An evaluation of intermediate-dose ketoconazole in hormone refractory prostate cancer

OBJECTIVES: The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer. METHODS: The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial psa measurements every 3 months. the principal endpoint was psa response. RESULTS: Of the 38 patients, 21 (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%-71.4%) with a median duration of 6 months (range 3-48 months). A PSA reduction >50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease >80% (95% confidence interval 19.6%-51.4%) with a median duration of 9 months (range 3-48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0-27 months) and the median survival was 12 months (range 3-48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects. CONCLUSION: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy.     

Bi-weekly epirubicin, etoposide and low-dose dexamethasone for hormone-refractory prostate cancer

BACKGROUND: Recent studies have demonstrated the efficacy and favorable toxicity profile of chemotherapy regimens given at lower doses and frequent intervals. The aim of our study was to evaluate the efficacy and toxicity of a bi-weekly chemohormonal regimen consisting of epirubicin, etoposide, and low-dose dexamethasone (EED) in patients with hormone-refractory prostate cancer (HRPC). METHODS: We treated a total of 32 patients who had failed hormonal therapy and antiandrogen withdrawal. Chemotherapy was given every 2 weeks and consisted of epirubicin (30 mg/m2 intravenously, day 1) and etoposide (50 mg/m2 orally, days 1-7). Dexamethasone (1.5 mg orally, every other day) was given continuously until disease progression. Twenty patients (63%) had received prior treatment with estramustine phosphate. Each patient's pain response was evaluated according to analgesic use. Toxicity was graded using the Common Toxicity Criteria (version 2.0). RESULTS: Prostate-specific antigen (PSA) levels showed a decline of 50% or greater in 16 of 32 patients (50%, 95% confidence interval [CI], 32-68%) with a median time to biochemical progression of 5 months (range, 4-9 months). The median survival for all patients was 10.5 months (range, 3-35 months). Four of 10 patients (40%) with measurable soft tissue lesions achieved partial response according to standard criteria. Eleven of 23 symptomatic patients (48%, 95% CI, 27-69%) experienced an improvement in pain with a median duration of 6 months. The regimen was tolerated well by the patients, with only four patients (12%) having grade 3 leukopenia. CONCLUSION: Chemohormonal EED regimen proved to be active and well-tolerated in patients with HRPC.     

Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer

OBJECTIVES: Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer. METHODS: From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2). RESULTS: A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months. CONCLUSIONS: The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.     

Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer

The purpose of this study was to investigate the efficacy and safety of combination chemotherapy using estramustine and vinorelbine in chemotherapy-na?ve patients with hormone-resistant prostate cancer (HRPC). The patients (n = 54) received oral estramustine 840 mg/day on Days 1 to 14 and IV vinorelbine 25 mg/m(2) on Days 1 and 8 of every 3 wk cycle. The median number of cycles per patient was 9 (range, 1 to 27). Fifty-three patients were evaluable for toxicity and survival and 52 for prostate specific antigen (PSA) response. Median age was 68 (range, 46-80). PSA sustained decrease >50% was seen in 52% of patients (95% CI: 38-66%). A complete response was seen in 3 and a partial response in 12 of 25 patients with measurable disease, for an overall objective response of 60% (95% CI: 41-79%). Improvement in performance status was observed in 30 out of 43 evaluable for clinical benefit response. The median duration of response was 7 mo and median time to progression was 6 mo. The median survival time was 15 mo. The most common adverse event was mild gastrointestinal toxicity. In general, toxicity G3-4 was low: granulocytopenia Grade 3-4 (8%), thrombocytopenia Grade 3 (6%), and anemia Grade 3 (13%). Other Grade 3 toxicities included deep vein thrombosis (4%), hepatic (2%), cardiac ischemia (2%), fatigue (6%), and sensory neuropathy (2%). There were 2 treatment-related deaths (4%). We conclude that vinorelbine and estramustine as used in this trial is an efficacious and well-tolerated therapeutic regimen in the management of HRPC.     

