Phase-II study of docetaxel, estramustine phosphate, and carboplatin in patients with hormone-refractory prostate cancer

OBJECTIVES: To determine the safety and efficacy of combination chemotherapy with docetaxel (DTX), estramustine phosphate (EMP), and carboplatin (CBDCA) in patients with hormone-refractory prostate cancer (HRPC). METHODS: This study included a total of 40 HRPC patients. We evaluated the activity of the following schedule: weekly DTX 30 mg/m(2) iv, daily EMP 10mg/kg po, and CBDCA AUC=6 iv on day 1 of a every 4-wk cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: All patients were assessable for response. A median of six consecutive cycles was administered per patient. Levels of prostate-specific antigen decreased by more than 50% in 95.0% of the patients. Consumption of medication for cancer-induced pain was reduced in 84.6%. Partial response was attained in 66.7% of measurable lesions. Of patients with bone metastasis, 8.3% demonstrated partial response. With a median follow-up of 11.4 mo, the median time to progression was 12.0 mo, and the median overall survival time was 26.6 mo. The predominant toxicities were grade-3 or -4 anemia in 32.5% of the patients, leukopenia in 20.0%, and thrombocytopenia in 17.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. There were no therapy-related deaths. CONCLUSIONS: Combination chemotherapy with DTX/EMP/CBDCA was found to have significant clinical activity with an acceptable toxicity profile in HRPC patients. More suitable selection of patients may be beneficial in terms of improved overall survival in the future.     

Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy

INTRODUCTION: Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint. METHODS: After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared. RESULTS: Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029). CONCLUSIONS: Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.     

9-Nitrocamptothecin as second line chemotherapy for men with progressive, metastatic, hormone refractory prostate cancer: Results of the CALGB 99901

BACKGROUND: Institution of early hormone therapy in the PSA era coupled with demonstration of clinical benefit with chemotherapy in hormone refractory prostate cancer (HRPC) and acceptance of PSA decline as a surrogate for response has resulted in introduction of chemotherapy earlier in the natural history of disease. There now exists a need to identify, effective agents for second line chemotherapy. 9-nitrocamptothecin (9-NC) a novel, oral camptothecin analogue was tested as second line chemotherapy for patients with progressive hormone refractory prostate cancer. PATIENTS AND METHODS: Eligible patients had metastatic hormone refractory prostate cancer with performance status (0-1) following progression on at least 1 prior cytotoxic chemotherapy. 9-NC was administered orally at the dose of 1.5 mg/m2/d for 5 days each week for 3 weeks, followed by rest for 1 week. Response was evaluated after 2 cycles according to the guidelines set forth for Phase II trials in HRPC by the PSA working group. RESULTS: Thirty-five patients were recruited to the study within a period of 6 months; 33 were evaluable for analysis. No patients had a >50% decline in PSA levels. Two out of 8 (25%) patients with measurable disease and 5/25 (20%) patients with nonmeasurable disease showed stable disease. The median time to disease and PSA progression was 2 months [95% confidence interval (CI), 0.9-2.8]. The median overall survival was 10 months (95% CI = 5-12). Seven patients are alive after a median follow-up of 23 months. CONCLUSIONS: 9-nitrocamptothecin failed to elicit clinical or PSA responses. Further study in pretreated HRPC patients is not warranted.     

Weekly low-dose docetaxel is an effective treatment with fewer adverse events for metastatic castration-resistant prostate cancer in Taiwanese patients

ObjectiveBased on the TAX 327 Phase III trial, docetaxel (DTX)-based chemotherapy is the standard first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). However, some heterogeneity is observed in clinical practice. The present study aimed to evaluate the outcomes of a weekly low-dose DTX regimen, which is clinical practice at our institution, and to compare it with the standard triweekly DTX use in the TAX 327 trial.Materials and methodsWe reviewed the charts of all mCRPC patients treated with DTX 30 mg/m² weekly on Days 1 and 8 of a 3-week cycle and prednisolone 5 mg twice daily between January 2006 and February 2014 in our hospital.ResultsIn the first-line setting, 19 patients with mCRPC received weekly DTX chemotherapy. The median four cycles of treatment were given in our cohort. The median follow-up period from the start of chemotherapy was 27.9 months (range 5.4–67.2months). The prostate-specific antigen (PSA) response rate was 47.3%, and the median overall survival was 15.8 months (range 1.2–34.5 months). The main toxicities were anemia (57%), fatigue (26%), and neuropathy (10%). Two patients had different Grade 3 to 4 adverse events (neutropenia and anemia). Our results revealed initial PSA <100 ng/mL, long duration (>12 months) of response to primary hormone therapy, rechallenge, and a higher accumulation dose of DTX were associated with good prognosis.ConclusionFor Taiwanese mCRPC patients, weekly DTX 30 mg/m² is an efficient regimen for disease control with relatively low Grade 3 or 4 hematological adverse effects. The proper treatment duration of DTX therapy for mCRPC in Taiwanese patients is still uncertain, so further research is needed.     

