Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Thirty-seven patients were treated with oral calcitriol (0.5 micro g/kg) on day 1 followed by docetaxel (36 mg/m(2)) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later. RESULTS: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy. CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.     

Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma

BACKGROUND: Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion. METHODS: From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy. RESULTS: Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen. CONCLUSIONS: Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP.     

Phase II study of paclitaxel and estramustine in patients with recurrent and refractory non-Hodgkin lymphoma

BACKGROUND: The current study was conducted to evaluate the efficacy of paclitaxel, administered weekly or once every 3 weeks, in combination with oral estramustine phosphate (EMP) in patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS: Between February 1996 and February 2001, 23 patients with recurrent NHL were enrolled onto this Phase II trial. The median age for all patients was 65 years (range, 27-80 years). The initial 12 patients (who received a mean number of 2.4 prior treatments, including 1 patient who received a prior peripheral blood stem cell transplant) received paclitaxel at a dose of 175 mg/m2 given as a 3-hour intravenous infusion every 21 days. The next 11 patients (who received a mean number of 2.8 prior treatments, including 1 patient who received prior peripheral blood stem cell transplant) were registered (1 patient refused treatment) to receive paclitaxel at a dose of 80 mg/m2 as a 1-hour intravenous infusion weekly for 6 weeks of an 8-week cycle. All patients received EMP at a dose of 600 mg/m2 orally per day beginning the day prior to each dose of paclitaxel for a total of 3 days. RESULTS: When paclitaxel was administered every 21 days, 4 partial responses were observed in 12 evaluable patients (33.3%). The median survival was 147 days. The median duration of response was 102 days (range, 42-127 days) and the median time to disease progression was 66 days. Grade 3 and Grade 4 neutropenia (according to the revised version of the Common Toxicity Criteria of the National Cancer Institute) were observed in 5 patients (42%) in this group. In an attempt to reduce the incidence of myelosuppression, paclitaxel dosing was changed to weekly dosing. In the cohort of patients receiving weekly paclitaxel, an objective response was reported to occur in 3 (1 complete response and 2 partial responses) of 11 evaluable patients (27%). The median survival was 132 days (range, 33-462 days). The median duration of response was 64 days and the median time to disease progression was 57 days. There was no significant difference noted between the cohort receiving paclitaxel three times weekly and those receiving paclitaxel weekly with regard to overall survival and time to disease progression (P = 0.7 and P = 0.8, respectively by the log-rank test). Grade 3 or 4 neutropenia was observed in only 2 of 11 patients (18%) in the weekly paclitaxel group. There were no significant differences noted in terms of thrombocytopenia, anemia, nausea, anorexia, or fatigue between the treatment groups. CONCLUSIONS: Paclitaxel given once weekly or three times weekly, in combination with oral EMP, was found to have comparable efficacy in patients with recurrent NHL, with an overall response rate of 30%. The response rate was found to be higher than that reported in prior studies of paclitaxel as a single agent in the treatment of NHL, suggesting that EMP may enhance paclitaxel efficacy in patients with NHL. Hematologic toxicity was diminished when paclitaxel was administered on a weekly schedule. The minimal myelotoxicity of weekly paclitaxel makes this a potentially attractive agent for combination regimens for patients with recurrent/refractory NHL.     

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 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.     

A Phase I Study of Paclitaxel/Doxorubicin/Thalidomide in Patients with Androgen-Independent Prostate Cancer

