Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical
ABSTRACT: Estramustine is nornitrogen mustard linked to estradiol. Itbinds to tubulin and to microtubule-associated proteins, depolymerizescytoplasmic microtubules, and disrupts the nuclear matrix. It has limitedclinical activity as a single agent, but preclinical studies suggest that it isan effective modulator of antitubulins. This paper reviews the rationale for thecombination of estramustine with antitubulins and the clinical toxicity profileof estramustine. Also discussed are data from phase II studies inhormone-resistant prostate cancer and in taxane-resistant breast cancer thatsuggest that the modulation of antitubulins by estramustine that has beendemonstrated in vitro is indeed clinically relevant. Finally, current approachesto improving the tolerability of estramustine are described. [ONCOLOGY 15(Suppl7):40-43, 2001]
Estramustine (Emcyt) is nornitrogen mustard linked toestradiol. The original concept behind the design of the drug was that the estradiolcould be used as a vehicle to deliver the alkylator into tumor cells thatexpressed estrogen receptors. It is now clear, however, that modified estrogenssuch as estramustine exert very little alkylating activity, andthat they act primarily as antitubulins.
Estramustine binds to tubulin and to microtubule-associatedproteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclearmatrix.[2-4] Of uncertain clinical relevance, it is also an inhibitor ofp-glycoprotein, the multidrug resistance protein.
Estramustine has been most extensively studied as an oral agent.While the half-life of the parent compound, estramustine phosphate, isapproximately 2 hours, the half-lives of the active metabolites estramustine andestromustine range from 50 to 100 hours. The drug is usually administered insplit daily doses to minimize nausea.
Estramustine as Single Agent
As a single agent, estramustine was studied in aplacebo-controlled, double-blind, randomized study by the Danish ProstaticCancer Group. Of 131 patients with hormone-refractory prostate cancer, 129were evaluable. Patients were randomized to receive oral estramustine phosphate(n = 61), administered continuously at the dose of 280 mg bid, or placebo (n =68) using the same schedule.
The most valuable results of this study lie in theplacebo-controlled evaluation of estramustine’s toxicity profile. Nausea andvomiting were experienced by 26 out of 61 (43%) of the estramustine patients,and considered severe in 8 out of 61 patients (13%). In the placebo group,however, this toxicity was experienced by 21 out of 68 (31%) patients and wassevere in 9 out of 69 (13%). This suggests that a large proportion of the nauseaand vomiting seen with this agent at this dose is related to pill taking or isanticipatory.
The only other toxicity seen in more than 10% of patients wasbreast tenderness or gynecomastia, which occurred in 25% of estramustinepatients and 1% of those receiving placebo. One patient in the estramustinegroup had a pulmonary embolism, and no cases of deep vein thrombosis werereported.
In terms of efficacy, this study reinforced the common wisdomthat prostate cancer is essentially chemoresistant. No objective responseswere observed and no differences in time to disease progression or survival wereseen between estramustine and placebo.
There was a suggestion of activity with estramustine using PSA(prostate-specific antigen) criteria, however. Of 94 patients whose baseline PSAwas at least twice the normal level, 16 out of 43 (37%) in the estramustinegroup had a ³ 50% reduction in PSA (PSA-50), while only 1 out of 51 (2%)patients in the placebo group displayed such a response.
Taxanes as Single Agents
Like estramustine, the taxanes exert their antitumor effect bytargeting the microtubular apparatus. Paclitaxel (Taxol) and docetaxel(Taxotere) polymerize the microtubules, but additionally inhibit Bcl-2 andBcl-xL by phosphorylation. These agents thus induce G2M arrest and apoptosis.
Studies have shown that paclitaxel as a single agent isessentially ineffective against prostate cancer. In a phase II study performedby the Eastern Cooperative Oncology Group (ECOG), 23 patients withhormone-refractory prostate cancer received paclitaxel as a 24-hour infusion atdoses ranging from 135 to 170 mg/m2. One patient (4%) had an objective response,and was the only one to have a response by PSA-50 criteria.
In contrast, docetaxel has modest activity as a single agent inthis disease. Preliminary results of two phase II studies of docetaxel at 75mg/m2 given every 3 weeks in hormone-refractory prostate cancer have beenreported. In a study reported by Picus et al of 35 patients, 20% had anobjective response, and 46% had a response by PSA-50 criteria. Friedland etal studied 21 patients, and reported a 5% objective response rate and PSA-50responses in 33%.