激素抵抗性前列腺癌(附39例报告)

目的探讨激素抵抗性前列腺癌的诊断和治疗,以提高其诊治水平。同时比较中国人和欧美人激素抵抗性前列腺癌生存期的差异。方法回顾性分析1995年6月～2004年10月39例激素抵抗性前列腺癌患者的临床资料。结果确诊激素抵抗性前列腺癌时,38例血PSA值较最低点均有不同程度升高,血PSA值0．2ng/ml～200ng/ml,平均(51．16±54．71)ng/ml,其中有4例血PSA值一直在4ng/ml以下,升高很少,主要靠转移灶来诊断。化疗是主要的治疗方法,常用的有磷酸雌二醇氮芥,磷酸雌二醇氮芥 足叶乙甙,环磷酰胺 足叶乙甙,磷酸雌二醇氮芥 环磷酰胺等。PSA有效率为44．4%～57．8%,平均有效时间3,8月～7．5月,软组织灶有效率为28．6%～50%。39例中已死亡21例,这21例诊断激素抵抗性前列腺癌后,中位生存期为16个月。结论绝大多数激素抵抗性前列腺癌患者可用PSA诊断和随访,但极少数患者PSA变化很小,需用癌灶和症状来随访。化疗是治疗激素抵抗性前列腺癌的主要方法,有一定的疗效。本组患者生存时间似较欧美患者长。     

Long-term disease stabilization by docetaxel plus estramustine for castration-resistant prostate cancer : report of a case

Chemotherapy with docetaxcel (DTX) plus estramustine (EMP) for castration-resistant prostate cancer (CRPC) was started 30 months after the patient, a 65-year-old man, was diagnosed as having advanced prostate cancer cT3aN1M1 (OSS) with an initial PSA of 490 ng/ml. Prostate biopsy specimens revealed moderately differentiated adenocarcinoma, Gleason's sum 4＋5. He was treated with DTX 30 mg/m2 on day 2 and oral EMP 560 mg/day days 1-3 weekly for 3 out of 4 weeks. PSA at start of DTX plus EMP was 81.7 ng/ml, and that after 59 months was 66.6 ng/ml. No objective change in computed tomography and bone scan were observed. He also had no cancer-related symptoms and activity of daily life was good. Chemotherapy was interrupted twice because of pleural effusion and dyspnea by DTX, at 3 and 4 months, respectively, long-term disease stabilization was obtained by this treatment. Other adverse events including interstitial pneumonia, cardiovascular disorders and myelosuppression were not observed. He was maintained on the same chemotherapy. DTX plus EMP chemotherapy is an effective treatment for CRPC patients. Continuing this therapy it is important to survey and control adverse events caused by DTX and EMP carefully.     

Serum PSA half-life as a predictor of survival for hormone-refractory prostate cancer patients: modelization using a standardized set of response criteria

OBJECTIVE: Changes of serum prostate-specific antigen (PSA) during chemotherapy have been validated as a marker of response for hormone-refractory prostate cancer (HRPC) patients. We retrospectively established new response criteria to assess the risk of death. METHODS: Two hundred fifty-six chemonaive HRPC patients treated with chemotherapy were included in the analysis. According to PSA half-life (HL) dynamics, three response categories were defined: responders (R), late-progressors (LP) and initial-progressors (IP), that were compared with Working Group (WG) criteria. PSA HL time to failure (TTF) and overall survival (OS) were estimated and compared between HT categories. Multivariate regression analysis was performed to isolate the impact on OS of these response categories. A new predictor of survival, delta-time PSA interval (DeltaT) was described. RESULTS: PSA HL categories were strongly related with WG criteria (P = 0.0001). PSA HL TTF differed among PSA HL categories: 4.2, 2.3, and 0.9 months for R, LP, and IP patients, respectively, and their respective median OS were 27, 19.7, and 12.3 months (P = 0.0001). For DeltaT > or = 3 versus <3 months, median OS significantly differed: 24.9 months versus 13.2 months (P = 0.0001). CONCLUSIONS: PSA HL dynamics during chemotherapy were able to accurately predict survival, earlier than WG-defined progression criteria. This criterion should be prospectively evaluated in randomized trials for HRPC patients in order to better estimate the risk of death.     