PurposeThe antiangiogenic and immunomodulatory effects of thalidomide induce responses in patients with androgen-independent prostate cancer (AIPC). Paclitaxel and doxorubicin also have significant antitumor activity. A phase I dose-escalation study was conducted to evaluate the use of these agents in combination to enhance the chemotherapeutic effects of treatment for refractory cancer.Patients and MethodsTwelve men with AIPC (mean age, 64.5 years) and a median prostate-specific antigen (PSA) level of 30 ng/mL were enrolled. Patients received starting doses of weekly paclitaxel (100 mg/m²) as a 1-hour intravenous infusion, weekly doxorubicin (20 mg/m²) as a 24-hour intravenous infusion, and daily oral thalidomide at escalating dose levels of 200 mg (dose level 0), 300 mg (dose level +1), and 400 mg (dose level +2). Paclitaxel and doxorubicin were administered for 3 consecutive weeks of a 5-week cycle. Exposure to thalidomide was daily. Patients were evaluated weekly for dose-limiting toxicities to determine the maximum tolerated dose. In addition, PSA levels were measured before each cycle of treatment. Response to treatment was defined as a ≥ 50% decrease in baseline PSA levels associated with stable radiographic disease, improvement of bone scan results with plain radiograph correlation, or improvement in soft tissue disease.ResultsFour patients were treated on dose level 0, 5 were treated on dose level +1, and 3 were treated on dose level +2. The thalidomide 400-mg dose level resulted in 3 of 3 patients experiencing grade 3 leukopenia. The maximum tolerated dose was 300 mg of thalidomide in combination with paclitaxel/doxorubicin. Nine of the 12 patients were evaluable for PSA response, with 88% exhibiting partial responses or stable disease. One patient (11%) had a significant response, with PSA levels decreasing > 90% from baseline values. Overall, PSA-level decreases ranged from 0.5 ng/mL to 39.5 ng/mL among the 9 evaluable patients. A maximum of 7 cycles of therapy were administered. Twelve patients were evaluable for toxicity: neutropenia (grade 3, 27%; grade 4, 54%), leukopenia (grade 3, 63%), constipation (grade 3, 27%), fatigue (grade 3, 27%), nausea (grade 3, 9%), and deep vein thrombosis (grade 3, 9%) were reported.ConclusionThe combined dosing of paclitaxel (100 mg/m² weekly), doxorubicin (20 mg/m² weekly), and thalidomide (300 mg daily) is tolerated by men with AIPC and merits continued phase II study.     

Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer.

PURPOSE: We evaluated the efficacy and toxicity of weekly paclitaxel in patients with previously treated advanced urothelial cancer. PATIENTS AND METHODS: Patients with urothelial cancer who had received one prior systemic chemotherapy regimen for advanced disease and had evidence of disease progression were eligible for enrollment. Patients received paclitaxel 80 mg/m(2) by 1-hour intravenous infusion weekly. A cycle of therapy consisted of four weekly treatments. RESULTS: The study enrolled 31 patients. Mean age was 66 years, and 45% of patients had three or more involved metastatic sites. Only 26% of patients had responded to prior chemotherapy. The median number of cycles delivered was three (range, one to eight) at a mean weekly paclitaxel dose of 79 mg/m(2). Three patients achieved a partial response (10%; 95% confidence interval, 0% to 20%). Median time to progression was 2.2 months, and median overall survival time was 7.2 months. Therapy was well tolerated with minimal hematologic toxicity. Grade 3 nonhematologic toxicities were also uncommon. CONCLUSION: Although the overall response rate to weekly paclitaxel in patients with previously treated advanced urothelial cancer was modest, the chemotherapy-refractory nature of the study population should be considered.     

Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non-small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment. PATIENTS AND METHODS: Patients with tumor evidence of EGFR by immunohistochemistry, performance status of 0 to 2, and measurable disease received paclitaxel 225 mg/m2 with carboplatin area under the curve = 6 on day 1 every 3 weeks. Cetuximab was administered at 400 mg/m2, 1 week before paclitaxel and carboplatin, then weekly at 250 mg/m2. The regimen continued until disease progression or intolerable toxicity. RESULTS: Thirty-one of 32 enrolled patients were treated. The most common cetuximab toxicity was rash in 84% of patients (grade 3 in 13%). Pharmacokinetic sampling did not reveal an interaction between carboplatin, paclitaxel, and cetuximab. An objective response was observed in eight patients (26%). With a median follow-up of 19 months, the median time to progression was 5 months, median survival was 11 months, and the 1- and 2-year survival rates were 40% and 16%, respectively. CONCLUSION: The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated in this population of stage IV patients. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone. A randomized phase II trial has completed accrual.     

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma

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 > or = 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.     

Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer.

PURPOSE: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. METHODS: Seventy-five patients with chemotherapy-na?ve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. RESULTS: After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. CONCLUSION: In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.     

Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study

ABSTRACT: BACKGROUND: The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients. METHODS: Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m2, administered in weeks 1-6 and 8-13). RESULTS: Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1-5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response?+?partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1-11.3) and 22 months (95% CI: 17-46). After alopecia, Common Toxicity Criteria grade ≥2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related. CONCLUSIONS: Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome.     

