A phase II study of weekly paclitaxel/estramustine/carboplatin in hormone-refractory prostate cancer

Purpose

The objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle.

Patients and Methods

Eighty-four patients were registered into the trial. Paclitaxel 80 mg/m² and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy.

Results

Intent-to-treat analysis revealed a ≥ 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade ≥ 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%).

Conclusion

Paclitaxel/estramustine/carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.     

Dose-finding study of weekly docetaxel plus estramustine in patients with hormone-refractory metastatic prostate cancer

OBJECTIVE: The aim of this phase I study was to find the maximum tolerated dose of weekly docetaxel in association with estramustine in hormone-refractory prostate cancer. METHODS: Eleven patients with hormone-refractory prostate cancer were treated with escalating weekly doses of docetaxel (level I, 3 patients, 30 mg/m2; level II, 3 patients, 35 mg/m2, level III, 3 patients, 40 mg/mz; level IV, 2 patients, 45 mg/m2) associated with fixed dosage of estramustine (840 mg/day). RESULTS: In level I, there was only one episode of grade 3 neutropenia; grade 1 nausea and vomiting were registered in 1 patient; in 1 patient mild edema of the lower limbs was noted. In level II, grade 2 stomatitis and grade 1 sensory symptoms occurred in 1 patient, and grade 1 edema in 1 case. In level Ill, grade 2 edema was noted in 2 patients, damage to nails in 1 patient, asthenia in 1 patient, grade 1 neuropathy in 2 patients, and grade 1 nausea in 1 patient. In level IV, grade 2 edema was present in 1 patient, grade 3 edema in 1 patient, changes with fall of nails and grade 2 erythema of face in 2 patients, asthenia in 2 patients, grade 1 neuropathy in both patients. Nine patients had a more than a 50% decrease in PSA after 2 cycles of therapy. CONCLUSIONS: The results of the study suggest a good tolerability of weekly 35 Mg/m2 docetaxel in hormone-refractory prostate cancer in association with estramustine.     

A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer

Background

Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.

Patients and Methods

A phase I trial of docetaxel/estramustine/imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m² to 60 mg/m² to 70 mg/m². Thirteen patients were treated.

Results

On dose level 3 (docetaxel 70 mg/m² and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m² and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.

Conclusion

The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.     

Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC. PATIENTS AND METHODS: Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE). RESULTS: Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups. CONCLUSION: Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.     

Intermittent docetaxel therapy with estramustine for hormone-refractory prostate cancer in Japanese patients

Background  We evaluated the efficacy and toxicity of intermittent docetaxel (DCT) with estramustine (EM) for hormone-refractory prostate cancer (HRPC). Methods  Fifteen patients were enrolled. They received injected DCT (70 mg/m² body surface) on day 1 in association with oral EM 560 mg/day (days 1–5). Treatments were repeated every 3 weeks. Serum prostate-specific antigen (PSA) levels were categorized based on the first three courses. Patients exhibiting either a response or stable disease (SD) could have a holiday from treatment (intermittent schedule). The holiday continued until elevation of the PSA level from the nadir baseline level occurred three times. All patients were evaluated for toxicity and quality of life (QOL). Survival curves were established using Kaplan-Meier graphs. Results  The median number of courses of DCT/EM therapy was five (range, 3–12 courses). The response rate of the first cycle was 53%: 3 patients with complete response (CR), 5 patients with partial response (PR), 4 patients with SD, and 3 patients with disease progression. Eight patients were able to begin the second re-entry cycle. No patients showed a CR, 2 patients exhibited PR, 4 patients had SD, and the overall response rate was 25%. The survival rates were 93% at 1 year, and 26.1% at 2 years Grade 3–4 anemia was observed in 2 patients (13.3%), neutropenia in 11 (73.3%), and thrombocytopenia in 2 (13.3%). The QOL scale showed good QOL after 6 months, with improvement in the score for nausea and vomiting. Conclusion  Intermittent DCT/EM therapy was well tolerated, and has the potential to prolong survival, with a high QOL, in patients with HRPC.     