Combination chemotherapy with docetaxel and cisplatin in patients with hormone-refractory prostate cancer

We investigated the efficacy of docetaxel and cisplatin for hormone-refractory prostate cancer (HRPC). Thirteen patients with HRPC were treated with 30 mg/m2 docetaxel weekly for 3 weeks and 70 mg/m2 cisplatin on day 1. Treatment was repeated every 21 days. They received 2 cycles and were evaluated for the responses to serum prostate-specific antigen (PSA) and tumor size. Ten (77%) of the 13 patients showed a 50% or greater decrease in PSA with a median time to progression of 3 months. One of the 2 patients with measurable soft tissue disease showed a reduction in disease. No severe toxicity of this regimen was observed. Combination chemotherapy with docetaxel and cisplatin in patients with HRPC was well tolerated and efficatious with a significant decrease in serum PSA and measurable disease.     

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.     

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.     

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.     

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.     

Hormonal chemotherapy for hormone-refractory prostate cancer

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.     

Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer

OBJECTIVES

To evaluate the efficacy of docetaxel/carboplatin (DC)‐based chemotherapy as first‐ and second‐line chemotherapy for patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

We retrospectively identified all patients with HRPC treated with DC‐based chemotherapy at the Dana‐Farber Cancer Institute. Regimens either included estramustine (EDC) or not (DC). We identified patients who received EDC as first‐line chemotherapy and patients who received DC as second‐line or subsequent chemotherapy. Patients treated with EDC received 20–70 mg/m² docetaxel every 1–4 weeks, estramustine 140 mg three times daily and carboplatin (area under the curve, AUC), (4–6) every 3–4 weeks. Patients treated with DC received docetaxel 50–70 mg/m² and carboplatin AUC (4–6) every 3–4 weeks.

RESULTS

In all, the study included 54 patients; 24 received EDC and 30 DC (median age 62.8 and 66.9 years, respectively); their prostate‐specific antigen (PSA) level at the start of chemotherapy was 112.7 and 213.3 ng/mL, respectively. There were declines of ≥50% in PSA level in 88% and 20% in the two groups, respectively. The median overall survival was 17.7 and 14.9 months in the EDC and DC groups, respectively. The most common reversible grade 4 toxicity with either regimen was neutropenia (4% and 7% in EDC and DC, respectively).

CONCLUSIONS

DC‐based chemotherapy is well tolerated and active in HRPC. Adding carboplatin to docetaxel provides an additional activity in 20% of patients as a second‐line or subsequent chemotherapy.     

Analysis of prognostic factor in 52 castration-resistant prostate cancer treated with docetaxel

The prognostic factor was retrospectively analyzed in 52 castration-resistant prostate cancer treated with docetaxel (DTX) in our institutions from April, 2006 to August, 2009. The treatment outcomes were decided with prostate specific antigen (PSA) progression-free survival and overall survival. These were calculated by Kaplan-Meier methods and tested with Log-rank test. Median PSA progression-free survival was 8.8 months and median overall survival was 24.1 months. Prognostic factors on PSA progression were PSA value before DTX treatment and rate of PSA decrement after DTX treatment. Prognostic factors on overall survival were Gleason score (GS), PSA value before DTX treatment, rate of PSA decrement after DTX treatment and positive of bone metastasis in Log-rank test. Odds ratio of PSA ≧20 ng/ml before DTX treatment was 2.99 and PSA decreasing rate < 30% was 3.65. These were statistically significant (p < 0.001) risk factors in the overall survival.     

