A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma
2001; Wiley; Volume: 91; Issue: 11 Linguagem: Inglês
10.1002/1097-0142(20010601)91
ISSN1097-0142
AutoresAnna C. Ferrari, Abraham Chachoua, Harvinder Singh, Mark Rosenthal, Samir S. Taneja, Myron Bednar, John Mandeli, Franco M. Muggia,
Tópico(s)Multiple Myeloma Research and Treatments
ResumoCancerVolume 91, Issue 11 p. 2039-2045 Original ArticleFree Access A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma Anna C. Ferrari M.D., Corresponding Author Anna C. Ferrari M.D. anna.ferrari@mssm.edu Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York Fax: 212-423-9458Mount Sinai Medical Center, Box 1129, One Gustave Levy Place, New York, NY 10029===Search for more papers by this authorAbraham Chachoua M.D., Abraham Chachoua M.D. Division of Oncology, New York University, New York, New YorkSearch for more papers by this authorHarvinder Singh M.D., Harvinder Singh M.D. Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorMark Rosenthal M.D., Mark Rosenthal M.D. Department of Clinical Hematology and Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this authorSamir Taneja M.D., Samir Taneja M.D. Department of Urology, New York University, New York, New YorkSearch for more papers by this authorMyron Bednar M.D., Myron Bednar M.D. Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorJohn Mandeli Ph.D., John Mandeli Ph.D. Department of Biomathematics, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorFranco Muggia M.D., Franco Muggia M.D. Division of Oncology, New York University, New York, New YorkSearch for more papers by this author Anna C. Ferrari M.D., Corresponding Author Anna C. Ferrari M.D. anna.ferrari@mssm.edu Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York Fax: 212-423-9458Mount Sinai Medical Center, Box 1129, One Gustave Levy Place, New York, NY 10029===Search for more papers by this authorAbraham Chachoua M.D., Abraham Chachoua M.D. Division of Oncology, New York University, New York, New YorkSearch for more papers by this authorHarvinder Singh M.D., Harvinder Singh M.D. Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorMark Rosenthal M.D., Mark Rosenthal M.D. Department of Clinical Hematology and Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this authorSamir Taneja M.D., Samir Taneja M.D. Department of Urology, New York University, New York, New YorkSearch for more papers by this authorMyron Bednar M.D., Myron Bednar M.D. Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorJohn Mandeli Ph.D., John Mandeli Ph.D. Department of Biomathematics, Mount Sinai School of Medicine, New York, New YorkSearch for more papers by this authorFranco Muggia M.D., Franco Muggia M.D. Division of Oncology, New York University, New York, New YorkSearch for more papers by this author First published: 31 May 2001 https://doi.org/10.1002/1097-0142(20010601)91:11 3.0.CO;2-RCitations: 20 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract BACKGROUND The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II–IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1–2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level ≥ 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I–IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I–IV, with 9 of 15 responders (60%) in Cohorts II–IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents. Cancer 2001;91:2039–45. © 2001 American Cancer Society. Chemotherapy as a treatment modality for patients with hormone-refractory prostate carcinoma is evolving rapidly, and its role in the management of these patients promises to increase greatly. Compared with the low response rates and significant toxicity experienced by men with hormone-refractory disease enrolled in clinical trials conducted in the past 3 decades,1 the results of recent randomized studies indicate that chemotherapy is becoming persuasively effective at improving quality of life for these patients.2, 3 Moreover, the biochemical and measurable response rates observed in recent Phase II trials also support the finding that survival may be improved.4-7 Preclinical testing8-13 of antimicrotubule agents targeting tumor cells in mitosis and interphase indicated that the limited activity of estramustine and paclitaxel as single agents could become synergistic