Estramustine and vinblastine for patients with progressive androgen-independent adenocarcinoma of the prostate

A phase II trial was performed to assess antitumor activity and toxicity of estramustine and vinblastine in 31 consecutive patients with androgen-independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels of less than 50 ng/dl and were treated for 6 consecutive weeks with three daily 140-mg doses of oral estramustine and vinblastine at 6 mg/m(2) weekly by intravenous bolus. Prostate specific antigen (PSA) levels decreased by greater than 50% from baseline in 13 (46%; 95% confidence intervals, 27%-66%) of 28 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Nonhematologic toxicity was mild, predominantly gastrointestinal. Hematologic toxicity was apparent in 13 patients with grade III granulocytopenia and in 7 patients with grade IV granulocytopenia. No patient was admitted to the hospital for neutropenic fever. Estramustine and vinblastine is a well-tolerated combination. This combination and the clinical significance of this decline in PSA warrants further investigation.     

Activity of ketoconazole after taxane‐based chemotherapy in castration‐resistant prostate cancer

Study Type – Therapy (case series)Level of Evidence 4

OBJECTIVE

To assess the efficacy of the androgen‐synthesis inhibitor ketoconazole as a secondary hormonal therapy in patients with castration‐resistant prostate cancer (CRPC) previously treated with chemotherapy, as persistent androgens appear to play a role in the development and maintenance of CRPC.

PATIENTS AND METHODS

We retrospectively identified 34 patients with CRPC who were treated with ketoconazole as a secondary hormonal therapy after paclitaxel‐ or docetaxel‐based chemotherapy for CRPC. They were treated with ketoconazole 200–400 mg three times daily with or without hydrocortisone. Patients with previous use of ketoconazole were excluded. Half the patients had received estramustine as part of their chemotherapy regimen. The primary endpoint was the proportion of patients with a decline of ≥50% in their prostate‐specific antigen (PSA) level. PSA progression was defined by the PSA Working Group 1 Criteria.

RESULTS

Eight of the 32 evaluable patients (25%) had a PSA decline of ≥50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2–5.4). A history of previous response to taxane‐based chemotherapy was not associated with the response to ketoconazole. However, previous use of oestrogens for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03).

CONCLUSIONS

Ketoconazole has moderate activity as secondary hormonal therapy in patients with CRPC previously treated with taxane‐based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.     

Evaluation of docetaxel plus estramustine in the treatment of patients with hormone-refractory prostate cancer

Objectives:   To investigate the feasibility and efficacy of docetaxel-based chemotherapy in patients with hormone-refractory prostate cancer (HRPC).
Methods:   Forty-six consecutive HRPC patients treated between January 2003 and March 2008 were included in this analysis. Docetaxel was given at a dose of 35 mg/m² twice every 3 weeks and oral estramustine concurrently for three consecutive days during weeks 1 and 2 of each cycle. During each treatment week, the dose of estramustine was 1260 mg on the first day, 980 mg on the second day and 840 mg on the third day. Patients were premedicated with 4 mg twice a day of oral dexamethasone for three consecutive days. Treatment was continued until evidence of disease progression or unacceptable toxicity. Prostate-specific antigen (PSA) levels were evaluated at least once every 4 weeks.
Results:   Patients received a median of three cycles of chemotherapy. Of the evaluable 46 patients, 25 (54%) had a ≥50% PSA decline and 12 (26%) had a ≥75% PSA decline. Median time to PSA progression and overall survival time were 10.1 and 27.0 months, respectively. Median follow-up was 15.0 months. Major severe toxicities were grade 3 or 4 leukopenia in five (11%) patients. Mild toxicities included grade 1 or 2 nausea in eight (17%) patients. Two patients could not continue the treatment because of interstitial pneumonitis and a gastric hemorrhage, respectively.
Conclusions:   Docetaxel plus estramustine chemotherapy represents an active and well tolerated treatment for Japanese HRPC patients.     

Estramustine in combination with vinblastine and mitomycin-C for patients with progressive androgen independent adenocarcinoma of the prostate

A phase II trial was performed to assess the antitumor activity and toxicity of estramustine in combination with vinblastine and mitomycin-C in 46 consecutive patients with androgen independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels and were treated for six consecutive weeks with three daily 140 mg doses of oral estramustine, vinblastine at 5 mg/m(2) weekly by intravenous bolus and mitomycin-C at 15 mg/m(2) every six weeks by intravenous bolus. Prostate specific antigen levels decreased by greater than 50% from baseline in 16 (41%; 95% CI 25-58%) and normalized in 11 (28%; 95% CI 14-45%) of 39 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Non-hematologic toxicity was mild, predominately gastrointestinal. Hematologic toxicity was apparent in five patients with Grade III granulocytopenia and in 21 patients with Grade IV granulocytopenia of 43 evaluable patients for toxicity. Three patients were admitted to the hospital for neutropenic fever. Eight patients had Grade III thrombocytopenia, four patients had Grade IV thrombocytopenia, no bleeding occurred. Estramustine in combination with vinblastine and mitomycin-C is an active regimen. The non-hematologic toxicity was tolerable, while the hematologic toxicity required individual dosage reduction. The combination and the clinical significance of the decline in the PSA warrants further investigation.     