Hormone-resistant prostate cancer with symptomatic pelvic tumours: patient survival and prognostic factors

OBJECTIVES: To determine the survival and investigate the prognostic significance of immunohistochemical variables and clinical factors in patients with hormone-resistant prostate cancer (HRPC) and symptomatic pelvic tumours, in whom preliminary observations indicated that survival exceeded the median 8-10 months of patients with HRPC and painful bone metastases. PATIENTS AND METHODS: Seventy-five patients with HRPC referred for palliative pelvic radiotherapy between 1980 and 1996 were identified. For all patients at least two prostate biopsies had been obtained, one before primary hormone treatment and at least one after clinical progression despite androgen deprivation (HRPC biopsy). Bone scans at the time of referral were assessed. The medical records were reviewed for clinical variables of possible prognostic significance. Histological grade was recorded, and prostate-specific antigen (PSA), androgen receptors (ARs), Ki-67 and p53 determined immunohistochemically. In 18 HRPC specimens the degree of AR amplification was analysed. RESULTS: Positive staining for ARs was high in the HRPC biopsies, although there was no association with AR amplification. Ki-67 positivity increased after the development of HRPC. The median (range) survival was 14 (1-141) months; age < 65 years was associated with increased survival. In a multivariate analysis the following variables remained independent prognostic factors for survival from the time of the HRPC biopsy: bone metastases (0-10 vs > 10 lesions, P < 0.001), low Ki-67 score (0 vs 1-3, P = 0.006) and low p53 positivity score (0 vs 1-3, P = 0.014) in the HRPC biopsy. CONCLUSIONS: The median survival of patients with HRPC and pelvic tumours requiring palliation seems to exceed that of patients with HRPC and dominating painful bone metastases by at least 4-6 months. Simple clinical (bone metastases) and immunohistochemical variables (Ki-67, p53) enable patients with particularly long survival times to be identified, and in whom palliative treatment needs to be improved.     

A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer

OBJECTIVE: To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulphone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clinical studies suggested activity against prostate cancer and synergy with cytotoxic agents. PATIENTS AND METHODS: Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and intravenous docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m2. Toxicity was then evaluated using standard criteria. RESULTS: The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m2, with escalation to 75 mg/m2 after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycaemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months. CONCLUSION: The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.     

Effectiveness of taxanes-based chemotherapy against hormone-refractory prostate carcinoma

We performed an investigative and clinical study of docetaxel, and evaluated its efficacy against hormone-refractory prostate carcinoma (HRPC). In an in vitro experiment, docetaxel suppressed the human prostate cell line proliferation not only in an androgen-dependent cell line, LNCaP, but also in androgen-independent cell line, PC-3, in a dose-dependent manner. In an in vivo experiment applying an SCID mouse xenograft model with PC-3, docetaxel administration suppressed the tumor growth more than 95%. In a clinical study, eight cases were enrolled to low-dose (20 mg/m2/wk) weekly regimen and an other eight to high-dose (60 mg/m2/wk) administration of docetaxel every three weeks. A prostate specific antigen (PSA) decline of more than 50% were observed in 4 (50%) in the low-dose group and 5 (63%) in the high-dose group. The median time to progression and overall survival were 8.5 and 13.2 months in the low-dose group and more than 5.5 and 8.5 months in the high-dose one, respectively. This regimen was well tolerated, and the incidence of adverse effect was relatively low and light. Grade 3 neutropenia or leukocytopenia without fever was seen in three patients (18.8%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed. In conclusion, docetaxel-based chemotherapy was well tolerated and an active treatment for HRPC cases.     

Prospective randomised trial comparing diethylstilboestrol and flutamide in the treatment of hormone relapsed prostate cancer

BACKGROUND: Patients with hormone relapsed prostate cancer (HRPC) are often treated with flutamide or diethylstilboestrol. However, which of these two options is the best treatment for HRPC remains unclear. METHODS: We carried out a prospective study to determine and compare the prostate-specific antigen (PSA) response and survival in patients with hormone relapsed prostate cancer (HRPC), all of whom had previously shown a good response to medical or surgical castration. The patients were randomised to treatment with diethylstilboestrol (DES) and aspirin, or the antiandrogen flutamide. In addition, quality of life was determined by interview and questionnaire. RESULTS: Twenty-eight patients were randomised for treatment options.There was a significantly greater fall in the PSA (65% vs 35%; P = 0.034) after treatment with diethylstilboestrol compared to treatment with flutamide. Median survival also rose after treatment with diethylstilboestrol (18 months) compared to flutamide (11 months), but this difference did not reach statistical significance. There was no difference in the quality of life parameters between the two groups. There were no cardiovascular complications in the stilboestrol group. CONCLUSIONS: In HRPC, treatment with stilboestrol is associated with a greater PSA fall and an increase in median survival when compared to flutamide treatment.