A phase II study of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory prostate carcinoma: Cancer and Leukemia Group B 99813

BACKGROUND: The authors determined the safety and efficacy of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor (G-CSF) support in patients with hormone-refractory prostate carcinoma. METHODS: In the current multicenter, cooperative group study, patients with advanced prostate carcinoma whose disease progressed despite androgen deprivation therapy were treated with a combination of oral estramustine(240 mg three times per day for 5 days), 70 mg/m2 of docetaxel, and carboplatin at a dose of (area under the curve) 5. G-CSF was used to minimize the neutropenia associated with this regimen. Each cycle was repeated every 21 days. RESULTS: Forty patients were treated with a median of 7 cycles of therapy. Of the 34 evaluable patients with elevated pretreatment prostate-specific antigen (PSA) levels, 23 (68%) had a > or = 50% decline in PSA and 20 (59%) had a > or = 75% decline. Twenty-one patients had measurable disease, with 1 complete response (5%) and 10 partial responses (47%), for an overall measurable response rate of 52% (95% confidence interval [95% CI], 30-74%). The most common Grade 3 or Grade 4 toxicities (according to the National Cancer Institute Common Toxicity Criteria) included neutropenia in 23% of patients, thrombocytopenia in 13%, and fatigue in 13%. Febrile neutropenia occurred in 1 patient (3%). The overall median time to disease progression was 8.1 months (95% CI, 6-10 months) and the overall survival period was 19 months (95% CI, 13-26 months). CONCLUSIONS: The combination of estramustine, docetaxel, and carboplatin with G-CSF support was found to have significant clinical activity with an acceptable toxicity profile in patients with progressive hormone-refractory prostate carcinoma.     

Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer

Background We aimed to determine the safety and efficacy of monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer (HRPC). Methods Patients with prostate cancer that was progressing despite androgen ablation therapy were treated with i.v. paclitaxel, 175 mg/m², over 3 h, followed by carboplatin (area under the curve, 5) on day 1, with oral estramustine phosphate, 280 mg twice daily, for a 28-day treatment cycle. Estramustine phosphate was precluded in those patients who had experienced adverse effects during prior chemotherapies. Patients were evaluated for response every cycle, and the treatment was continued until the cancer progressed. Results Twenty-one patients with progressive hormone-refractory disease were treated for a median of 4 cycles (range, 1 to 11 cycles). Estramustine phosphate was precluded in seven patients. Post-therapy decreases in serum prostate-specific antigen levels of 50% and 75%, respectively, were seen in 43% and 19% of the patients (95% confidence intervals, 22% to 64% and 2% to 36%). Of the nine patients with measurable disease, 1 (11%) had a complete response and 2 (22%) had a partial response. The overall median time to progression was 4 months, and the median survival time for all patients was 11 months. Major grade 3 or 4 adverse effects were anemia (29%), neutropenia (48%), and thrombocytopenia (24%). Mild peripheral neuropathy and myalgia/arthralgia were observed in 11 (52%) and 9 (43%) patients, respectively. Conclusion Monthly paclitaxel and carboplatin with oral estramustine phosphate has significant antitumor activity and is well tolerated in patients with progressive HRPC.     

A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel

BACKGROUND: Prostate cancer is the second leading cause of cancer mortality among men in the U.S. To the authors' knowledge, there is no proven, effective, second-line therapy for docetaxel-refractory disease. Recent data suggest that platinum salts may be effective when combined with taxanes in metastatic hormone-refractory prostate cancer (HRPC). The authors conducted a phase 2 trial of docetaxel plus carboplatin chemotherapy in this disease setting. METHODS: Eligible men had metastatic HRPC that had progressed during or within 45 days after the completion of docetaxel-based chemotherapy. Patients were treated with intravenous docetaxel at a dose of 60 mg/m(2) plus carboplatin at an area under the curve of 4 once every 21 days until they had either disease progression or unacceptable toxicity. RESULTS: Thirty-four patients were enrolled. Therapy was tolerated reasonably well; Grade 3 leukopenia (graded according to the Common Toxicity Criteria grading system) was the most common adverse event (experienced by 56% of patients), but there was only 1 episode of febrile neutropenia reported. Prostate-specific antigen (PSA) declines > or =50% were noted in 18% of patients, and measurable responses were observed in 14%. The median duration of PSA response was 5.7 months. The median progression-free survival was 3 months, and the median overall survival was 12.4 months. Patients were more likely to respond to the combination if they previously had responded to docetaxel. CONCLUSIONS: In men with HRPC who developed progressive disease during or shortly after treatment with docetaxel, the addition of carboplatin resulted in modest additional activity. Taxane-refractory HRPC is an area of unmet need, and the current trial has provided evidence that platinum chemotherapy may be an important therapeutic option.     

Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy

Few treatment options are available for patients with metastatic hormone-refractory prostate cancer (HRPC) that is not responsive to or continues to progress after taxane-based chemotherapy. Although single-agent carboplatin has modest activity in HRPC, carboplatin chemotherapy could induce a synergistic effect when combined with taxanes in patients with disease resistant to taxane-based chemotherapy. We report a case series of 4 consecutive patients treated with docetaxel (60-70 mg/m2) plus carboplatin (area under the curve of 4/5) following progression after taxane-based chemotherapy. Prostate-specific antigen levels decreased by > 50% in all 4 patients and were associated with improvement in symptoms in 3 of 4 patients. Treatment was well tolerated, with fatigue as the most common reported side effect. Patients received 4-11 cycles of treatment and, after initiation of docetaxel/carboplatin chemotherapy, survival ranged from 4.5 months to 12 months. In this small series, there is a suggestion of a greater than expected response with carboplatin and docetaxel for patients who exhibit disease progression despite taxane-based chemotherapy or do not respond to therapy. A clinical trial to evaluate this effect has been initiated.     

A weekly schedule of docetaxel for metastatic hormone-refractory prostate cancer

RATIONALE: Docetaxel has proven its efficacy in the management of hormone-refractory prostate cancer (HRPC). Schedules of docetaxel administration differ. This prospective phase II study was designed to reevaluate the activity and toxicity of docetaxel administered weekly at an optimal dose to a large cohort of HRPC patients. PATIENTS AND METHODS: Sixty-four patients were treated with docetaxel 40 mg/m(2) i.v., administered weekly for 6 consecutive weeks followed by a 2-week recovery period. Three treatment cycles were planned in the absence of progression or toxicity. The principal end point was the biochemical response based on the prostate-specific antigen (PSA) level (a decline of more than 50% for at least 4 weeks). Secondary end points were objective response to measurable disease, survival and toxicity. RESULTS: Toxicity was assessed in 64 patients. Toxicity was acceptable, with no toxicity-related deaths. Twenty-one percent of the patients developed grade 3-4 hematological toxicity. Sixty-four patients were evaluable for the PSA response. Forty-one patients (64%) achieved a decrease in PSA of >50%, 13 of whom had a PSA <4 ng/ml. Two out of 12 patients with measurable disease exhibited an objective response. With respect to PSA, the median progression-free survival was 29 weeks (95% confidence interval: 18-46 weeks). The global 1-year survival rate was 58%. CONCLUSION: Weekly docetaxel at a dosage of 40 mg/m(2) is a well-tolerated treatment, which has very promising activity on the reduction of PSA in metastatic HRPC. A large phase III study is underway.     

Results from a pilot Phase I trial of gefitinib combined with docetaxel and estramustine in patients with hormone-refractory prostate cancer