Safety and efficacy of docetaxel,estramustine phosphate and hydrocortisone in hormone‐refractory prostate cancer patients

Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone‐refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate‐specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3–4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4–5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.     

Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer

PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.     

Combination chemotherapy with docetaxel, estramustine and suramin for hormone refractory prostate cancer

PURPOSE: To investigate more effective chemotherapy against hormone refractory prostate cancer (HRPC) with the combination of estramustine (EM), docetaxel, and suramin. PATIENTS AND METHODS: A total of 42 patients with symptomatic, progressive HRPC were included in this study. We evaluated the activity of the following schedule: EM 10 mg/kg orally daily on Days 1 to 21 every 28 days, docetaxel 70 mg/m(2) IV on Day 2 every 28 days and a total doses of 2150 mg of suramin in every cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Median follow-up was 23.4 months. A median of 8.8 consecutive cycles was administered per patient. In the 25 patients with lymphadenopathy, there were three (12%) complete and 18 (72%) partial responses for a measurable disease response rate of 84%. Levels of prostatic specific antigen (PSA) decreased by greater than 50% in 100% of patients and by greater than 90% in 76.2%. The median time to progression was 57 weeks and median overall survival was 132 weeks. A decline in PSA of > or =50% lasting > or =30 days was significantly associated with a prolonged median time to progression and median overall survival. Tumor volume reduction and/or antitumor treatment effects were observed in 88% of patients. A significant decrease in mean pain score from 7.8 (range, 6-10) to 2.2 (range, 0-4) (P < 0.001) was achieved in 78%. Of patients with bone metastasis, 30.5% demonstrated a partial response. The mean Eastern Cooperative Oncology Group (ECOG) performance score improved from 2.8 to 1.5 at the end of treatment period. There was no therapy-related death. The predominant toxicities were Grade 3 or 4 leukopenia in 33.3%, anemia in 21%, thrombocytopenia in 21.4%, cardiac ischemia in 4.7%, and rash in 4.7%. CONCLUSION: The combination of docetaxel, EM, and suramin is a highly effective regimen for HRPC. Although hematologic and gastrointestinal toxicities were modest, these were easily managed medically.     

Chemotherapy of embryonal carcinoma of the testis with lymph node invasion and/or pulmonary metastases. Results of a VBP type protocol

Fourteen patients with histologically proven embryonal carcinoma of the testis with pulmonary metastasis (10 pts) or para-aortic nodal involvement (4 pts) were treated by a chemotherapy regimen including vinblastine, bleomycin and cisplatin. Extreme ages were 19 and 51 years with a median age of 32 years. Median duration of treatment was 6 months (6 cycles of chemotherapy) without maintenance treatment. After completion of chemotherapy, 6 patients in complete remission received para-aortic node irradiation (45 Grays in 25 fractions). One patient had a para-aortic node dissection, histologically negative. With a median follow-up of 47 months (maximum 92 months, minimum 12 months), eleven patients are in complete remission (78.6%). Three patients are dead from the disease, in spite of salvage chemotherapy. There were no toxic deaths. Disease-free actuarial survival is 74% at 4 years. Our results confirm the excellent therapeutic results of this chemotherapy regimen in embryonal carcinoma of the testis with pulmonary metastasis and/or para-aortic nodal involvement.     

Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancer

BACKGROUND: The purpose of the present study was to evaluate the antitumor activity and toxicity of oral estramustine phosphate (EMP) in combination with oral etoposide in patients with hormone-refractory prostate cancer. METHODS: Twenty patients with adenocarcinoma of the prostate that progressed after one or more regimens of androgen-deprivation therapy were enrolled into this trial. Oral EMP was administered twice daily, for a total daily dose of 560 mg, and oral etoposide (50 mg/bodyweight per day) was given on days 1-21 and was stopped on days 22-35. Treatment was continued until evidence of disease progression appeared or two consecutive rises in the prostate-specific antigen (PSA) value were observed. RESULTS: Ten of 20 patients showed a decrease of 50% or greater in the PSA value from initially elevated PSA levels after therapy. The median progression-free duration and 2 year cause-specific survival rate of these 10 patients were 208 days (range 71-693 days) and 67.5%, respectively. There were no significant differences in age, pretreatment PSA value, duration from initial treatment to relapse, prior therapy or survival between patients who had a decrease of 50% or greater in PSA values after this combination therapy and those who did not. The main toxicities (> or =grade 2) were anemia, leukocytopenia, thrombocytopenia, gastrointestinal and hepatic disorders, which occurred in 40, 15, 10, 15 and 5% of patients, respectively. CONCLUSIONS: The combination of oral EMP and etoposide is considered to be a well-tolerated outpatient treatment regimen for patients with hormone-refractory prostate cancer and the therapy deserves further investigation.     

Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancer

A total of 42 patients with hormone-refractory prostate cancer received E-E therapy. Oral estramustine phosphate (EMP) was administered twice daily for a total daily dose of 560 mg every day and oral etoposide (E-E therapy, 50 mg/body/day) was given on days 1-21 and stopped on days 22-35. Treatment was continued until the disease progression was confirmed radiographically or PSA had increased from base line of at least 25%. The median follow-up period after E-E therapy was 77.4 months (range : 12.5 to 122.3). Nineteen patients (43%) achieved a PSA decrease of 50% or greater. The median survival time of the patients who had a decrease of 50% or greater in the PSA value (PSA responder) was 29.3 months and the patients who did not (PSA non-responder) was 14.1 months (p = 0.01). There were no significant differences between PSA responders and non-responders when taking into account variables. Excluding those patients with only PSA elevation, the survival time was 14.9 months with no significant difference between PSA responders and non-responders. The toxicities (grade 3 or more) were identified as anemia, leukocytopenia thrombocytopenia, cardiovascular events, and gastrointestinal and hepatic disorders, which occurred in 0, 5, 2, 2, 14, and 2% of the patients, respectively. E-E therapy was considered to be an active oral regimen and well-tolerated for outpatients with hormone-refractory prostate cancer in Japanese patients.     

A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer

OBJECTIVE: To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS: In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS: Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS: In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.     

Ketoconazole Retains Activity in Advanced Prostate Cancer Patients with Progression Despite Flutamide Withdrawal

Purpose

We tested the hypothesis that certain patients with hormone refractory prostate cancer retain hormonal sensitivity even after progression following antiandrogen withdrawal. The efficacy of ketoconazole and hydrocortisone in this patient population was evaluated.

Materials and Methods

A total of 50 consecutive patients with advanced prostate cancer received ketoconazole and hydrocortisone at progression after antiandrogen withdrawal. Prostate specific antigen (PSA) response was defined as greater than a 50% decrease in PSA from baseline that was maintained for at least 8 weeks.

Results

Overall, of 48 evaluable patients 30 (62.5%, 95% confidence interval 47.3 to 76.1%) had greater than a 50% decrease in PSA, while 23 (48%) had greater than an 80% decrease. The median duration of response was 3.5 months but 23 of 48 patients continue to exhibit a response, ranging from 3.25 to 12.75 or more months. The ketoconazole response rate in patients with no response to prior antiandrogen withdrawal was not different from that in patients with such a response (65 versus 40%, p = 0.35). Toxicity was mild. Grade 1 or 2 nausea, fatigue, edema, hepatotoxicity and rash occurred in 10.4 (5 of 48), 6.25, 6.25, 4.2 and 4.2% of patients, respectively, and anorexia occurred in 2%.

Conclusions

Failure to respond to antiandrogen withdrawal does not identify patients with truly hormone refractory disease. Ketoconazole retains significant activity in this setting and is extremely well tolerated.     

A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate

ObjectiveChemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results.Materials and methodsChemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m² and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m² and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy.ResultsData for 31 men (median age, 63 years [range, 41–74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%–99.9%) from a baseline value of 14.3 ng/ml (range, 1.9–497.9 ng/mL). Median time to progression was 34+ months (range, 14–68+ months). Median OS was 56+ months (range, 17–73+ months).ConclusionsCombination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial.     

