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© 2001 American Society for Clinical Oncology Paclitaxel, Estramustine Phosphate, and Carboplatin in Patients With Advanced Prostate CancerFrom the Genitourinary Oncology Service, Division of Solid Tumor, Department of Medicine, Departments of Nursing, Radiology, Pharmacology, Clinical Chemistry, and Nuclear Medicine, and Division of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and Department of Medicine, Joan and Sanford Weill Medical College of Cornell University, New York, NY; Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, and Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Genitourinary Oncology Service, Department of Medical Oncology, University of California San Francisco, San Francisco, CA. Address reprint requests to William Kevin Kelly, DO, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 473, New York, NY 10021-6007; email kellyw{at}mskcc.org
PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m2), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m2 without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.
THIS STUDY WAS ONE of a series of trials designed to investigate the impact of estramustine-based combination chemotherapy programs on the natural history of prostate cancer. This trial built on the observation by us and others that combinations of agents that target microtubules have activity in this disease.1-3 The study extended the finding that estramustine combined with paclitaxel administered in a 96-hour infusion produced measurable disease regression in four of nine patients with androgen-independent disease and a  50% decrease in prostate-specific antigen (PSA) levels from baseline in 17 (53%) of 33 patients.4 In addition, estramustine combined with cisplatin or carboplatin with etoposide have shown antitumor activity in patients with aggressive phenotypes of prostate cancer; however, myelosuppression is often a treatment-limiting factor.5 In an attempt to improve the safety of the program while maintaining drug delivery, we explored weekly paclitaxel combined with estramustine and carboplatin (TEC). The rationale was based on the following: the single-agent activity profile of carboplatin,6 the observation that paclitaxel and carboplatin administered weekly are synergistic and platelet sparing,7-9 the known synergy of estramustine and paclitaxel,4,10 and work suggesting that estramustine may increase drug retention through its effect on P-glycoprotein.11 Preliminary data have also indicated that the transcription of genes that encode P-glycoprotein may be repressed in androgen-dependent tumors, suggesting increased susceptibility to chemotherapy.12,13 Consequently, patients with androgen-independent disease (castrate levels of testosterone) and patients with androgen-dependent disease (noncastrate levels of testosterone) were studied.14 The clinical trial consisted of two parts. In part 1, a safe dose of weekly paclitaxel in combination with a fixed dose of estramustine and carboplatin was established. In part 2, a multicenter phase II evaluation was conducted in patients with androgen-independent disease and patients with androgen-dependent disease. This report covers the dose-escalation study and the experience in patients with progressive androgen-independent disease.
Patient Eligibility and Evaluation Patients with histologically confirmed androgen-dependent or androgen-independent prostate cancer were considered for the study. Patients with androgen-dependent disease included patients with locally advanced adenocarcinoma of the prostate and an estimated 3-year relapse-free survival rate of less than 25% (T3/T4N0/1M0 or Gleason score 7 and serum PSA levels 20 ng/mL)15; patients with local relapse after radiation therapy or radical prostatectomy, with measurable disease on a computed tomography (CT) scan or magnetic resonance image; and patients with poor-risk metastatic disease (bone scan showing 20 osseous lesions or visceral metastatic disease). Patients with small-cell or neuroendocrine carcinoma of the prostate were also eligible. Patients with androgen-dependent disease who met one of the inclusion criteria were eligible for the study if they had been undergoing androgen ablation for less than 3 months.
Patients with androgen-independent disease were required to have documentation of progressive disease after discontinuation of treatment with an antiandrogen,16 castrate levels of testosterone (< 30 ng/mL), and a life expectancy of more than 3 months and to have had no more than one prior course of chemotherapy (patients could have been treated with one previous estramustine- or taxane-based regimen), palliative radiotherapy, or radioisotope therapy. Disease progression was considered to have occurred if at least one of the following criteria was met: an increase in PSA level of
Each patient had a Karnofsky performance status (KPS) score The pretreatment evaluation included a complete history and a complete physical examination with determination of a baseline KPS score. Laboratory studies included an automated blood and platelet count (complete blood cell count), measurement of serum electrolyte levels, a comprehensive screening profile (alkaline phosphatase, lactate dehydrogenase, aspartate transglutaminase, blood urea nitrogen, creatinine, calcium, phosphorus, uric acid, total protein, albumin, total bilirubin, and electrolyte levels), measurement of 12-hour creatinine clearance, and determination of testosterone, serum acid phosphatase, and PSA levels. Imaging studies included an abdominal and pelvic CT scan or magnetic resonance image, bone scan, and chest radiograph. In all cases, a baseline ECG was obtained, and further cardiac work-up was performed if indicated. Patients underwent a weekly complete blood cell count before chemotherapy, and a comprehensive screening profile and determination of acid phosphatase and PSA levels were repeated every 2 weeks during the study. Measurable disease, when present, was re-evaluated at 8-week intervals, and radionuclide bone scans were repeated every 12 weeks.
