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.     

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.     

Phase II trial of docetaxel/capecitabine in hormone-refractory prostate cancer

Background

Docetaxel is the most active single agent in the treatment of hormone-refractory prostate cancer (HRPC). Because of the preclinical and clinical evidence of synergy of capecitabine and docetaxel, it was hypothesized that this combination would be active and tolerable in HRPC.

Patient and Methods

Patients received docetaxel 60 mg/m² intravenously over 60 minutes on day 1 of each 21-day cycle and capecitabine 1000 mg/m² administered orally twice daily on days 1-14 of each cycle for a maximum of 8 cycles or until disease progression or intolerable toxicity. Seventy-seven patients were enrolled at 43 US Oncology sites. The median age was 69.3 years (range, 48-86 years); 86% were white, and the Eastern Cooperative Oncology Group performance status scores of 0 and 1 were 49% and 51%, respectively. Sixty-nine (90%) patients were evaluable for prostate-specific antigen response.

Results

Overall, 41% of patients had a decreased prostate-specific antigen level ≥ 50%. There were 4 complete responses (6%), 24 partial responses (35%), 29 incidences of stable disease (43%), and 11 incidences of progressive disease (16%). Nine patients had stable disease ≥ 6 months, and the clinical benefit rate was 54%. The median time to response was 1.5 months (range, 1-6 months), and the median duration of response was 5.2 months (range, 1-16.9 months). The estimated survival at 12 and 24 months was 65% and 22%, respectively, with a median survival of 17 months (range, < 1-27 months). There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (50%), leukopenia (22%), hand-foot syndrome (17%), fatigue (11%), and nausea (11%).

Conclusion

Docetaxel/capecitabine is an active and tolerable combination in HRPC. Toxicity was acceptable and anticipated. Response rate and survival are comparable with other docetaxel combinations.     

Three-weekly docetaxel with prednisone is feasible for Japanese patients with hormone-refractory prostate cancer: a retrospective comparative study with weekly docetaxel alone

BACKGROUND: We previously reported that weekly treatment with docetaxel alone is useful for and well tolerated by patients with hormone-refractory prostate cancer (HRPC). Here, we compare it with the regimen of docetaxel once every 3 weeks (q3w) plus daily prednisone (PSL) based on a TAX 327 trial in order to clarify the efficacy and toxicity of docetaxel regimens in Japan. METHODS: Thirty-two patients with HRPC were treated with docetaxel weekly (regimen 1) or docetaxel q3w plus PSL daily (regimen 2) at Tsukuba University Hospital and the changes in serum prostate-specific antigen (PSA), tumor size and survival were evaluated. The dose of docetaxel in regimen 1 was based on our previous report and that of regimen 2 was modified from a TAX 327 trial. RESULTS: A >50% decrease in PSA was observed in 53% of the patients with a median time to progression of 3.5 months and 69% with 8.5 months with regimens 1 and 2, respectively. Patients who received regimen 2 had a significantly better survival rate than those who received regimen 1. Myelosuppression and neuropathy were statistically more frequent in regimen 2 than in regimen 1. CONCLUSION: A regimen of docetaxel q3w with PSL daily was associated with a high rate of PSA reduction and prolongation of patient survival. Although docetaxel has not been approved in Japan yet, this treatment is considered feasible for Japanese patients with HRPC.     

Chemotherapy for advanced prostate cancer: docetaxel and beyond

To place appropriately into context the current status of chemotherapy as a management option for patients with hormone-refractory metastatic prostate cancer, it is important to reflect on the widely held historical belief that advanced prostate cancer is a chemotherapeutic-insensitive neoplasm. This article focuses on three disease subsets: (1)metastatic, hormone-refractory, chemotherapy-naive prostate cancer;(2) metastatic, hormone-refractory, progressive prostate cancer after frontline chemotherapy; and (3) locally advanced prostate cancer.Yagoda and Petrylak evaluated the results of 26 phase II trials of antineoplastics in advanced prostate cancer published between 1987 and 1991 and found the average objective response rate was less than 10% with only a few studies having response rates in the 10% to 20%range.     

Reversion of primary hyperfibrinogenolysis in patients with hormone-refractory prostate cancer using docetaxel

Tumor-associated proteases play a major role in determining the biologic behavior and aggressiveness of prostate cancer. Several authors have described the association between the increased levels of urokinase plasminogen activator in the plasma and in the malignant prostatic tissue with the metastatic potential of prostate cancer. However, the direct effect of this activity in producing fibronogenolysis in patients with prostate cancer has not been addressed. To evaluate the role of chemotherapy in reversing fibrinogenolysis in patients with prostate cancer, eight patients with hormone-refractory prostate cancer, bleeding, and laboratory evidence of primary hyperfibrinogenolysis were treated with docetaxel. The drug was given 48 hr after initiation of all supportive measures. Laboratory data, including plasminogen, alpha 2-antiplasmin, and fibrinogen, were recorded before and after treatment. Prostate-specific antigen (PSA) was measured at the time of referral and before subsequent cycles (3 weeks). Five patients had resolution of the fibrinolytic process after one cycle of treatment with docetaxel. This was demonstrated by improvement in both the laboratory parameters and the bleeding episodes. Further follow-up showed stabilization of the hematologic parameters and reduction in PSA values in these patients. Two patients died from uncontrolled bleeding despite all supportive measures. One patient did not demonstrate response to this treatment in terms of normalization of the fibrinolytic indicators or reduction in PSA. Primary fibrinogenolysis associated with metastatic prostate cancer is a serious complication. Docetaxel appears to be effective in reversing this process in some hormone-refractory patients. Although this response appears to be due to antitumor activity, a direct effect on the fibrinolytic pathway induced by the tumor cannot be excluded. Further work in this area is warranted.     