against androgen independent prostate carcinoma cells.14 When 96-hour infusions of paclitaxel at 120 mg/m2 every 21 days were given with continuous oral estramustine at 600 mg/m2 for 21 days in patients with hormone-refractory prostate carcinoma, Hudes et al.15 observed a decline in the level of serum prostate specific antigen (PSA) ≥ 50% in 53% of patients and measurable disease responses in 44% of patients lasting a median of 22 weeks. The spectrum of toxicity included 21% of patients with Grade 3 and 4 granulocytopenia and neuropathy attributed primarily to paclitaxel and 10% of patients with serious gastrointestinal and thrombotic complications attributed primarily to estramustine. A similar spectrum of toxicity and response rates were described by Petrylak et al.7 with one infusion of docetaxel at 75 mg/m2 and 5 days of estramustine at 840 mg every 21 days. To improve on these regimens, it became a priority to decrease toxicity and maintain or improve response rates. One approach was to modify the frequency, dose, and length of administration of each drug. Preclinical data16 and clinical data17, 18 supported that weekly 1-hour infusions of paclitaxel < 100 mg/m2 could be as effective as higher doses at inducing tumor cell death and clinical response with substantially less side effects. New information concerning an intermittent schedule of estramustine became available when the results of a Phase I study19 of 3 days of oral estramustine at 900 mg/m2 or 1200 mg/m2 and 3-hour infusions of paclitaxel at 100 mg/m2 or higher every 21 days were analyzed. In this study, gastrointestinal side effects were reduced, whereas clinical responses were observed in 4 of 15 and in 6 of 14 heavily pretreated women with refractory breast and ovarian carcinoma, respectively. These studies gave backing to a Phase I–II clinical trial to assess the maximum tolerated dose (MTD) safety and efficacy of weekly, 1-hour infusions of escalating doses of paclitaxel and a brief, intermittent schedule of oral estramustine in patients with hormone refractory prostate carcinoma. MATERIALS AND METHODS Study Design To determine the MTD, safety, and efficacy of paclitaxel and estramustine in this modified schedule, we used a Phase I–II design. The initial plan was to have a maximum of six cohorts of three patients. Each cohort would be treated with an incremental dose of paclitaxel starting at 40 mg/m2. Oral estramustine initially was planned to be given at 600 mg/m2 based on the existing experience with this dose. However, soon after the first cohort of patients had been enrolled, the results of our Phase I study19 became available, suggesting that 900 mg/m2 may be required for activity of estramustine on a brief, intermittent schedule. Therefore, the protocol was amended to increase the dose of estramustine to 900 mg/m2 from Cohort II onward. Each cohort would receive a minimum of 12 consecutive weeks of therapy with a break on Week 7. The cohort would be expanded by three additional patients at the same paclitaxel dose level if one patient developed Grade 3 or 4 toxicity. The MTD would be reached if two patients in a given cohort experienced Grade 3 or 4 toxicity. At this point, no further dose escalation would be allowed. Patient Selection Eligible patients had a histologic diagnosis of adenocarcinoma of the prostate with progressive systemic disease despite at least two endocrine manipulations. One of the manipulations included either orchiectomy, a luteinizing hormone-releasing hormone (LHRH) analogue with or without antiandrogens, megesterol acetate, or diethylstilbestrol. For patients on an antiandrogen, discontinuation of the agent was required as a second hormonal manipulation for a minimum of 4 weeks with evidence of subsequent rising PSA level or progressive, measurable disease. Patients were required to have a minimum life expectancy of 3 months and an Eastern Cooperative Oncology Group performance score ≤ 2. Additional requirements were adequate hepatic and renal function, granulocyte count ≥ 1500/μL and platelet count ≥ 100,000/μL. Patients were required to be at least 3 weeks beyond surgery, recovered from infectious process, and have no significant active medical illness that would preclude protocol treatment or survival. Prior radiation to a symptomatic