Synergistic Action of Taxanesand Estramustine Combined
The modest activity of the taxanes and of estramustine as singleagents in hormone-refractory prostate cancer clearly provides little rationalefor combining them for use in this disease. When combined in vitro, however, theantitubulin activity of these agents is synergistic, with estramustine acting asa modulator of the taxane.
Phase II studies of combined estramustine and paclitaxel (Table1), [13,14] and combined estramustine and docetaxel (Table2) [15-18] inhormone-refractory prostate cancer have been reported. These combinations haveresulted in impressive objective (11%-27%) and PSA-50 (39%-82%) response ratesin this disease and warrant further investigation. Although these data are fromsingle-institution phase II studies, and the schedules of both estramustine andthe taxanes vary significantly, indirect comparison of these results with thosefrom single-agent studies suggests that the demonstrated in vitro synergism ofthese agents may indeed be clinically relevant.
Two studies have assessed the role of estramustine incombination with a taxane in metastatic breast cancer (Table3). Garcia et alreported a 20% response rate in 18 evaluable breast cancer patients entered in aphase I study of paclitaxel and estramustine. All of the patients hadpreviously received paclitaxel. Talbot et al reported a 25% response rate in aphase II study of combined docetaxel and estramustine in patients withmetastatic breast cancer. Interestingly, the same response rate was observed inpatients both with and without previous paclitaxel exposure. As in prostatecancer, these data suggest that in breast cancer, estramustine is an effectivemodulator of taxanes.
Thromboembolic events complicate the course of approximately 10%of patients treated with combined estramustine and taxanes. Although not aprominent toxicity in the single-agent estramustine studies, thromboembolicevents are more likely related to the estrogen moiety of the estramustine thanto any synergism between the two agents. This complication was documented instudies of both prostate and breast cancer, and at all doses and schedules ofestramustine, with the exception of the study by Sinibaldi et al, in whichall patients received prophylactic warfarin (Coumadin) with excellent effect.
New strategies are required to improve the toxicity profile ofthe estramustine/taxane combination if it is to become a part of routineoncology practice. The most appealing optionto minimize toxicities is simply to reduce the dose. As estramustine is beinggiven as a modulator of taxanes rather than as an antineoplastic agent in itsown right, it may not be necessary to administer it at the maximum tolerateddose to achieve the required biological effect. If lower doses can modulate thetaxanes as effectively as doses that have been studied to date (generally 600-840mg/d in prostate cancer and approximately 1,500 mg/d in breast cancer), it maybe possibleto abrogate toxicities without further intervention.
The problem of nausea and vomiting is already being addressed.An intravenous formulation of estramustine is now in clinical development. Itappears to be associated with less nausea than the oral formulation, and can beadministered once per cycle on the same day as the chemotherapy. Intravenousestramustine is now being incorporated into combinations with taxanes and withvinorelbine (Navelbine), and will probably eventually replace the oralpreparation in the clinic.
The study by Sinibaldi et al demonstrates that thromboemboliccomplications can be minimized with the use of prophylactic oralanticoagulation. Low-dose warfarin should therefore be considered in allstudies using estramustine at daily doses of 600 mg or higher.
In hormone-resistant prostate cancer, combinations of taxanesand estramustine offer clinically significant activity in a disease that was,until recently, effectively untreatable. These combinations are now beingcompared in front-line phase III studies (eg, SWOG 9916) against the combinationof mitoxantrone (Novantrone) and prednisone.
Estramustine with vinorelbine has also been tested in patientswith hormone-resistant prostate cancer, again with promising results. Theactivity of estramustine with single-agent antitubulins thus provides a strongrationale for the development of triplets comprising a taxane, vinorelbine, andestramustine. A phase I study of paclitaxel, vinorelbine, and estramustine,which is being conducted at New York University Medical Center, will soon becompleted. A report on the study is to be made at the American Society ofClinical Oncology (ASCO) meeting in May 2001 (Sewak et al). A phase II studywill follow in hormone-refractory prostate cancer.
In metastatic breast cancer, combinations of estramustine andtaxanes have moderate activity in taxane-pretreated populations, but thetoxicity profile of the combination currently limits its development in thisdisease, which has a far broader range of therapeutic options available.
Finally, although initially developed for use inhormone-responsive tumors, estramustine, as a modulator should theoretically beeffective in any tumor with sensitivity to antitubulins. Thusestramustine/antitubulin combinations may have a role in tumors originating insites other than the prostate and breast, including lung, head and neck, ovary,endometrium, and bladder.