Evaluation of Response
Baseline serum PSA concentration (Tandem-E; Hybritech, San Diego, CA; upper limit of normal, 4.0 ng/mL) was defined as the PSA concentration within 2 weeks of initiation of therapy, and changes from baseline were assessed from this level. Baseline serum PSA levels had to be The time to progression (TTP) was calculated from the start of therapy to the off-study date—either the date defined by the criteria for progression based on PSA level or measurable or osseous disease or the date of removal from the study because of toxicity or death. The serum PSA level used to document PSA level progression was the first PSA level increase that could be confirmed by two sequential increases in serum PSA concentration 2 or more weeks apart.
Treatment
For the dose-escalation portion of the study, patients were entered in groups of three, with no intrapatient dose escalation. The dose of paclitaxel was escalated every 4 weeks if the previous cohort of patients did not experience dose-limiting toxicity (DLT). On the basis of other studies,21 DLT was defined as grade 3 or 4 thrombocytopenia or neutropenia lasting more than 2 weeks or any grade 3 or 4 gastrointestinal or neurologic toxicity occurring during the first cycle of therapy. If one patient experienced DLT during the first 4 weeks of therapy, three additional patients were added to the cohort receiving therapy at that dose level, for a total of six patents. If three or more of the six patients experienced DLT in cycle 1, that level was considered the dose-limiting level, and the preceding dose was then considered the maximum-tolerated dose (MTD). If escalation to the highest dose level was achieved without DLT, that dose was chosen as the phase II dose; otherwise, the dose chosen was the MTD.
If on the day of a scheduled treatment, the WBC count was less than 3.0/mm3 or the platelet count was less than 100,000/mm3, therapy was not begun until the WBC count was During the escalation phase of the study, paclitaxel levels were measured at baseline and 30, 60, 90, and 120 minutes and approximately 18 hours after the start of the infusion. Samples were placed on ice and immediately centrifuged at 3,000 rpm for 10 minutes to separate the plasma. The plasma (3 to 5 mL) was transferred to a 15-mL conical polypropylene tube, appropriately labeled, and stored at -20°C until analyzed. The plasma was analyzed for paclitaxel by reverse-phase high-performance liquid chromatography, according to previously published methods.22 Pharmacokinetic parameters were calculated using noncompartmental techniques. AUC was estimated using the linear trapezoidal method, with extrapolation to zero using WinNonLin version 2.1 (Pharsight Corp, Mountain View, CA). Therapy was continued for up to 10 cycles, until there was progression of disease or development of intolerable adverse effects. Additional hormonal therapy, chemotherapy, or radiation therapy was not permitted during the study. No other anticancer drugs were allowed, with the exception of LHRH analogs. Patients taking LHRH analogs continued to do so, to maintain castrate status. To maintain constant levels of androgen suppression in patients with androgen-dependent disease, concomitant LHRH agonist therapy was given to these patients during the study. Initially, all patients were given aspirin 325 mg/d PO (unless contraindicated), in an effort to prevent thromboembolic disease. When it became apparent that the incidence of deep vein thrombosis (DVT) was not altered by aspirin, low-dose warfarin (1 mg/d) was substituted (12 patients). Phase II study. For the phase II portion, patients were treated at dose level 4 (paclitaxel dose of 100 mg/m2). In this phase of the study, patients were divided into two groups: patients with androgen-dependent disease (noncastrate levels of testosterone) and patients with androgen-independent disease (castrate levels of testosterone). Entry criteria were the same as in the dose-escalation study. The dose-escalation study was performed at Memorial Sloan-Kettering Cancer Center (New York, NY), and the phase II portion of the study was conducted there and at two academic centers (University of California San Francisco, San Francisco, CA; and Dana-Farber/Partners CancerCare, Boston, MA). The phase II portion of this study was designed as a two-stage study, with 14 patients enrolling on the first phase. If one of these 14 patients had a 50% decrease in PSA levels or a partial or complete response with regard to a measurable lesion, 11 more patients would be enrolled. If no responses were documented in the first 14 patients, the study would be terminated. Clinical responses as defined by the protocol were seen in the first cohort of patients, and the enrollment was increased to a total of 50 patients with androgen-independent disease, to define the level of benefit in terms of the proportion who respond and the duration of benefit. On the basis of enrollment of 50 patients, the probability of response can be estimated to be within ± 0.14. The results of the dose-escalation study and the outcomes of the patients with androgen-independent disease in the dose-escalation and phase II portions of this study are reported here. The clinical outcomes of patients with androgen-dependent cancer will be reported once the data mature.
