to the patient and necessitate withdrawal of treatment. Cardiovascular complications are a more serious, though less frequently encountered, adverse effect of the drug. However, these complications may be avoided by careful patient selection and prophylactic treatment measures. Unlike some other antineoplastic agents, estramustine phosphate is rarely associated with myelosuppression.

In addition to producing similar objective response rates to other established agents, estramustine phosphate improves the subjective status of many patients and has been shown to reduce the intensity of pain and improve the performance status of patients.

Thus, estramustine phosphate is a valuable single-agent treatment for patients with hormone-refractory or untreated advanced prostate cancer and, pending results of future phase III trials, may also play an important role as part of a combination regimen (with other agents such as paclitaxel, vinblastine and etoposide) in the treatment of patients with hormone-refractory prostate cancer.

Pharmacodynamic Properties

Estramustine phosphate sodium (estramustine phosphate) is an antitumour drug with a unique dual mode of action. Estrone and estradiol, products of the metabolism of estramustine phosphate, have shown antigonadotrophic activity resulting in reduced testosterone levels similar to those achieved after surgical castration. Estramustine, the cytotoxic metabolite produced by dephosphorylation of the parent compound, undergoes further metabolism to estromustine; both these metabolites are selectively taken up by prostate cells and exert antimitotic effects essentially mediated by microtubule depolymerisation. Estramustine has cytotoxic activity against human prostatic cancer cell lines and in animal models. Combinations of estramustine phosphate with the antimicrotubular agents vinblastine or paclitaxel, or with the topisomerase II inhibitor etoposide, have demonstrated synergistic cytotoxic activity.

Pharmacokinetic Properties

Approximately 75% of estramustine phosphate is absorbed after oral administration. Thereafter, estramustine phosphate undergoes rapid presystemic dephosphorylation (predominantly in the gastrointestinal tract) to yield the active cytotoxic metabolite estramustine which is subsequently partially oxidised to produce the active cytotoxic isomer, estromustine. Both metabolites undergo partial hydrolysis to produce the estrogen derivatives estrone and estradiol, respectively. The absorption of estramustine phosphate is markedly impaired by calcium ions which form an insoluble calcium phosphate salt with the drug. Thus, oral estramustine phosphate should not be administered concomitantly with dairy products, other calcium-rich foods or drugs. The plasma elimination half-life of estramustine phosphate is relatively short (1.27 hours). However, the plasma half-life of the active cytotoxic metabolite estromustine is much longer ranging between 8.88 and 22.7 hours in one study. Both estramustine and estromustine are excreted via the biliary route.

Therapeutic Efficacy

Estramustine phosphate has been predominantly evaluated as a second-line option in patients with hormone-refractory prostate cancer. In noncomparative studies, objective response rates ranging between 19 and 69% have been reported after estramustine phosphate single-agent therapy. An analysis of 634 patients with hormone-refractory disease who received second-line treatment with estramustine phosphate single-agent therapy revealed a mean objective response rate of 37%. More recently, several noncomparative studies have investigated the therapeutic efficacy of combinations of estramustine phosphate with either vinblastine, etoposide or paclitaxel in patients with advanced hormone-refractory prostate cancer, using declining prostate-specific antigen (PSA) levels to monitor clinical response. Objective response rates were higher and improvements in subjective parameters were greater than those achieved with single-agent estramustine phosphate therapy. However, results of phase III comparative trials are needed before the apparent superiority of these combination regimens over single-agent treatments can be confirmed.

In patients who relapsed following hormonal therapy, estramustine phosphate was more effective than streptozocin, had a similar therapeutic efficacy to epirubicin, but was less effective than medroxyprogesterone in producing objective responses (although there was no apparent difference in progression-free or observed survival between medroxyprogesterone and estramustine phosphate treatment groups). Estramustine phosphate and mitomycin appeared to be equally effective in patients with progressive disease; the mean time to disease progression was 5 months and the median survival time was 10 months in both treatment groups. A combination of estramustine phosphate and cisplatin achieved a higher objective response rate and longer median survival than either estramustine phosphate or cisplatin administered as single-agent therapy.

Estramustine phosphate has also been evaluated as primary treatment in patients with hormone-responsive advanced prostate cancer, achieving objective response rates in approximately 80% of patients. In comparative trials, estramustine phosphate was at least as effective as various orally and intramuscularly administered estrogen formulations and flutamide.

Patients with localised prostate cancer (and >lymph node involvement) who received estramustine phosphate as adjuvant treatment to definitive radiotherapy had a longer progression-free survival than similar patients who received cyclophosphamide as an adjuvant treatment. Estramustine phosphate administered as a neoadjuvant treatment 6 weeks before radical prostatectomy resulted in a significantly lower incidence of positive surgical margins for patients with T2 tumours compared with patients who had not received estramustine phosphate neoadjuvant treatment.

Tolerability

The most frequently encountered adverse effects of oral estramustine phosphate therapy are nausea and vomiting; these are generally mild to moderate in nature, although more severe symptoms may require a reduction in dosage or discontinuation of treatment. Cardiovascular complications (including ischaemic heart disease, venous thromboembolism and cardiac failure) have been reported in 10% of patients during the first 20 weeks of treatment and in 25% of patients after more than 20 weeks of treatment. To minimise the risk of such complications, careful patient selection and prophylaxis with anticoagulants, aspirin (acetylsalicylic acid), and diuretics have been advocated by some investigators. However, data suggest that estramustine phosphate recipients are at lower risk of experiencing cardiovascular symptoms than recipients of conventional estrogen therapy. Elevated serum transaminases, reversible upon the withdrawal of treatment, have been observed in some patients during treatment with estramustine phosphate. As with conventional estrogens, recipients of estramustine phosphate may experience gynaecomastia. Estramustine phosphate is rarely associated with myelosuppression.

Dosage and Administration

The recommended dosage of oral estramustine phosphate ranges from 140 to 1400 mg/day in 2 to 3 divided doses, administered more than 1 hour before or 2 hours after meals. Treatment should be initiated at 560 to 1120 mg/day (in 3 divided doses), with adjustment according to therapeutic response and gastrointestinal tolerability. Patients should not consume dairy products, or calcium-containing foods or drugs (e.g calcium-based antacids) concomitantly with oral doses of estramustine phosphate.

Intravenous estramustine phosphate may be administered at a dosage of 300 to 450 mg/day for a maximum of 3 weeks. Thereafter, the drug is given as a 300mg dose twice a week.

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    Caroline M. Perry & Donna McTavish

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Various sections of the manuscript reviewed by: L. Balducci, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida, USA; G.C.W. Howard, Directorate of Clinical Oncology, Western General Hospitals NHS Trust, Edinburgh, Scotland; R.P. Huben, Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA; J-E. Johansson, Department of Urology, Örebro Medical Center Hospital, Örebro, Sweden; W.K. Kelly, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; D.W.W. Newling, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands; W. Roessler, Department of Urology, Hospital St Josef, Regensburg, Germany; K.D. Tew, Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; H. Van Poppel, Katholieke Universiteit, Leuven, Belgium.

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Perry, C.M., McTavish, D. Estramustine Phosphate Sodium. Drugs & Aging 7, 49–74 (1995). https://doi.org/10.2165/00002512-199507010-00006

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