Prognostic model of event-free survival for patients with androgen-independent prostate carcinoma

BACKGROUND: The current study was conducted to develop a prognostic model of event-free survival (EFS) in men with androgen-independent prostate carcinoma (AIPC). METHODS: Data from 160 patients diagnosed with AIPC between 1989-2002 were reviewed. No patient had received cytotoxic chemotherapy. A univariate Cox proportional hazards model identified significant predictors of EFS. Recursive partitioning analysis divided these significant variables into prognostic risk groups. The final prognostic model was tested with a Cox proportional hazards model. RESULTS: The final prognostic risk model included the presence of metastatic disease at the time of androgen-independent disease progression (P = 0.040), time to prostate-specific antigen (PSA) recurrence (P = 0.043), and PSA doubling time (P < 0.01). Three highly independent risk groups were identified. The observed median EFSs were 6.1 months (95% confidence interval [95= CI], 3.4-8.8 months), 33.6 months (95= CI, 25.3-41.9 months), and 96.1 months (95= CI, 57.9-134.3 months) for the low-risk, intermediate-risk, and high-risk groups, respectively. Each risk group was found to be independently predictive of EFS (P < 0.01). Patients who died of prostate carcinoma experienced significantly more clinical events than those who died of other causes (P < 0.01). CONCLUSIONS: The prognostic model in the current study stratified patients into three highly significant and independent risk groups for EFS. A detailed PSA history and knowledge of metastatic disease are sufficient to risk-stratify patients with AIPC. One very unique aspect of this model was that it was developed from a patient cohort that never received chemotherapy.     

A phase I study of paclitaxel/doxorubicin/ thalidomide in patients with androgen- independent prostate cancer

Purpose

The antiangiogenic and immunomodulatory effects of thalidomide induce responses in patients with androgen-independent prostate cancer (AIPC). Paclitaxel and doxorubicin also have significant antitumor activity. A phase I dose-escalation study was conducted to evaluate the use of these agents in combination to enhance the chemotherapeutic effects of treatment for refractory cancer.

Patients and Methods

Twelve men with AIPC (mean age, 64.5 years) and a median prostate-specific antigen (PSA) level of 30 ng/mL were enrolled. Patients received starting doses of weekly paclitaxel (100 mg/m²) as a 1-hour intravenous infusion, weekly doxorubicin (20 mg/m²) as a 24-hour intravenous infusion, and daily oral thalidomide at escalating dose levels of 200 mg (dose level 0), 300 mg (dose level +1), and 400 mg (dose level +2). Paclitaxel and doxorubicin were administered for 3 consecutive weeks of a 5-week cycle. Exposure to thalidomide was daily. Patients were evaluated weekly for dose-limiting toxicities to determine the maximum tolerated dose. In addition, PSA levels were measured before each cycle of treatment. Response to treatment was defined as a ≥ 50% decrease in baseline PSA levels associated with stable radiographic disease, improvement of bone scan results with plain radiograph correlation, or improvement in soft tissue disease.

Results

Four patients were treated on dose level 0, 5 were treated on dose level +1, and 3 were treated on dose level +2. The thalidomide 400-mg dose level resulted in 3 of 3 patients experiencing grade 3 leukopenia. The maximum tolerated dose was 300 mg of thalidomide in combination with paclitaxel/doxorubicin. Nine of the 12 patients were evaluable for PSA response, with 88% exhibiting partial responses or stable disease. One patient (11%) had a significant response, with PSA levels decreasing > 90% from baseline values. Overall, PSA-level decreases ranged from 0.5 ng/mL to 39.5 ng/mL among the 9 evaluable patients. A maximum of 7 cycles of therapy were administered. Twelve patients were evaluable for toxicity: neutropenia (grade 3, 27%; grade 4, 54%), leukopenia (grade 3, 63%), constipation (grade 3, 27%), fatigue (grade 3, 27%), nausea (grade 3, 9%), and deep vein thrombosis (grade 3, 9%) were reported.