1. Tew KD, Stearns ME: Hormone-independent, non-alkylatingmechanism of action of cytotoxicity for estramustine. Urol Res 15:155-160, 1987.
2. Tew KD, Glusker JP, Hartley-Asp B, et al: Preclinical andclinical perspectives on the use of estramustine as an antimitotic drug.Pharmacol Ther 56:323-339, 1992.
3. Dahllof B, Billstrom A, Cabral F, et al: Estramustinedepolymerizes microtubules by binding to tubulin. Cancer Res 53:4573-4581, 1993.
4. Speicher LA, Laing N, Barone LR, et al: Interaction of anestramustine photoaffinity analogue with cytoskeletal proteins in prostatecarcinoma cells. Mol Pharmacol 46:866-872, 1994.
5. Speicher LA, Barone LR, Chapman AE, et al: P-glycoproteinbinding and modulation of the multidrug resistance phenotype by estramustine. JNatl Cancer Inst 86:688-694, 1994.
6. Gunnarsson PO, Andersson SB, Johansson SA, et al:Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancerpatients. Eur J Clin Pharmacol 26:113-119, 1984.
7. Iversen P, Rasmussen F, Asmussen C, et al: Estramustinephosphate versus placebo as second line treatment after orchiectomy in patientswith metastatic prostate cancer: DAPROCA study 9002. Danish Prostatic CancerGroup. J Urol 157(3):929-934, 1997.
8. Stein CA: Mechanisms of action of taxanes in prostate cancer.Semin Oncol 26(5 suppl 17):3-7, 1999.
9. Roth BJ, Yeap BY, Wilding G, et al: Taxol in advanced,hormone-refractory carcinoma of the prostate. Cancer 72:2457-2460, 1993.
10. Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy inthe treatment of hormone-refractory prostate cancer: Preliminary results. SeminOncol 26(5):14-18, 1999.
11. Friedland D, Cohen J, Miller R Jr, et al: A phase II trialof docetaxel (Taxotere) in hormone-refractory prostate cancer: Correlation ofantitumor effect to phosphorylation of Bcl-2. Semin Oncol 26(5):19-23, 1999.
12. Speicher LA, Barone L, Tew KD et al: Combinedantimicrotubule activity of estramustine and Taxol in human prostatic carcinomacell lines. Cancer Res 52:4433-4440, 1992.
13. Hudes GR, Nathan F, Khater C, et al: Phase II trial of96-hour paclitaxel plus oral estramustine phosphate in metastatichormone-refractory prostate cancer. J Clin Oncol 15(9):3156-3163, 1997.
14. Smith DC, Esper P, Strawderman M, et al: Phase II trial oforal estramustine, oral etoposide, and intravenous paclitaxel inhormone-refractory prostate cancer. J Clin Oncol 17(6):1664-1671, 1999.
15. Savarese D, Taplin ME, Halabi S, et al: A phase II study ofdocetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men withhormone-refractory prostate cancer: Preliminary results of Cancer and LeukemiaGroup B Trial 9780. Semin Oncol 26(5 suppl 17):39-44, 1999.
16. Kreis W, Budman DR, Feten J, et al: Phase I trial of thecombination of daily estramustine phosphate and intermittent docetaxel inpatients with metastatic hormone refractory prostate carcinoma. Ann Oncol10(1):33-38, 1999.
17. Petrylak DP, Macarthur R, O’Connor J, et al: Phase I/IIstudies of docetaxel (Taxotere) combined with estramustine in men withhormone-refractory prostate cancer. Semin Oncol 26(5 suppl 17):28-33, 1999.
18. Sinibaldi VJ, Carducci M, Laufer M, et al: Preliminaryevaluation of a short course of estramustine phosphate and docetaxel (Taxotere)in the treatment of hormone-refractory prostate cancer. Semin Oncol 26(5 suppl17):45-48, 1999.
19. Garcia AA, Keren-Rosenberg S, Parimoo D, et al: Phase I andpharmacologic study of estramustine phosphate and short infusions of paclitaxelin women with solid tumors. J Clin Oncol 16(9):2959-2963, 1998.
20. Talbot S, Weitzman A, Petrylak D, et al: A phase II study ofdocetaxel in combination with estramustine as salvage therapy for metastaticbreast cancer (abstract 437). Proc Am Soc Clin Oncol 19:113a, 2000.
21. Borrega Garcia P, Bolaños M, Rodriguez A, et al: Phase IIstudy of vinorelbine-estramustine in the treatment of patients withhormonoresistant prostate cancer (abstract 1480). Proc Am Soc Clin Oncol19:374a, 2000.