BACKGROUND: Gefitinib, which is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated activity against hormone-refractory prostate cancer (HRPC) in preclinical studies. In this pilot Phase I trial, the authors evaluated the tolerability, efficacy, and pharmacokinetics of gefitinib combined with estramustine and docetaxel in patients with HRPC. METHODS: Patients received gefitinib (at a dose of 250 mg/day or 500 mg/day) on each day of a 21-day treatment cycle. Docetaxel (at a dose of 60 mg/m(2)) was administered on Day 1, and estramustine (at a dose of 280 mg) was administered 3 times daily on Days 1 through 5. RESULTS: Fifteen patients were recruited at each gefitinib dose level. The most common adverse events observed were consistent with the known profiles of gefitinib, docetaxel, and estramustine. No dose-limiting toxicity was observed. Adverse events considered to be gefitinib related included diarrhea (n = 23 patients), rash (n = 8 patients), nausea (n = 7 patients), dry skin (n = 6 patients), and emesis (n = 6 patients). Overall, 9 of 22 evaluable patients (40.9%) experienced a pain response. and 9 of 30 patients (30%) had a prostate-specific antigen response. A partial objective tumor response was demonstrated in 1 of 13 evaluable patients (7.7%) in each dose group; the median time to progression for both doses combined was 185 days (range, 28-233 days). Data comparisons within individual patients suggested that docetaxel and estramustine had no effect on gefitinib steady-state levels. Gefitinib had no effect on docetaxel exposure at the 250-mg dose but decreased exposure at the 500-mg dose. However, gefitinib may increase exposure to estramustine, particularly at the 500 mg/day dose. CONCLUSIONS: The results of the current study demonstrated that gefitinib combined with estramustine and docetaxel had acceptable and predictable tolerability. However, it is unclear whether gefitinib provides an additional clinical benefit over docetaxel and estramustine alone.     

A phase II trial of docetaxel and vinorelbine in patients with hormone-refractory prostate cancer

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m² on day 1 and vinorelbine 15 mg/m² on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2–6 and 9–13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by >50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy.This trial was supported in part by research grants from Aventis, Amgen, and P30 CA72720-01-03.     

Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer.

PURPOSE: Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). PATIENTS AND METHODS: One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily). RESULTS: One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic. CONCLUSION: The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.     

A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer.

PURPOSE: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy. EXPERIMENTAL DESIGN: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. RESULTS: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m(2) i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (C(ss)) was a significant determinant of antitumor activity; mean C(ss) values were higher in responders compared with nonresponders (6.24 +/- 1.68 versus 4.27 +/- 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen C(ss) or response. CONCLUSIONS: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen C(ss).     

A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer.

BACKGROUND: The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer. PATIENTS AND METHODS: Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week. RESULTS: From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50-83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0-802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75-10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%). CONCLUSIONS: Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.     

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m(-2) of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1-3, 8-10, 15-17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1-9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44-72) and median duration of PSA response was 8.0 months (95% CI: 6.9-9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.     

A phase II trial of dexamethasone, vitamin D, and carboplatin in patients with hormone-refractory prostate cancer

BACKGROUND: A Phase II prospective trial was performed to study the efficacy of combination therapy with dexamethasone, calcitriol (1,25-dihydroxyvitamin D3), and carboplatin in patients with hormone-refractory prostate cancer (HRPC). Preclinical data from prostate cancer cell lines suggested a synergistic effect of these therapies. METHODS: All patients had pathologically confirmed prostate cancer with at least 2 consecutive increases in prostate-specific antigen (PSA). Treatment started with 1 mg of oral dexamethasone given daily with 0.5 mcg of daily calcitriol added at the start of Week 5. Carboplatin (area under the concentration time curve = 2) was started at the beginning of Week 7. Initially, carboplatin was given weekly; however, the protocol was changed later to give carboplatin for the first 4 weeks of a 6-week cycle. Of 40 patients who consented to participate, 6 patients were ineligible or declined to start therapy, leaving 34 treated patients. The median follow-up was 80.7 weeks (range, 11.5-260 weeks). RESULTS: A formal PSA response was seen in 13 of 34 treated patients (38.2%; 95% confidence interval [95% CI], 22.2-56.4%). The median overall survival was 97.7 weeks (95% CI, 61-114 weeks). Significant adverse events that were observed during the trial period included 2 deaths (myocardial infarction and cardiogenic shock), 4 patients with Grade 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria, version 2.0), 2 patients with thrombosis, 2 patients with inflammatory bowel symptoms, and 2 patients with new-onset diabetes mellitus. CONCLUSIONS: The novel combination of dexamethasone, calcitriol, and carboplatin for patients with HRPC produced a PSA response in 13 of 34 patients and had an acceptable side-effect profile.     

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.

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/m(2)), 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/m(2) 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.     

A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of carboplatin, given weekly to patients with advanced esophageal or gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males; median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and 10 had stable disease, accounting for an overall response rate of 54%. CONCLUSIONS: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x min/ml.