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Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma
Article first published online: 8 JAN 2004
Copyright © 2004 American Cancer Society
Volume 100, Issue 4, pages 746–750, 15 February 2004
How to Cite
Vaughn, D. J., Brown, A. W., Harker, W. G., Huh, S., Miller, L., Rinaldi, D. and Kabbinavar, F. (2004), Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma. Cancer, 100: 746–750. doi: 10.1002/cncr.11956
- Issue published online: 3 FEB 2004
- Article first published online: 8 JAN 2004
- Manuscript Accepted: 11 NOV 2003
- Manuscript Revised: 3 NOV 2003
- Manuscript Received: 6 AUG 2003
- Bristol-Myers Squibb Oncology (Princeton, NJ)
- androgen-independent prostate carcinoma;
- prostate-specific antigen
The current study determined the efficacy and toxicity of weekly paclitaxel in combination with estramustine phosphate (EMP) in patients with androgen-independent prostate carcinoma (AIPC).
Patients with progressive AIPC received 90 mg/m2 paclitaxel by 1-hour intravenous infusion weekly for 3 weeks, followed by a 1-week treatment rest. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received 1 mg warfarin daily to prevent thromboembolism.
Sixty-six patients with progressive AIPC received treatment at 29 centers. Forty-two percent of patients had a 50% decline in prostate-specific antigen (PSA; 95% confidence interval [CI], 30–54%). For 26 patients with bidimensionally measurable disease, the objective response rate was 15% (95% CI, 1–30%). The median time to disease progression was 6.3 months, and the median time to PSA progression was 11.4 months. The median survival period was 15.6 months. Grade 3–4 toxicities were uncommon and included thromboembolism (8%), anemia (3%), neutropenia (3%), and peripheral neuropathy (2%). There was one treatment-related death.
This regimen of EMP plus weekly paclitaxel was an active and well tolerated treatment for patients with AIPC. Cancer 2004;100:746–50. © 2004 American Cancer Society.
Prostate carcinoma is the second leading cause of malignancy-related death among American men. According to statistics, 28,900 deaths are predicted in 2003.1 For decades, androgen ablation therapy has been used to treat patients with advanced disease. However, most patients with metastatic disease will develop androgen-independent prostate carcinoma (AIPC) and ultimately die of this disease. Historically, the median survival of patients with progressive metastatic disease despite castration who were treated with chemotherapy was < 1 year.2 However, more recent chemotherapy trials have demonstrated a median survival period of 14–22 months.3
Estramustine phosphate (EMP) is a nornitrogen mustard-estrogen conjugate that is dephosphorylated to estramustine (EM). EM inhibits the growth of prostate carcinoma cell lines through alterations of microtubule assembly.4 Preclinical studies have demonstrated that EM is synergistic with M-phase-specific agents, including the taxanes paclitaxel and docetaxel.5 During the last several years, investigators have studied various combinations of EMP and the taxanes in AIPC.
Weekly administration of paclitaxel offers the theoretic advantages of increased dose density and improved tolerability.6 In addition, weekly administration of agents such as paclitaxel may have an anti-angiogenesis effect.7 Studies of weekly paclitaxel have been reported in breast, ovarian, lung, and bladder carcinoma.6, 8, 9–11 For these reasons, we performed a Phase II trial of EMP and weekly paclitaxel in patients with AIPC.
MATERIALS AND METHODS
Patients ≥ 18 years with histologically confirmed adenocarcinoma of the prostate and progressive metastatic disease despite androgen ablation were eligible. Eligibility criteria were based on guidelines published by the Prostate-specific Antigen (PSA) Working Group.12 Patients receiving luteinizing hormone–releasing hormone agonists continued to receive these agents during treatment and had documented testosterone levels < 50 ng/dL. Disease progression was defined as 1) progressive bidimensionally measurable disease independent of changes in serum PSA level; 2) bone scan progression with at least 1 new lesion and PSA ≥ 5 ng/mL; or 3) nonprogressive bidimensionally measurable or evaluable bone disease with an increasing PSA level ≥ 5 ng/mL. An increasing PSA level was defined as 2 successive increases with the first increase a minimum of 1 week from the baseline and the second increase a minimum of 1 week from the first increase.12 Patients discontinued flutamide or nilutamide ≥ 4 weeks before registration and bicalutamide ≥ 6 weeks before registration. Patients did not receive previous cytotoxic chemotherapy and must have completed radiotherapy ≥ 4 weeks before registration.
Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and have adequate hematologic, renal, and hepatic function. Excluded from the study were patients with preexisting peripheral neuropathy ≥ Grade 2, patients with serious cardiac disease that was not controlled adequately, and patients with a history of deep venous thrombosis or pulmonary embolism. Written informed consent was obtained from all patients and the study met institutional review board guidelines.
Paclitaxel, 90 mg/m2, was administered by 1-hour intravenous infusion weekly for 3 weeks followed by a 1-week treatment break. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received a 1 mg oral dose of warfarin daily to prevent thromboembolism. Premedications were administered intravenously 30–60 minutes before paclitaxel and consisted of 8–20 mg dexamethasone, 50 mg diphenhydramine, and an H2 blocker, such as 300 mg cimetidine or 50 mg ranitidine. Alternatively, dexamethasone could be administered as 8 or 10 mg orally 12 and 6 hours before paclitaxel. Treatment was continued until disease progression, unacceptable toxicity, or patient/physician decision to discontinue therapy.
The protocol allowed dose modification, from 90 mg/m2 per week paclitaxel to 70 mg/m2 per week paclitaxel and from 140 mg EMP 3 times daily to 140 mg EMP twice daily, based on hematologic and nonhematologic toxicity. For a day-of-treatment absolute neutrophil count (ANC) of 1200–1799 cells per microliter or a platelet count of 75,000–99,999 cells per microliter, the paclitaxel dose was decreased to 70 mg/m2, with no change in the EMP dose. Treatment was withheld for ANC < 1200 cells per microliter or platelet count < 75,000 cells per microliter. If the ANC and platelet count did not recover after 2 weeks or if patients required more than 1 dose reduction, patients were withdrawn from the study. Patients who experienced febrile neutropenia were retreated at the decreased dose when the episode was resolved and ANC was ≥ 1800 cells per microliter. Patients who developed Grade 2 neuropathy were treated with 70 mg/m2 paclitaxel. Patients with Grade 3 neuropathy were released from the study. For other nonhematologic toxicities, treatment was withheld for patients with ≥ Grade 3 toxicity. If the toxicity improved to ≤ Grade 2, patients were treated at the decreased dose. Patients who developed thromboembolism were released from the study.
Response and Toxicity Assessment
Prestudy evaluation included a complete history and physical examination, performance status assessment, complete blood count with differential, serum chemistry profile, protime (with International Normalized Ratio [INR]), and PSA level. Baseline tumor measurements included a computerized tomography scan of the abdomen/pelvis, chest X-ray, and bone scan within 30 days of study entry. An electrocardiogram was obtained within 30 days of study entry. Complete blood counts and toxicity assessment were performed weekly before each treatment. Performance status evaluation and serum chemistry profiles were repeated every 4 weeks. PSA levels were reevaluated at the start of each monthly cycle. Tumor measurements, using the same methods that determined the baseline evaluation, were repeated every 2 cycles (8 weeks) for the first year and every 3 cycles (12 weeks) thereafter, if indicated. Toxicities were evaluated and documented at weekly visits. Toxicities were reported using Version 2 of the National Cancer Institute Common Toxicity Criteria.
Response assessment was based on the guidelines of the PSA Working Group.12 A 50% PSA decline was defined as a decline from the baseline value of ≥ 50% confirmed by a second PSA ≥ 4 weeks later. PSA progression was defined as a 25% increase over pretreatment PSA or nadir and an increase of ≥ 5 ng/mL confirmed by a second value ≥ 4 weeks later. For patients with bidimensionally measurable disease, objective tumor response criteria included complete (CR) and partial (PR) responses. A complete response (CR) was defined as the disappearance of all clinical and radiographic evidence of disease determined on 2 observations ≥ 4 weeks apart. A PR was a ≥ 50% decrease in the sum of products of measurable lesions confirmed on 2 observations ≥ 4 weeks apart, along with no simultaneous increase of ≥ 25% in the size of any lesion or the appearance of any new lesion.
