Hoosier Oncology Group, Walther Cancer Institute and Division of Hematology/Oncology, Indiana University, Indianapolis, IN, USA
Received 25 February 2002; revised 25 April 2002; accepted 8 May 2002
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Abstract |
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Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC).
Patients and methods:
Patients were treated with docetaxel 35 mg/m2 on day 2 and estramustine phosphate 280 mg p.o. tds days 13 weekly for 3 of 4 weeks, for a maximum of six treatment cycles.
Results:
Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen.
Conclusions:
Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.
Key words: docetaxel, estramustine, metastatic breast cancer
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Introduction |
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Docetaxel is a semisynthetic taxane that entered breast cancer trials in 1992 [2]. It works by arresting the cell cycle in M-phase through promotion of microtubule assembly and prevention of tubulin depolymerization, an effect that is opposite to that of the vinca alkaloids. Two initial studies showed objective response rates of 53% and 57% in patients with metastatic breast cancer resistant to anthracyclines [3, 4]. Many subsequent studies have confirmed the success of docetaxel in patients with metastatic breast cancer; its role in the neoadjuvant and adjuvant settings is currently under evaluation.
Estramustine phosphate is a conjugate of estradiol and nitrogen mustard linked by a carbamate ester. The drug was specifically developed for the treatment of breast cancer at a time when it was becoming apparent that normal and malignant breast tissues express receptors for estradiol [5]. The estrogen was initially thought to serve as a carrier for the cytotoxic mustard moiety; however, estramustine was later found to exert its antitumor activity through binding to microtubule-associated proteins [6, 7].
The fact that estramustine and taxanes act upon different microtubule targets suggests that combinations of the two agents may have additive antitumor activity. Indeed, in vitro data with estramustine and taxol show synergistic cytotoxic effects [7]. Based upon studies using prostate cancer cell lines, this synergism may be even more pronounced with the combination of docetaxel and estramustine than with paclitaxel and estramustine [8].
Clinical development of estramustine has been directed toward both breast and prostate cancers. A phase II trial of estramustine in patients with anthracycline and taxane-refractory advanced breast cancer showed a response rate of 17.5% [9]. Studies evaluating estramustine and vinblastine chemotherapy in hormone refractory prostate cancer (HRPC) patients showed a 50% or greater decrease in serum prostate specific antigen (PSA) in 42% of patients [1012]. A phase III trial comparing estramustine and vinblastine with vinblastine alone in HRPC resulted in improved time to progression and PSA decline for combination therapy [13]. Other randomized trials involving estramustine therapy in HRPC are underway.
Encouraged by the efficacy of combined microtubule blockade in HRPC and the single agent activity of estramustine in metastatic breast cancer, we performed this phase II trial to evaluate combination therapy with docetaxel and estramustine in patients with metastatic breast cancer.
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Patients and methods |
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Patients were treated with docetaxel 35 mg/m2 infused over 1 h on days 2, 9 and 16 of each 4-week cycle. Premedication included oral dexamethasone, 4 mg the night before infusion and 4 mg b.i.d. on the day of infusion. Estramustine 280 mg p.o. tds (total dose of 840 mg/day) was administered on days 13, 810 and 1517 of each 4-week cycle. Treatment was continued until evidence of progression or undue toxicity, or for a maximum of six cycles.
All toxicities were graded according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC). Dose modifications were based on nadir blood counts and interval toxicity. Estramustine was reduced by 50% for grade 3 or 4 nausea and vomiting felt to be secondary to estramustine rather than docetaxel. A 25% dose reduction of docetaxel was mandated for the following: febrile neutropenia, severe thrombocytopenia requiring platelet transfusion, nadir platelet count 20 000/mm3, grade 3 or 4 mucositis, or grade 3 or 4 diarrhea. Hepatic toxicity (aspartate aminotransferase
2 x upper limit of normal or bilirubin <1.5 mg/dl) required a 50% dose reduction of docetaxel once the abnormalities returned to baseline.