Conclusion

The combined dosing of paclitaxel (100 mg/m² weekly), doxorubicin (20 mg/m² weekly), and thalidomide (300 mg daily) is tolerated by men with AIPC and merits continued phase II study.     

Weekly paclitaxel in metastatic breast cancer patients: a phase II study

AIMS ANID BACKGROUND: Paclitaxel, a microtubule inhibitor, is one of the most active drugs in metastatic breast cancer. A weekly schedule, at a median dose-intensity of 91 mg/m2, is effective and has less side effects than a 3-week schedule. In this phase II study, we evaluated the toxicity and the activity of weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. STUDY DESIGN: Between February 1999 and February 2001, 26 patients with metastatic breast cancer were treated with weekly paclitaxel (60-90 mg/m2/1 hour iv infusion/weekly). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, paclitaxel was stopped after 6 months of therapy. RESULTS: At a median follow-up of 18.7 months (range, 6.8-30.8), all patients are assessable for response and toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and 10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1-48.5). The median duration of response was 7.6 months (range, 1.8-12.4); median time to progression was 4.86 months (range, 1.4-12.4); median overall survival was 9.9 months (range, 1.7-29.2+). Treatment was well tolerated. Hematological toxicity was mild and only one patient developed grade 3 anemia. Two patients experienced grade 3 cardiovascular toxicity; both had received anthracycline-based regimens. CONCLUSIONS: In our experience, weekly administration of paclitaxel shows a substantial degree of activity even in pretreated metastatic breast cancer patients. The toxicity profile is favorable.     

A phase II study of weekly vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer

BACKGROUND: Trastuzumab combined with cytotoxic agents presents encouraging results in metastatic breast cancer (MBC), but cardiac toxicity limits some combinations. The synergism shown with trastuzumab and the favorable tolerability profile of vinorelbine provided the rationale for investigating this combination. PATIENTS AND METHODS: Patients with HER2-positive MBC who had received <2 lines of chemotherapy for metastatic disease were included. Vinorelbine (25 mg/m2 on day 2, then weekly on day 1) and trastuzumab (4 mg/kg on day 1, then 2 mg/kg weekly) were administered for a maximum of 6 cycles (1 cycle=3 weeks). RESULTS: A total of 52 patients were enrolled. The median age was 50 years (range, 26-79 years). Ninety percent of the patients had received adjuvant chemotherapy, 42% received a first line of chemotherapy for MBC, and 69% had disease at visceral sites. The overall response rate was 58% (95% CI, 43%-71%). The median time to progression and overall survival were 7 months (95% CI, 5-9 months) and 26 months (95% CI, 20-32 months), respectively. Grade 4 neutropenia was present in 3 courses; neutropenic fever was not reported. The main grade 3 nonhematologic toxicities were asthenia, neuropathy, diarrhea, alopecia, and nausea/vomiting. No patients experienced serious cardiac toxicity. CONCLUSION: These results confirm that weekly vinorelbine/trastuzumab is an active and safe regimen in patients with HER2-positive MBC with an unfavorable prognosis.     

Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma

BACKGROUND: The authors evaluated the combination of oral cyclophosphamide, oral prednisone, and diethylstilbestrol (DES) in patients with androgen-independent prostate carcinoma (AIPC). METHODS: Thirty-seven patients with prostate carcinoma refractory to androgen ablation who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled in the current study. They were treated with oral cyclophosphamide 100 mg per day on Days 1-20, prednisone 10 mg per day continuously, and DES 1 mg continuously, on a 30-day cycle. Warfarin 1 mg per day was given as prophylaxis for thrombosis. Patient levels of prostate-specific antigen (PSA) were monitored on a monthly basis, with imaging studies every 3 months. Patients continued to receive therapy until disease progression or the occurrence of significant toxicity. The effect of therapy on the patient's quality of life was assessed using the Functional Assessment of Cancer Therapy-Prostate. RESULTS: Thirty-six patients were evaluable for response. Of the 36 patients, 15 (42%) had a 50% or greater decline in PSA levels from pretreatment levels and 1 patient (6%) with measurable disease had a partial response to therapy. The median duration of response was 4.5 months (range, 4-18 months). The overall median survival period was 16.4 months. The treatment was well tolerated, with only three patients removed from the study for toxicities associated with treatment. One patient, who had been treated for more than 24 months, developed acute leukemia. Quality of life evaluation in 17 patients showed a significant improvement in responders, whereas nonresponders had no deterioration while receiving therapy. CONCLUSIONS: Cyclophosphamide, prednisone, and DES represent a well tolerated, low-cost combination therapy with significant activity in the treatment of patients with AIPC.     

Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer.

PURPOSE: The purpose is to determine a safe weekly dose of i.v. estramustine phosphate (EMP) to combine with weekly paclitaxel and monthly carboplatin in patients with advanced prostate cancer. EXPERIMENTAL DESIGN: Patients with advanced prostate cancer (castrate and noncastrate) were administered escalating doses of weekly 1-h infusion of i.v. EMP (500-1000-1500 mg/m(2)) in combination with weekly paclitaxel (100 mg/m(2) over 1 h) and i.v. carboplatin (area under the curve 6 mg/ml-min every 4 weeks). Four weeks of therapy were considered one cycle. In the first three cohorts, EMP was given i.v. 3 h before paclitaxel. Cohorts 4 and 5 reversed the administration order: EMP (doses 1000-1500 mg/m(2)) was given immediately after the end of paclitaxel infusion. Plasma levels of EMP and its metabolites, estramustine and estromustine, were monitored at time 0, at 120 min, and approximately at 20, 21, and 168 h from the start of EMP infusion. Paclitaxel concentrations were determined at basal (0), 30, 60, 90, and 120 min and 18 h after the start of paclitaxel infusion, and a concentration-time curve was estimated. Pharmacokinetic evaluation was performed in cycles 1 and 2 during the first week of therapy. RESULTS: Nineteen patients were entered on the initial three dose levels (cohorts 1-3). Dose-limiting transient hepatic toxicity was encountered in cohort 3 (EMP = 1500 mg/m(2)). An additional 13 patients were treated with paclitaxel (100 mg/m(2)) first, followed by i.v. EMP at 1000 mg/m(2) (cohort 4), and 1500 mg/m(2) (cohort 5). No dose-limiting toxicities were seen, and cohort 5 was determined safe for Phase II studies. Thromboembolic events were observed in 9% of patients (no prophylactic coumadin was used). Plasma concentrations of EMP and metabolites increased proportionally with dose. In all cohorts, there was a slight decrease in EMP and estramustine plasma concentrations between cycles 1 and 2. Although not significant, higher levels of estromustine at cycle 2 were observed in comparison to cycle 1. Decreased clearance of paclitaxel leading to higher than expected paclitaxel plasma concentrations was observed during the first cycle of therapy. Paclitaxel plasma concentrations were lower during cycle 2. In 17 patients with androgen-independent disease, 59% had >/=50% posttherapy decline in PSA and 22% showed measurable disease regression. CONCLUSIONS: The regimen of weekly i.v. EMP in combination with paclitaxel and carboplatin can be safely administered with hepatic toxicity being transient and reversible. Pharmacokinetic results suggest that EMP competitively inhibits the biotransformation of paclitaxel after the first administration. This effect is counterbalanced, after repeated administrations, by a possible induction of the metabolic system caused by EMP. Phase II testing is ongoing to evaluate the efficacy of this combination.     

Weekly regimen of epirubicin and paclitaxel as second-line chemotherapy in patients with metastatic transitional cell carcinoma of urothelial tract: results of a phase II study

Until recently, there was no standard second-line treatment for advanced urothelial carcinoma. Although included in first-line regimens, role of anthracyclines was never investigated as second-line therapy. Single-agent paclitaxel showed modest results in this setting. The purpose of this study was to assess the efficacy and toxicity of concomitant weekly administration of epirubicin plus paclitaxel in patients with metastatic urothelial carcinoma previously treated with platinum-based regimens. Between March 2004 and May 2008, thirty-five consecutive pretreated patients with metastatic transitional cell carcinoma of the urothelial tract were enrolled. Median age was 64 years (range 45-72 years), and median ECOG PS was 1 (range 0-1). Patients received epirubicin 25 mg/m(2) and paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days. All patients were evaluable for efficacy and toxicity; a median of four cycles was administered. One patient (3%) showed a complete response (CR), nine patients (26%) had partial response, stable disease was observed in eight patients (23%) for a disease control rate (DCR) of 52%. The median time to progression (TTP) was 7.6 months (95% CI 3.2-10.7 months) with a median survival time (MST) of 12.6 months (95% CI 4.6-18.8 months). Toxicity was acceptable and manageable: no cases of febrile neutropenia occurred and only two patients (6%) developed grade 3 neuropathy. This is the first study that evaluated the role of anthracyclines in combination with paclitaxel as second-line chemotherapy in metastatic transitional cell carcinoma of the urothelium. Our findings show the substantial activity of weekly regimen of paclitaxel and epirubicin: due to its manageable profile of toxicity, this schedule could represent an interesting therapeutic option in previously treated patients with advanced urothelial carcinoma.     