Ketoconazole in Taiwanese castration-resistant prostate cancer patients: Evaluation of response rates,durations, and predictors

Background/purposeTo evaluate the efficacy of ketoconazole in castration-resistant prostate cancer.Materials and methodsWe reviewed the medical records of consecutive patients with pathologically confirmed prostate cancer from May 2006 to December 2008. The inclusion criteria were: (1) receiving 200 or 400 mg ketoconazole three times daily and replacement doses of prednisolone; (2) antiandrogen withdrawal for at least 2 months before ketoconazole treatment; and (3) no prior cytotoxic agents or other CYP17 inhibitors. Treatment consisted of ketoconazole at 200 mg three times daily (Group A) and 400 mg three times daily (Group B). Patients' characteristics, time to prostate-specific antigen (PSA) progression, duration of PSA response, and adverse events were evaluated.ResultsOf the 37 patients in Group A, 14 (37.8%) experienced a PSA response. Of the seven patients in Group B, four (57.1%) experienced a PSA response. Median durations of time to progression in those who experienced a > 50% PSA decline were 7.5 and 11.5 months in Group A and Group B, respectively. Median duration of PSA response was 5.5 and 9.0 months in Group A and Group B, respectively. There was no difference in the PSA response or time to progression between the two groups. Orchiectomy had a borderline unfavorable effect on the PSA response rate (p = 0.067).ConclusionThe present study demonstrated that ketoconazole contributed to the PSA response in patients with castration-resistant prostate cancer. The efficacy and toxicity profiles were comparable to those in previous studies. Orchiectomy had a borderline unfavorable effect on PSA response rate. Further studies are required to confirm the efficacy of ketoconazole therapy in surgically castrated patients.     

Progression after docetaxel-based chemotherapy in androgen-independent prostate cancer

OBJECTIVE: To assess the clinical pattern of progression and prostate-specific antigen doubling time (PSA-DT) after exposure to docetaxel-based chemotherapy in patients with androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Fifty-five patients received docetaxel-based chemotherapy; data were collected retrospectively from three different departments. Progression was known in 44 (79%) and the PSA-DT was available in 33 patients. RESULTS: Of the 29 patients with soft-tissue and soft-tissue plus bone metastases, 22 (76%) developed soft-tissue progression. Among the 35 patients with bone and bone plus soft-tissue metastases, 27 (77%) had osseous progression. There was no difference between the PSA-DT at progression before and after docetaxel-based therapy (mean 3.1 vs 2.7 months, P = 0.592, Student's t-test.). However, the median (range) PSA-DT at progression after docetaxel-based therapy was 0.84 (0.3-4) months in patients with a PSA response, significantly shorter than the median of 3.1 (0.3-12) months of patients with no biochemical response (P = 0.002, Student's t-test). The PSA-DT dynamics at progression had no effect on survival (P = 0.63, log-rank test). CONCLUSION: The pattern of progression after docetaxel-based chemotherapy is predominantly osseous in patient with bone metastases and mostly soft-tissue in those with soft-tissue disease. Progression after docetaxel-based chemotherapy in AIPC does not modify the PSA-DT before docetaxel. Evaluation of a larger population is needed to assess the clinical relevance of PSA dynamics after docetaxel therapy.     

Safety and efficacy of sorafenib in patients with castrate resistant prostate cancer: a Phase II study

PurposeWe determined the safety and efficacy of sorafenib in patients with castrate resistant prostate cancer (CRPC).MethodsSixty-four chemotherapy and radiotherapy naïve patients with CRPC received 400 mg sorafenib orally twice daily in 6-week cycles. All patients had bone metastasis, while 16 had lymph node-, 9 had liver-, and 10 had lung metastases. Treatment was continued until disease progression or excessive toxicity.ResultsAll patients were assessable for response. A median of 6.4 consecutive cycles was administered per patient. Median overall survival for all patients was 14.6 months (confidence interval [CI], 8.2–22.2). No complete response (CR) occurred. Of the 35 patients with measurable extraosseous disease, 7 (20%) had a partial response. Overall, 13 patients (20.3%; 95% CI, 4%–32%) achieved a 50% or greater reduction (partial response [PR]) in prostate-specific antigen (PSA) level after two cycles. The median response duration was 2.5 months (95% CI, 1.4 to 4.8), and the median time to progression was 5.9 months (95% CI 3.6 to 7.6). There was no treatment-related death. Toxicities were well tolerated.ConclusionsSorafenib demonstrated some antitumor activity. Further studies are necessary to determine a subgroup of patients who would likely respond better to sorafenib.