Dose-Escalation Phase Fifteen patients were enrolled onto the phase I portion of the study in four cohorts. These patients included six patients with androgen-dependent disease, eight with androgen-independent disease, and one patient with small-cell carcinoma of the prostate whose tumor had progressed after androgen ablation. Median age was 60 years, and the median KPS score was 90. Baseline patient characteristics and biochemical parameters are summarized in Tables 2 and 3.
The dose of weekly paclitaxel was escalated from 60 to 100 mg/m2 without achievement of a MTD. In the first 4 weeks of therapy, cohort 1 included one patient with grade 3 hyperglycemia, cohort 2 included one patient with DVT (who was anticoagulated and continued therapy), and one patient in cohort 3 was admitted to the hospital for grade 3 constipation (transient ileus) that resolved in 24 hours. The latter event necessitated the addition of three more patients to cohort 3. No DLTs were experienced by the three additional patients. In cohort 4, one patient had DVT (and was anticoagulated and continued therapy), one patient had grade 3 hyperglycemia, and one patient had grade 3 hyperphosphatemia. These conditions were not considered DLTs. In all cohorts, 54 (90%) of the 60 weekly doses of paclitaxel were given in the first cycle of therapy (cohort 1: 11 of 12; cohort 2: 11 of 12; cohort 3: 21 of 24; cohort 4: 11 of 12). The most common reasons that a dose of chemotherapy was withheld were transient leukopenia (WBC < 3.0/mm3) and thrombocytopenia (platelet count < 100,000/mm3), both resolving sufficiently for treatment to be resumed within 1 week. There were no episodes of neutropenic fever or bleeding, nor were there allergic reactions to paclitaxel when dexamethasone was being tapered. Mean (± SD) maximum plasma paclitaxel concentrations, paclitaxel concentrations at 18 hours, and paclitaxel AUCs, volumes of distribution, and total clearance at the corresponding dose levels are listed in Table 1. The calculated AUCs in this study at dose levels 60, 80, and 100 mg/m2 (2.76, 3.90, and 5.19 µg x hr/mL, respectively) were higher than the AUCs at the same dose levels (2.69, 3.34, and 4.24 µg x hr/mL, respectively) in an ovarian trial involving only a 1-hour weekly infusion of paclitaxel.23 However, the 18-hour paclitaxel concentrations in our study were similar to those in other studies.21 The 100-mg/m2 weekly dose of paclitaxel, given in combination with estramustine and carboplatin (TEC), was determined safe and was recommended for the phase II portion of the study.
Results in Patients With Androgen-Independent Prostate Cancer
The number of patients with metastasis to soft tissue structures such as retroperitoneal lymph nodes, liver, or lung was roughly equal to the number of patients with metastasis to bone only. The median serum PSA level was 100 ng/mL (range, 0.03 to 1364 ng/mL). Biochemical parameters are listed in Table 5.
Posttherapy tumor assessments. All 56 patients were assessed for clinical outcome. Clinical outcomes are listed in Table 6.
We did not formally assess quality of life and pain in this trial. However, of the 24 patients who had significant pain before the trial, pain that required treatment with opioid analgesics, 19 (79%; 95% confidence interval [CI], 62% to 96%) had a decrease in pain, with a concomitant decrease in doses of or discontinuation of the opioid analgesics.