metastatic site that was not the only measurable or evaluable lesion was allowed. Radiation therapy and corticosteroids had to be completed at least 2 weeks before therapy. Hydronephrosis with impaired renal function had to be adequately decompressed. Patients with central nervous system metastasis, unstable angina, uncontrolled congestive heart failure, or arrhythmia were excluded. All patients were required to sign informed consent in accordance with institutional, state, and federal guidelines. Evaluation Criteria A complete history and physical examination with complete blood count, serum chemistry profile, and PSA level were performed at baseline, in Week 7, and in Week 13. Radionuclide bone scans and, computed tomography (CT) scans of the abdomen and pelvis were required at baseline and at the end of the study or as indicated by biochemical or clinical progression. Clinical evidence of toxicity and complete blood counts were assessed weekly. Treatment Program Therapy was administered in the outpatient setting. All patients continued on a LHRH agonist. Paclitaxel was given as a weekly 1-hour intravenous infusion for two cycle of 6 weeks, with a break on Week 7. The dose escalations of paclitaxel planned for each cohort were 40 mg/m2, 60 mg/m2, 75 mg/m2, 90 mg/m2, 100 mg/m2, and 110 mg/m2. Two days preceding the paclitaxel infusion, patients began a 3-day course of oral estramustine given in three divided doses 1 hour before or 2 hours after meals. The dose of estramustine was 600 mg/m2 per day for patients in Cohort I; however, starting with Cohort II, it was raised to 900 mg/m2 per day in an attempt to decrease toxicity and maintain efficacy. One hour before paclitaxel infusion, patients received intravenous diphenhydramine 50 mg, ranitidine 50 mg, and dexamethasone 20 mg, which was reduced subsequently to 8 mg if no reactions were observed. At the discretion of the treating physician, responding patients were offered an opportunity to continue on the same regimen after the study period. Toxicity and Response Criteria Toxicity was graded according to the revised National Cancer Institute common toxicity criteria. Efficacy was assessed by changes in PSA levels,20-22 changes in measurable disease (assessed by CT scans of the abdomen and pelvis and chest X-rays), and changes in evaluable disease (assessed on bone scans). A complete biochemical response was defined as normalization of PSA levels (< 4.0 ng/mL), a partial response was defined as a decline in PSA levels ≥ 50% from baseline values, and disease progression was defined as rising PSA levels 50% above baseline values. Stable disease was defined as PSA changes that did not meet the criteria for partial response or disease progression. PSA responses required confirmation on a second determination at least 2 weeks apart. Measurable disease was assessed in bidimensionally measurable lesions with clearly defined margins by imaging X-rays and scans. A complete response was defined as the resolution of all measurable masses and the absence of any lesions or anomalies, a partial response was defined as a reduction > 50%, and a minor response was defined as a reduction between 25% and 50% in the measurable lesions. The duration of response23 was calculated from the date of PSA decline ≥ 50% from the initiation of treatment to the date of 50% increase above the nadir PSA value or an increase > 25% in the smallest sum of all tumor measurements obtained during the best response. Response was analyzed on an intent-to-treat basis for all patients enrolled in the study and for those in Cohorts II–IV who received the same high dose of estramustine. RESULTS Patient Characteristics The pretreatment characteristics of the 18 patients are listed in Table 1. The median age was 69 years (range, 44–76 years). There were eight African-American patients, eight Caucasian patients, and two Hispanic patients. Seventeen patients had a performance status of 0, and only 1 had a performance status of 1. The median baseline PSA level was 111 ng/mL (range, 38–2853 ng/mL). Eighteen patients had bony metastasis, and 3 had pelvic lymph node enlargement. None had parenchymal organ involvement. At study entry, all patients had evidence of disease progression by rising PSA levels after two hormonal manipulations