The primary study endpoint was the proportion of patients with a 50% PSA decline. Secondary endpoints were objective response rates, time to PSA progression, time to disease progression, overall survival, and toxicity. Patients were analyzed on an intent-to-treat basis. Time to PSA progression was defined as the time from initiation of treatment to obtaining a 50% increase in PSA above the nadir and a minimum of 5 ng/mL for responders and a 25% increase in PSA above baseline in nonresponders. Time to disease progression was defined as the time from study enrollment to evidence of clinical, radiologic, or PSA progression (whichever was achieved first). Overall survival was calculated from time of study enrollment until death. Patients who died without documented disease progression were censored on the day of death or last follow-up. Time to progression and overall survival distributions were estimated using the Kaplan–Meier method.13
Between June 2000 and October 2002, 66 patients were enrolled and treated. The characteristics of the patients are shown in Table 1. Their mean age was 72 years (range, 51–90 years). Forty-four patients were ≥ 70 years old. Most patients (93%) had an ECOG performance score of 0 or 1. The median baseline PSA level was 127.8 ng/mL. Ninety-one percent of patients had bone metastases and 33% had lymph node or soft tissue disease. Lung and liver involvement were present in 11% and 6% of patients, respectively. Twenty-one percent of patients had progressive bidimensionally measurable disease, 47% had bone scan progression, and 32% had PSA progression in the setting of documented metastatic disease. Thirty-eight percent of patients had baseline pain.
|ECOG performance status|
|African American||6 (9)|
|Baseline PSA ng/mL|
|Involved metastatic site|
|Lymph node/soft tissue||22 (33)|
|Entry criteria for disease progression|
|Bidimensionally measurable disease||14 (21)|
|Bone scan progression||31 (47)|
|PSA progression||21 (32)|
Patients received a median of 4 cycles (range, 1–21 cycles). Overall, therapy was well tolerated. Eleven patients (17%) underwent dose modifications for adverse events. The highest degree of toxicity observed is reported in Table 2. Grade 3–4 toxicities were uncommon and included thromboembolism (8%), anemia (3%), neutropenia (3%), and peripheral neuropathy (2%). Six patients (9%) discontinued therapy because of toxicity and 31 (47%) patients discontinued therapy because of progressive disease. There was one treatment-related death: a patient died of pneumonia not related to neutropenia.
|Toxicity||Grade 1 (%)||Grade 2 (%)||Grade 3 (%)||Grade 4 (%)|
|Neutropenia||4 (6)||0||1 (2)||1 (2)|
|Thrombocytopenia||0||1 (2)||1 (2)||0|
|Anemia||9 (14)||6 (9)||2 (3)||0|
|Peripheral neuropathy||11 (17)||6 (9)||1 (2)||0|
|Fatigue||21 (32)||16 (24)||0||0|
|Nausea||21 (32)||5 (8)||1 (2)||0|
|Musculoskeletal toxicity||19 (29)||15 (23)||4 (6)||0|
|Thromboembolism||1 (2)||0||5 (8)||0|
Efficacy data were analyzed on an intent-to-treat basis and are summarized in Table 3. Among the 65 patients with a baseline PSA level ≥ 5 ng/mL, 42% of patients had a 50% PSA decline (95% confidence interval [CI], 30–54%). For the 26 patients with bidimensionally measurable disease, the objective response rate was 15% (95% CI, 1–30%). The median time to PSA progression was 11.4 months. The median time to disease progression by any criteria was 6.3 months. With a median follow-up of 15 months, the median overall survival time was 15.6 months. The 1-year survival rate was 66%. There were no statistically significant differences in PSA response rate, objective response rate, time to progression, and overall survival for patients age < 70 years versus patients age ≥ 70 years.
|Proportion with 50% PSA decline (n = 65)||42% (95% CI, 30–54%)|
|Bidimensionally measurable disease response rate (n = 26)||15% (95% CI, 1–30%)|
|Median time to PSA progression (n = 66)||11.4 mos|
|Median time to disease progression (n = 66)||6.3 mos|
|Median survival (n = 66)||15.6 mos|
|1 yr survival rate (n = 66)||66%|
Chemotherapy options for patients with AIPC continue to evolve. Most of the recently developed regimens have focused on the combination of EMP plus taxanes, a combination with preclinical synergy. EMP/paclitaxel and EMP/docetaxel regimens have been reported and are now used in clinical practice. The Southwest Oncology Group (SWOG) is completing a Phase III trial of EMP/docetaxel versus mitoxantrone/prednisone, a regimen with established palliative benefit.14 Despite recent improvements in chemotherapy regimens, most patients with AIPC are not cured. The goal of chemotherapy in AIPC is largely palliative. For this reason, development of well tolerated effective outpatient regimens is important.