Fifty-four patients were assessable for posttherapy changes in serum PSA concentrations. Of these, 42 (78%) had a reduction in serum PSA levels (compared with baseline values) ranging from 18% to 100% (median, 90%). Of the 56 patients, 36 (67%; 95% CI, 55% to 79%) had a
CT scans or magnetic resonance images showed bidimensional disease in 33 patients at baseline. Two patients (6%) had a complete response: one in retroperitoneal lymph nodes and one in a mediastinal mass. An additional 13 patients (39%) had a partial response, in retroperitoneal lymph nodes, lung, liver, and pelvic masses. The overall response rate (complete response plus partial response) was 45% (95% CI, 28% to 62%). All patients with measurable disease regression also had a parallel decrease in PSA concentrations of Forty-eight patients had osseous metastases. Before 3-month bone scans had been obtained, 12 patients were withdrawn from the study because of toxicity or clinical progression. Thirty-six patients underwent bone scintigraphy at 3 months. These scans showed stable disease in 26 patients and disease progression in 10 patients. Of the 26 patients with stable disease, two had clinical progression before 6-month bone scans had been obtained. Twenty-four patients underwent bone scintigraphy at 6 months for comparison with baseline and 3-month radiographs. Four patients had documented resolution of bone lesions on serial radionuclide scans that was associated with a decrease in the BSI (median decrease in the BSI, 53%; range, 37% to 75%). Fourteen had stable disease, and six showed progression of osseous disease on bone scans at 6 months. The overall best responses as demonstrated on bone scans were improvement in four (8%) of 48 patients, stable disease in 22 (46%), and progression in 22 (46%). In the majority of cases, posttherapy changes in PSA levels correlated with changes on radionuclide scans. In three cases, 3-month bone scans showed osseous disease progression, but changes in PSA levels did not indicate disease progression. Two patients had less than a 50% posttherapy decrease in PSA levels, and one patient had a posttherapy decrease in PSA concentrations of more than 50%. Because these patients received palliative benefits from the therapy, they continued treatment, but in the TTP analysis they were considered to have disease progression at 3 months.
The overall median TTP for all 56 patients was 21.2 weeks (range, 1 to 123 weeks). The median TTP for the patients in the dose-escalation study was 23 weeks (range, 14 to 104 weeks); for the patients in the phase II study, the median TTP was 21 weeks (range, 1 to 123 weeks). The median TTP for the patients who had a 50% to 79% posttherapy decrease in PSA levels was 21 weeks (range, 8 to 40 weeks), compared with 36 weeks (range, 14 to 123 weeks) for patients with a The median follow-up as of June 8, 2000, was 22.4 months (range, 14 to 37 months). The median survival time for all patients was 19.9 months. Adverse events. The therapy was generally well tolerated and the majority of patients continued to work full time, with treatment having minimal impact on normal daily activities ( Table 7). There were no deaths due to therapy. Mild nausea (grade 1 or 2) occurred in 77% of patients and seemed to be related to the estramustine therapy. Hyperglycemia (serum blood sugar level > 250 mg/dL) was seen in 38% of patients and required intervention (hypoglycemics) in less than 10% of the cases. Hypophosphatemia was a common abnormality and was associated with mild lower-extremity cramping that resolved after discontinuation of chemotherapy.
Transient grade 3 or 4 leukopenia occurred in 22% of patients, but only one patient (2%) was hospitalized because of neutropenic fever, which resolved within 24 hours. Anemia was common, and seven patients underwent blood transfusions. Two patients developed atrial fibrillation that was medically controlled without further cardiac complications. No cerebral vascular accidents were noted. DVT was diagnosed in 12 patients (21%), and two patients had pulmonary embolus. All anticoagulated patients were anticoagulated with warfarin and continued therapy. One patient receiving anticoagulation therapy for DVT developed a nonfatal pulmonary embolus. The median time to develop DVT was 55 days (range, 25 to 245 days). Initially, patients were treated with aspirin (325 mg/day) in an effort to decrease the incidence of thrombosis. However, 12 (27%) of 44 patients (95% CI, 14% to 40%) developed DVT or pulmonary embolus while taking aspirin. Therefore, 1 mg of warfarin was substituted for aspirin in the later portion of the study (12 patients received warfarin). Two (17%) of 12 patients (95% CI, 0% to 38%) developed DVT or pulmonary embolus while taking warfarin. No bleeding complications were associated with aspirin or warfarin therapy. Mild lower-extremity edema was seen in a third of the patients. Although peripheral edema is a common finding in DVT, fluid retention due to the estramustine therapy and in the absence of thrombosis was also noted. No patients developed pulmonary edema or cardiac failure from the therapy, and peripheral edema responded to fluid restriction and treatment with a diuretic. Alopecia occurred in all patients. Mild fatigue was common and was usually associated with anemia. Despite prolonged administration of carboplatin and paclitaxel, there were no cases of grade 3 or 4 neuropathy.