that included antiandrogen withdrawal for 4–6 weeks. Three patients had received prior chemotherapy, and 11 patients had received radiation to a metastatic site. Table 1. Patient Characteristics Characteristic No. No. eligible patients 18 No. evaluable 18 Race African American 8 Caucasian 8 Others 2 Median age in yrs (range) 69 (44–76) ECOG performance status 0 17 1 1 2 0 Sites of metastases Bone only 15 Bone and soft tissue 3 Median baseline PSA (range) 111 (38–2853) Median no. of hormonal therapies (range) 2 (2–4) Prior chemotherapy (%) 3 (16.7) Prior radiotherapy (%) 11 (61.1) ECOG: Eastern Cooperative Oncology Group; PSA: prostate specific antigen. Patient Distribution Among Cohorts The three patients in Cohort I were enrolled to receive paclitaxel 40 mg/m2 and estramustine 600 mg/m2. All patients completed two cycles of therapy. In Cohort II, three patients were enrolled to receive paclitaxel 60 mg/m2 with estramustine 900 mg/m2. One patient was lost to follow-up after 5 weeks of treatment. Two patients completed two cycles. For Cohort III, six patients were enrolled to receive paclitaxel 75 mg/m2 with estramustine 900 mg/m2. The cohort was expanded, because one patient developed Grade 3 nausea and diarrhea, requiring treatment interruption. Five patients completed two cycles. In Cohort IV, six patients were enrolled to receive paclitaxel 90 mg/m2 with estramustine 900 mg/m2. The cohort also was expanded, because 1 patient developed Grade 3 edema with pulmonary embolism during the second week of the first cycle and was removed from protocol. One patient discontinued therapy after 4 weeks, and one patient developed Grade 3 neutropenia. Four patients completed two cycles. According to the MTD criteria, no further escalations were made after Cohort IV. In summary, 14 patients completed two cycles of therapy, and 4 patients did not complete the first cycle. Toxicity Assessment Toxicity could be evaluated in all patients enrolled in the study, because the discontinuation of treatment in four patients occurred after they had started treatment. Overall, there were no therapy-related deaths. A detailed account of the spectrum of toxicity and the number of patients for each grade of toxicity are listed in Table 2. Grade 1 and 2 paresthesias were observed in three patients, and Grade 1 musculoskeletal symptoms were documented in another patient. Partial loss of hair was seen in five patients. There was only one patient with Grade 3 neutropenia without febrile complications. At the time of enrollment, 17 patients had Grade 1 and 2 anemia secondary to prolonged androgen ablation and chronic disease. There were no new patients with Grade 1 or 2 anemia or progression of anemia during therapy. Four patients had superficial phlebitis with erythema at the site of intravenous injection without evidence of deep vein thrombosis, which resolved with local therapy. One patient had Grade 3 lower extremity edema and subsequently developed a pulmonary embolism with pleuritic chest pain and shortness of breath without hemodynamic complications. Symptoms improved rapidly with standard anticoagulation treatment with heparin and warfarin, and the patient was removed from study. Nausea was the most common gastrointestinal symptom and was experienced by six of seven patients as Grade 1–2 and by one patient as Grade 3. Grade 2 emesis was seen in two patients, and Grade 3 diarrhea was experienced by one patient. Table 2. Distribution of Toxicity Events by Type and Grade Toxicity Grade 1 2 3 4 Neuropathy 2 1 0 0 Musculoskeletal 1 0 0 0 Alopecia 3 2 0 0 Neutropenia 0 0 1 0 Phlebitisaa Phlebitis refers to induration and erythema at the site of intravenous infusion. 