Treatment of androgen-independent, hormone-refractory prostate cancer with docetaxel in Japanese patients

Background Although patients with prostate cancer with metastatic lesions initially respond to androgen ablation therapy, most patients ultimately develop a hormone-refractory state. Effective treatment for men with hormone-refractory prostate cancer (HRPC) has not been established. We performed a clinical study of docetaxel in HRPC patients, and evaluated its efficacy.Methods Nine patients with HRPC were administered 55 mg/m² docetaxel, every 3 weeks, simultaneously with hormonal therapy, with a luteinizing hormone-releasing hormone analog, and daily oral dexamethasone. Change in serum prostate-specific antigen (PSA) was determined as the primary endpoint.Results The mean age of the patients was 64 years (range, 49 to 76 years). Median follow-up time was 8.5 months (range, 5.3 to 16.7 months). In eight patients whose pretreatment serum PSA was elevated, six patients (75.0%) had a PSA decline of more than 50%, and four (50.0%) had a PSA decline of more than 75%. Median time to progression for all patients was 7.9 months (range, 0.0 to 11.6 months; 95% confidence interval [CI], 0.0 to 26.3). The median overall survival was 8.5 months (range, 5.3 to 16.7 months; 95% CI, 8.1 to 13.8). Four of six patients (66.7%) with pain before treatment obtained pain relief and were able to discontinue analgesic agents. This regimen was well tolerated. Grade 3 or 4 neutropenia or leukocytopenia without fever was seen in three patients (33.3%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed.Conclusion Docetaxel was an active agent in Japanese HRPC patients, and was well tolerated in this population. To establish its efficacy and safety in Japanese HRPC patients, a large-scale study in Japan is warranted.     

Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma

BACKGROUND: The current Phase II study investigated the clinical benefit, impact on quality of life (QOL), and tolerability of weekly docetaxel in symptomatic patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: Patients received weekly docetaxel 35 mg/m(2) intravenously for 6 consecutive weeks followed by a 2-week rest repeatedly for a maximum of 24 weeks of treatment. Clinical benefit evaluations, based on Karnofsky performance status (KPS) and pain, were assessed weekly during therapy. A clinical benefit response was defined as a sustained (> or = 4-week) improvement in at least one of these parameters without worsening in the other. Patient-assessed QOL (using the European Organization for Research and Treatment of Cancer QLQ-C30), changes in prostate-specific antigen (PSA) levels, tumoral response, and toxicity also were evaluated. RESULTS: Thirty men (median age, 67 years), 15 of whom had received previous chemotherapy, were treated. Overall, 46% of patients achieved a positive pain response and 48% achieved a 50%-or-greater reduction in PSA. KPS was high at baseline (80%), and no significant changes in this parameter were observed. Compared with baseline, all scores improved after the first cycle of therapy, particularly emotional (P = 0.015), pain (P = 0.001), constipation (P = 0.001), and global QOL (P = 0.011) scores. After the second cycle, dyspnea scores decreased (P = 0.010). At the last QOL assessment, there also was deterioration in terms of fatigue (P = 0.013), dyspnea (P = 0.010), and physical functioning (P = 0.017). Toxicity was mild and included neutropenia (Grade 3-4, n = 2). CONCLUSIONS: Of these elderly symptomatic patients with HRPC, half had received previous chemotherapy. Weekly docetaxel was found to be associated with improvements in clinical benefit response and in QOL and was well tolerated.     

Fatal interstitial pneumonitis associated with docetaxel administration in a patient with hormone-refractory prostate cancer

Taxanes are widely used chemotherapeutic agents with the potential to induce pulmonary injury through a variety of mechanisms. Patients receiving these agents are at risk of acute or subacute pulmonary damage. The case is presented of a 72-year-old man with hormone-refractory prostate cancer and weekly administration of 30 mg/m2 docetaxel who developed subacute interstitial pneumonitis-related pulmonary fibrosis after seven doses and died despite mechanical ventilation and high-dose corticosteroid treatment. Even though only a few cases of this adverse event have been reported in the literature, severe docetaxel-induced pulmonary toxicity needs to be considered in the differential diagnosis when such patients present with respiratory symptoms.     

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

Purpose

This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial.

Methods

Patients with prostate cancer were treated with intravenous docetaxel (60–75 mg/m²) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored.

Results

Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03).

Conclusion

Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.     

（125）I放射粒子永久性植入治疗激素难治性前列腺癌

目的探讨125I放射粒子永久性植入治疗激素难治性前列腺癌的临床疗效及其价值。方法直肠B超引导下,经会阴穿刺前列腺125I放射粒子植入治疗激素难治性前列腺癌22例,其中3例合并骨转移。结果 22例手术顺利,平均植入125I放射粒子42粒,平均手术时间60分钟,平均住院时间5天,术后随访8-28月,术后3月前列腺缩小,术后短期IPSS评分上升,但3月后开始好转。完全反应16例,部分反应3例,病情稳定3例,PSA无进展生存率100.0%,未发生严重并发症。结论 125I放射粒子植入治疗激素难治性前列腺癌安全、微创、并发症发生率低,疗效肯定、患者生活质量高。     

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.     

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.