This study shows that weekly paclitaxel (100 mg/m2) can be administered safely in combination with estramustine and carboplatin in patients with advanced prostate cancer. Pharmacokinetic analysis revealed a linear increase in the AUC of paclitaxel as the dose was escalated from 60 to 100 mg/m2.23 Higher doses of paclitaxel were not given, because studies involving patients with breast or ovarian cancer have shown a greater morbidity with limited clinical benefit at doses greater than 100 mg/m2.21,23 Although the number of patients per cohort was small, a trend toward a higher AUC of paclitaxel per dose level was observed relative to findings of studies in which similar doses of paclitaxel alone were used.23 This trend may suggest a decreased clearance with the combination. Similar findings have been reported with estramustine and docetaxel therapy24 and more recently with IV estramustine.25 Further investigations of these interactions are needed. The initial dose-escalation study was performed at one institution, and the subsequent phase II study involving patients with progressive metastatic (androgen-independent) disease (castrate levels of testosterone) was conducted at that same institution and at two academic centers.14 The larger sample and the increased number of investigators permitted better estimation of the toxicity profile, response proportions, and duration of response.16,26 In this setting, the TEC regimen is safe and well tolerated. Mild myelosuppression was the most common adverse event, although the degree of myelosuppression with this combination was less than that in pretreated ovarian cancer patients who received 80 mg/m2 of paclitaxel alone.23 Similarly, a lower degree of myelosuppression was noted in patients treated with vinblastine alone relative to those treated with estramustine and vinblastine in a prospective randomized trial.27 These data suggest that estramustine has a myeloprotective effect. The frequency of grade 3 and 4 neuropathy was also lower than that in single-agent trials and the condition was not a DLT in patients, even after 10 months of treatment. This finding suggests a neuroprotective effect. However, these apparent palliative effects require prospective validation. Thromboembolic events were the most serious adverse events. Twelve patients developed DVT, and two had pulmonary embolic events. This frequency is higher than the frequencies in other trials and is probably related to the dose of estramustine administered (280 mg PO tid, 5 days per week). Alternatively, the longer duration of therapy may have contributed to the increased number of thrombotic events. Patients treated with TEC were treated for a median of 16 weeks, whereas in other studies, patients received continuous estramustine and vinblastine therapy for a median of 11 weeks.1,2 Although thrombosis occurred in a median of 55 days (range, 25 to 245 days), six of the 12 patients had DVT after 11 weeks of therapy. Development of DVT did not require discontinuation of therapy; patients receiving anticoagulation therapy were administered full doses of chemotherapy, and the majority of these patients had no further complications. Although a limited number of patients were treated with low-dose warfarin, the incidence of thromboembolic disease among these patients seemed to be similar to that among the patients treated with aspirin. These data suggest that in future studies involving long-term administration of estramustine, full anticoagulation with warfarin or low molecular weight heparin should be considered. To decrease the incidence of thrombosis, other investigators have reduced the number of days of estramustine administration or decreased the total dose of estramustine.24 However, although the frequency seemed to be less in these studies, thromboembolic disease persisted.
Antitumor effects were observed, and changes in serum PSA levels, bone scans, and measurable disease were reported separately16 to allow other investigators to compare these results with other clinical studies. Posttherapy decreases in serum PSA levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% of patients, respectively. In 17% of patients with a posttherapy decrease, PSA levels were nondetectable or
The findings of this multi-institutional trial are comparable to those of other single-institution studies involving administration of estramustine and taxanes ( Table 8). Hudes et al4 used a 96-hour infusion of paclitaxel combined with estramustine and found that 17 of 32 patients had a
The results of this study and of other estramustine-taxane–based investigations4,24,30 show that effective chemotherapy can be safely administered to patients. The response rates are similar to those associated with breast, colon, lung, and urothelial tumors, and prostate cancer should be added to the list of chemotherapy-responsive neoplasms. The level of benefit that chemotherapy offers in terms of improved survival needs to be established, and trials designed to address this issue are ongoing.32
Supported by American Cancer Society (Atlanta, GA) Cancer Training Grant 97-118-01-CCE, CaPCURE, the Association for the Cure of Cancer of the Prostate (Santa Monica, CA), Bristol-Myers Squibb (Stamford, CT), and the PepsiCo Foundation (New York, NY).
1. Seidman AD, Scher HI, Petrylak D, et al: Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 147: 931-934, 1994
2.
Hudes GR, Greenberg R, Krigel R: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10: 1754-1761, 1992
3.
Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12: 2005-2012, 1994 4. Hudes GR, Nathan F, Khater C, et al: Phase II trial of 96-hour paclitaxel plus oral estramustine in metastatic hormone refractory prostate cancer. J Clin Oncol 15: 3156-3163, 1997[Abstract] 5. Frank SJ, Amsterdam A, Kelly WK, et al: Platinum-based chemotherapy for patients with poorly differentiated hormone-refractory prostate cancers (HRPC): Response and pathologic correlations. Proc Am Soc Clin Oncol 14: 232a, 1995 (abstr 601) 6. Canobbio L, Guarneri D, Miglietta L, et al: Carboplatin in advanced hormone refractory prostatic cancer patients. Eur J Cancer 29A: 2094-2096, 1993 7. Ozols RF: Combination regimens of paclitaxel and the platinum drugs as first-line regimens for ovarian cancer. Semin Oncol 22: 1-17, 1995 8. Shea T, Graham M, Bernard S, et al: A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer. Semin Oncol 22: 80-85, 1995 9. Obasaju C, Johnson S, Rogatko A, et al: Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. Clin Cancer Res 2: 549-552, 1996[Abstract]
10.
Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and Taxol in human prostatic carcinoma cell lines. Cancer Res 52: 4433-4440, 1992
11.
Speicher LA, Barone LR, Chapman AE, et al: P-Glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine. J Natl Cancer Inst 86: 688-695, 1994 12. Jin S, Wilson A, Scotto KW: In vivo footprinting analysis of the class I P-glycoprotein promoter in drug-sensitive and resistant cells. Proc Am Assoc Cancer Res 37: A2210, 1996 (abstr) 13. Egan DA, Scotto KW: Glucocorticoids repress transcription of the hamster class I P-glycoprotein gene through an activator site occlusion mechanism. Proc Am Assoc Cancer Res 37: A2207, 1996 (abstr) 14. Scher HI, Heller G: Clinical states in prostate cancer: Toward a dynamic model of disease progression. Urology 55: 323-327, 2000[Medline]
15.
Zelefsky MJ, Leibel SA, Wallner KE, et al: Significance of normal serum prostate-specific antigen in the follow-up period after definitive radiation therapy for prostatic cancer. J Clin Oncol 13: 459-463, 1995
16.
Scher HI, Mazumdar M, Kelly WK: Clinical trials in relapsed prostate cancer: Defining the target. J Natl Cancer Inst 88: 1623-1634, 1996 17. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline] 18. Imbriaco M, Larson SM, Yeung HW, et al: A new parameter for measuring metastatic bone involvement by prostate cancer: The Bone Scan Index. Clin Cancer Res 4: 1765-1772, 1998[Abstract]
19.
Sabbatini P, Larson SM, Kremer A, et al: Prognostic significance of extent of disease in bone in patients with androgen independent prostate cancer. J Clin Oncol 17: 948-957, 1999 20. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748-1756, 1989[Abstract] 21. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16: 3353-3361, 1998[Abstract] 22. Longnecker SM, Donehower RC, Cates AE, et al: High-performance liquid chromatographic assay for Taxol in human plasma and urine and pharmacokinetics in a phase I trial. Cancer Treat Rep 71: 53-59, 1987[Medline]
23.
Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacokinetic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187-192, 1997
24.
Petrylak DP, MacArthur RB, O’Connor J, et al: Phase I trial of docetaxel with estramustine in androgen independent prostate cancer. J Clin Oncol 17: 958-967, 1999 25. Kelly WK, Zhu AX, Curley T, et al: Intravenous (IV) estramustine (EMP), paclitaxel (T) and carboplatin (C) in patients with advanced prostate cancer (PC). Proc Am Soc Clin Oncol 19: 347a, 2000 (abstr 1364)
26.
Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate Specific Antigen Working Group. J Clin Oncol 17: 3461-3467, 1999
27.
Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17: 3160-3166, 1999
28.
Kelly WK, Curley T, Leibertz C, et al: Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer. J Clin Oncol 13: 2208-2213, 1995 29. Dawson NA, Cooper MR, Figg WD, et al: Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76:453-462, 19965
30.
Smith DC, Esper P, Strawderman M, et al: Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer. J Clin Oncol 17: 1664-1671, 1999
31.
Kreis W, Budman DR, Fetten J, et al: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma. Ann Oncol 10: 33-38, 1999 32. Savarese DM, Taplin M-E, Marchesani B, et al: A phase II study of docetaxel, estramustine, and low dose hydrocortisone in hormone refractory prostate cancer: CALGB 9780. Proc Am Soc Clin Oncol 18: 321a, 1999 (abstr 1234) Submitted December 2, 1999; accepted July 18, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
4 ng/mL), and nine patients’ PSA levels decreased to 