Response to treatment was evaluated after each course of treatment by physical examination and by radiological evaluation of measurable disease sites every two cycles (8 weeks). Patients who discontinued the trial for reasons other than disease progression (toxicity, patient choice) prior to completion of two cycles of therapy were not considered to be evaluable for response. However, patients who discontinued the trial early due to cancer-related symptoms were considered to have progressive disease. A clinical complete response (CR) was defined as complete disappearance of all clinically detectable malignant disease, confirmed by repeat scanning at least 4 weeks later. Partial response was defined as a 50% decrease in tumor area (calculated by multiplying the longest perpendicular diameters) for at least 4 weeks without increase in size of any area of known malignant disease by >25%, and without new areas of malignant disease. Stable disease was defined as no significant change in measurable disease for at least 4 weeks. Progression was defined as significant increase in the size of lesions present at the start of therapy, appearance of new metastatic lesions known not to be present at the start of therapy, or stable objective disease associated with a deterioration in ECOG performance status of
1 level if related to malignant disease.
Sample size calculations used a two-stage design with a goal of rejecting the combination for a response rate of <20% and recommending further study for a response rate of 40%. In the first stage, 19 patients were entered; if four or more responses were observed, an additional 17 patients were accrued. Therefore, if the true response rate was
40%, the chance of terminating the trial early was <3% and the overall chance of rejecting the treatment was <10%. However, if the response rate was <20%, the probability of early rejection was >45% and the overall probability of rejection was >91%. This design would yield a power of 90.2% and a type I error of 8.6%.
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Results |
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One patient experienced grade 4 pulmonary toxicity, having sudden respiratory arrest 30 min after her first dose of estramustine; she was subsequently removed from the study. Six patients experienced grade 3 pulmonary symptoms, resulting in study discontinuation in one. Five of six patients with these symptoms had pulmonary involvement of their cancer. Two patients experienced grade 34 neurological toxicities: one with grade 4 depression and another with grade 3 headaches. Other toxicities were mild, with only one estramustine dose reduction due to nausea and vomiting. Docetaxel doses were held in two patients due to transient mild elevation of liver function tests that subsequently normalized.
The median number of cycles of treatment received was 3.8. Objective responses were obtained in 15 patients (47%); two patients (6%) obtained a CR. Seven patients (22%) were found to have stable disease for 4 weeks or longer. The median time to progression was 9 months (275 days), time to treatment failure 6 months (185 days) and median survival 1 year (362 days). The two patients who obtained a CR remain without progression at 1 and 2 years after enrollment on study.
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Discussion |
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The incidence of pulmonary symptoms in this study was noteworthy, with six episodes of grade 3 and one episode of grade 4 pulmonary toxicity. Docetaxel has been associated with severe interstitial pneumonitis [14, 15], and a phase II study of docetaxel, estramustine and hydrocortisone in prostate cancer resulted in 22% of patients with grade 34 dyspnea. However, given that five of the seven patients also had pulmonary metastatic disease and one experienced grade 4 toxicity due to a pulmonary embolus, it is difficult to determine the exact etiology of their pulmonary symptoms.
Estramustine added significant thromboembolic toxicity to this regimen. Studies of estramustine in HRPC have resulted in similar toxicity. The vinblastine and estramustine arm of a phase III trial resulted in three of 95 patients (3%) with thrombotic events; a phase II study of docetaxel, estramustine and hydrocortisone resulted in four of 46 patients (9%) with thromboses [16]. Current clinical trials of estramustine in HRPC patients require thromboembolism prophylaxis with low-dose coumadin and/or aspirin. Although other toxicities seen in our study were minimal, the rate of thromboembolic events seen is unacceptable.
Given the low response rates with estramustine as a single agent in metastatic breast cancer and the toxicity observed when used in combination with docetaxel, it is unlikely that estramustine will play a role in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.
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Acknowledgements |
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Footnotes |
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References |
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