0 4 0 0 Edema 0 0 1 0 Thrombosis/embolism 0 0 0 1 Nausea 3 3 1 0 Emesis 2 0 0 0 Diarrhea 0 0 1 0 a Phlebitis refers to induration and erythema at the site of intravenous infusion. Overall, there were four events of Grade 3 toxicity and one event of Grade 4 toxicity. Table 3 summarized the number of Grade 3–4 toxicity events by cohort. There was one patient with Grade 3 nausea and diarrhea in Cohort III, and one patient with Grade 3 neutropenia and one patient with edema and pulmonary embolism in Cohort IV. Table 3. Distribution of Grade 3 and 4 Toxicity Events among Cohorts III and IV Toxicity Cohort III Cohort IV Neutropenia 0 1 Edema 0 1 Thrombosis/embolism 0 1 Nausea 1 0 Emesis 0 0 Diarrhea 1 0 PSA Response Table 4 summarizes the clinical responses for each cohort according to PSA criteria and intent-to-treat analysis results. Cohort I had one patient with stable PSA levels and two patients with PSA progression. Cohort II had one patient who was lost to follow up after 5 weeks of treatment, one patient had PSA progression, and one had PSA decline ≥ 75%. In Cohort III, one patient was removed early, one patient had stable PSA, one patient had PSA decline ≥ 50%, and three patients had PSA decline > 75%. In Cohort IV, two patients were removed early, one patient had PSA decline > 50%, and three patients had PSA decline > 75%. Table 4. Prostate Specific Antigen Response by Cohort Cohort Paclitaxel Estramustine No. Treatment discontinued Progressed Stable PSA decline > 50% Intent to treat response (%) I 40 600 3 0 3 0 0 0 of 3 II 60 900 3 1 1 0 1 1 of 3 IIII 75 900 6 1 0 1 4 4 of 6 IV 90 900 6 2 0 0 4 4 of 6 Total — — 18 4 4 1 9 9 of 18 (50) PSA: prostate specific antigen. The PSA response rate estimated on the basis of the intent-to-treat analysis showed that 9 of 18 patients (50%) enrolled in the study had a PSA decline ≥ 50%. Because the group of patients in Cohorts II–IV received a dose of estramustine 1.5 times greater than Cohort I, and this alone may have affected the PSA response irrespective of the dose of paclitaxel, we also analyzed them as a group. The intent-to-treat analysis showed that 9 of 15 patients (60%) had a PSA decline > 50%; in 7 patients, the decline was ≥ 75%. The median duration of response (n = 9 patients) was 16.7 weeks, with a range from 3+ weeks to 48.6 weeks. Fifteen of 18 patients (83%) had metastatic disease limited to bone, including 12 patients in Cohorts II–IV. Seven of these patients (58%) experienced PSA decline > 50% from baseline. Stabilization with mild improvement was reported in two patients. Three patients had measurable disease to lymph nodes, one patient had a measurable response with a PSA decline > 75%, another patient had no response with a PSA decline > 50%, and one patient did not complete therapy. Bone scan abnormalities persisted in all patients. DISCUSSION In this report, we present the toxicity profile and response of patients with hormone-refractory prostate carcinoma to a new schedule and dose range of paclitaxel and oral estramustine. This regimen was based on previous experience with other tumors suggesting that more frequent24, 25 and lower doses of paclitaxel,17, 26 as well as intermittent but higher doses of estramustine,19 could improve the toxicity profile of each drug without compromising their synergistic activity. Therefore, weekly 1-hour infusions of paclitaxel were given in escalating doses of 40 mg/m2, 60 mg/m2, 75 mg/m2, and 90 mg/m2 combined with 3 days of oral estramustine. The dose of estramustine, which was established at 600 mg/m2 in the original design and was received by patients in Cohort I along with 40 mg/m2 of paclitaxel, was increased subsequently to 900 mg/m2 and fixed at that level for all subsequent paclitaxel dose levels. The results of this trial indicate that the grade and spectrum of toxicity associated with taxanes in previous studies of this combination7, 15 can be improved markedly. Compared with the 20% and 53% incidence rates of Grade 3–4 granulocytopenia, there was only one patient without febrile complications in our series. Similarly, there were no new incidents of anemia or worsening of preexisting anemia compared with the 18% and 59% incidence rates reported in the previous studies, and there were no incidents of thrombocytopenia. Neurologic and musculoskeletal symptoms also were infrequent and predominantly were Grade 1. Hypersensitivity reactions, arrhythmia, or hypotension were not reported during the infusions. The incidence of peripheral edema also was reduced markedly. Gastrointestinal complications commonly associated with oral estramustine27 were ameliorated but not eliminated with the brief and intermittent schedule that was used. Despite the high dose of estramustine, the frequency and severity of nausea, emesis, and diarrhea was low7, 28 and was limited to the days of treatment. This may explain why, compared with other