First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study

Despite extensive evaluation of first-line bevacizumab-containing therapy in randomized trials in locally recurrent/metastatic breast cancer (LR/mBC), data from Japanese populations are limited. We conducted a phase II study exclusively in Japanese patients to evaluate bevacizumab combined with weekly paclitaxel. Patients with HER2-negative measurable LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg, days 1 and 15, in combination with paclitaxel 90 mg/m(2), days 1, 8, and 15, repeated every 4 weeks, until disease progression, unacceptable toxicity, or patient/physician decision. Co-primary endpoints of this single-arm open-label phase II study were progression-free survival (PFS) and safety. A total of 120 patients (median age 55 years) received study therapy. At the time of data cut-off, the median duration of therapy was 11.1 months (range 0.5-24.7 months). Median PFS was 12.9 months (95% CI: 11.1-18.2) according to Independent Review Committee assessment and 14.9 months by investigator assessment. Median PFS was 9.6 months in the subgroup of 38 patients with triple-negative LR/mBC. The overall response rate was 74% (95% CI: 64.5-81.2%). Median overall survival (OS) was 35.8 months (95% CI: 26.4-not estimated) and the 1-year OS rate was 88.9% (95% CI: 83.2-94.6). The regimen was well tolerated and the safety profile was generally consistent with previous reports of bevacizumab-paclitaxel combination therapy. Grade 3 hypertension was reported in 17% of patients. Grade 4 hypertension, grade 3/4 proteinuria, and gastrointestinal perforation were absent. There were no new bevacizumab safety signals. In 50 patients (42%), treatment was continued for ≥ 1 year. Conclusion: The high activity of first-line bevacizumab in combination with weekly paclitaxel observed in our study confirms the results of the E2100 trial. Our results suggest that the activity and tolerability of first-line bevacizumab-containing regimens demonstrated in E2100 can be reproduced in Japanese populations.     

Long-term outcome of a phase II study of weekly docetaxel with a short course of estramustine and enoxaparine in hormone-resistant prostate cancer patients

Objective The objective was to define the toxicity and activity of weekly docetaxel administered with a short course of estramustine and enoxaparine in patients with hormone-resistant prostate cancer (HRPC). Patients and methods Twenty-four patients were treated with the next regimen: weekly docetaxel 36 mg/m² iv for three consecutive weeks every 28 days, and estramustine 280 mg three times a day for three consecutive days beginning the day before docetaxel (days 1–3, 8–10 and 15–17). In order to prevent thromboembolic events, 40 mg of subcutaneous enoxaparine was administered daily sc on the same days as estramustine. Primary endpoints were: toxicity, especially the presence of thromboembolic events, PSA response rate and response in measurable disease. Secondary endpoints were: time to PSA progression and overall survival. Results Nineteen of 24 patients (79.1%, 95% CI 71–87%) had a PSA response ≥50%. Four of the eleven patients with measurable disease had a partial response. The median time to PSA progression was 7 months (CI 95%: 6.5–9) and the median survival was 19 months (IC 95%: 11–24). Toxicity was manageable with no treatment-related mortality. Only two patients had grade 4 neutropenia. Two patients had thrombotic events, one deep venous thrombosis and one stroke. The main grade 3 non-haematologic toxicity was diarrhoea and asthenia, both in 25% of patients. Conclusions Weekly docetaxel with a short course of estramustine and enoxaparine is active and tolerable in HRPC patients. The observed incidence of thrombosis was lower than previously reported but the association of enoxaparine was not enough to completely prevent the thromboembolic events.