The regimen of EMP with weekly paclitaxel reported in the current study is active and has acceptable toxicity. The PSA response rate and median overall survival fall within the range of what has been previously reported in other Phase II trials of EMP and paclitaxel. Hudes et al.15 treated 34 patients with AIPC with EMP plus paclitaxel 120 mg/m2 by 96-hour infusion every 21 days. Fifty-three percent of patients achieved a 50% PSA decline and the median survival was 16.4 months. Vaishampayan et al.16 treated 28 patients with AIPC with EMP plus paclitaxel 150 mg/m2 weekly for 3 of 4 weeks. This regimen was similar to that reported in the current study, except for the higher weekly paclitaxel dose. Sixty-two percent of patients achieved a 50% PSA decline (95% CI, 38–74%), and the median survival was 13 months. However, these regimens have some disadvantages. The 96-hour regimen is cumbersome and requires the use of an ambulatory infusion device. The weekly regimen involving 150 mg/m2 paclitaxel results in significantly more Grade 3 peripheral neuropathy (21%) than is reported in the current study (2%). Therefore, our regimen of EMP plus weekly paclitaxel offers convenience and less toxicity without decreasing the effectiveness of the regimen. The ECOG has completed accrual to a trial of EMP plus 90 mg/m2 paclitaxel weekly for 6 weeks followed by a 2-week rest. In a preliminary report on 62 patients, 58% had achieved a 50% PSA decline, and the toxicity profile was similar to the one presented in the current study.17
Which taxane is optimal in the treatment of patients with AIPC? Preclinical data suggest that the dose of docetaxel combined with EM required to inhibit the growth of prostate carcinoma cell lines is 60 times less than the corresponding dose of paclitaxel and EM.5 In the clinical setting, EMP/docetaxel regimens have significant activity in AIPC. Savarese et al.18 reported the Cancer and Leukemia Group B trial 9780 combining 70 mg/m2 docetaxel every 3 weeks plus EMP and hydrocortisone. Sixty-eight percent of patients achieved a 50% PSA decline, and the median survival was 20 months. Sinibaldi et al.19 treated 42 patients with AIPC with EMP and 70 mg/m2 docetaxel every 21 days. In that study, 45% of patients demonstrated a 50% decline in PSA (95% CI, 29–62%) and a median survival of 13.5 months. Although these regimens were associated with significantly more Grade 3–4 neutropenia (48–56%) compared with the current regimen (4%), febrile neutropenia was uncommon. A randomized comparison of EMP/ paclitaxel versus EMP/docetaxel has not been performed.
Recently, investigators have questioned the necessity of EMP in taxane-based chemotherapy regimens in AIPC. Eliminating EMP could potentially decrease specific EMP-related toxicities such as thromboembolism. Preliminary reports of single-agent docetaxel without EMP demonstrate significant activity in AIPC.20, 21 However, the randomized trial conducted by Hudes et al.22 demonstrated that the combination of EMP plus vinblastine was superior to vinblastine alone in AIPC with respect to time to progression and the proportion of patients with a 50% PSA decline. Whether the same is true for the taxane regimens remains to be determined. If EMP continues to play a major role in AIPC, studies will need to address how to prevent EMP-related thromboembolism. Recent trials range from no prophylaxis to combinations of both warfarin and aspirin. In the current trial, 1 mg warfarin daily was not effective prophylaxis, as evidenced by the thromboembolism rate of 8%.
EMP plus weekly paclitaxel is an active and well tolerated treatment for patients with AIPC. The previously described ongoing SWOG randomized trial comparing EMP/docetaxel with mitoxantrone/prednisone will help to better define the role of EMP/taxane chemotherapy in AIPC.
- 1American Cancer Society. Cancer facts and figures, 2003. Available from URL: www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf [accessed 16 Dec 2003].
- 17Phase II study of weekly paclitaxel (P) by 1-hour infusion plus reduced dose oral estramustine (EMP) in metastatic hormone-refractory prostate carcinoma (HRPC): a trial of the Eastern Cooperative Oncology Group [abstract]. Proc Am Soc Clin Oncol. 2001; 20: 175a., , , et al.