regimens using lower doses of estramustine for prolonged periods of time,28 anorexia and weight loss were rare. This treatment schedule did not appear to prevent the development of thromboembolic events previously reported with regimens containing estramustine,27 as illustrated by the patient who developed a pulmonary embolism in the second week of therapy. Given the proximity of the episode to the initiation of therapy, the possibility cannot be excluded that it may have been related to the advanced stage of the disease rather than the treatment. Also, because we did not observe other patients with deep vein thrombosis, and recent studies quote 8–10% thromboembolic events with lower28 and intermittent7 dosing of estramustine, we do not have evidence that the higher dose used in this trial played a role. In recognizing this risk, prophylaxis of thrombosis using low doses of warfarin and aspirin currently are included in the treatment plan of new trials containing estramustine. Based on the fact that Cohort IV required expansion because there were two patients with Grade 3 and 4 toxicity, we concluded that the MTD for this regimen had been reached. A second objective of this study was to evaluate the efficacy of the combination by PSA response and, whenever possible, by measurable disease parameters. The intent-to-treat analysis by PSA response criteria showed an overall response rate of 50%, because 9 of 18 patients enrolled in the study had a PSA decline > 50% from baseline. When looking at PSA response rates by cohort, it appears that a dose of paclitaxel between 75 mg/m2 and 90 mg/m2 was required to achieve synergism with 900 mg/m2 of estramustine. These PSA response rates are higher than the 23% rate reported with 24-hour infusions of paclitaxel at 135–170 mg/m2 every 3 weeks29 or weekly 1-hour infusions of paclitaxel at 150 mg/m2.30 They also are superior to the 14% rate observed with continuous estramustine at 560–840 mg daily.31 We took into consideration the facts that the 15 patients enrolled in Cohorts II–IV had received a 1.5 times larger dose of estramustine compared with patients in Cohort I and that this alone may have influenced their response independent of the dose of paclitaxel. The 60% response rate observed in the intent-to-treat analysis reflects the fact that the 9 responders were among the 15 patients in this group. It is noteworthy that seven of these responders had a PSA decline > 75% from baseline and that the drop in PSA levels for eight of these patients occurred within the initial 6 weeks of treatment, which may have affected the median PSA response duration determination23 of 16.7 weeks, because, at the time of first evaluation of response, PSA levels had decreased beyond 50%. Although they were limited because of the nature of the study, the PSA response rates observed in the intent-to-treat analysis were within the 53% and 63% response rates reported previously with either paclitaxel or docetaxel every 3 weeks and continuous or intermittent lower doses of estramustine.7, 28 The time to response and duration of response also were within the 8 weeks and 20–22 weeks observed, respectively, in those studies. We also evaluated whether there was any evidence of response in bone metastasis or measurable disease. Like what is seen frequently with metastatic bone disease in patients with hormone-refractory prostate carcinoma, we observed decreased intensity of bony lesions in two patients, but no decrease in the number of bone lesions was observed. We did observe a partial response in one patient with measurable disease to the lymph nodes, whereas the PSA level had declined more than 75%. These preliminary observations suggest that measurable responses also may be expected with this schedule after a decline in the PSA level > 50%.15 This study supports the finding that the MTD of paclitaxel in a weekly 1-hour infusion schedule is 90 mg/m2 with intermittent estramustine at 900 mg/m2 for 3 days. The current schedule had markedly improved hematologic and neurotoxicity profile and milder gastrointestinal side effects compared with higher doses of paclitaxel at 3-week intervals and continuous estramustine in patients with hormone-refractory prostate carcinoma. 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