Search

Purpose: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel., Patients and Methods: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated., Results: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥ 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients., Conclusion: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Background: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC)., Patients and Methods: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP)., Results: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase., Conclusions: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Purpose: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy., Methods: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression., Results: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003)., Conclusion: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC., Methods: Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase)., Results: The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia., Conclusions: Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC)., Experimental Design: Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks., Results: Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved > or =40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate., Conclusions: This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.

Purpose: To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era., Patients and Methods: We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT., Results: A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition., Conclusion: Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.

Based on the pre-clinical spectrum of activity in taxane-resistant cell lines, we evaluated KOS-862 (epothilone D; 12,13-desoxyepothilone B) as second-line chemotherapy in androgen-independent prostate cancer.Thirty-eight men with metastatic androgen-independent prostate cancer and evidence of progression following docetaxel-based chemotherapy were treated with KOS-862, 100 mg/m(2) (maximum of 240 mg) i.v. weekly for 3 weeks, repeated every 4 weeks. The primary objective for this study was to determine the antitumor activity, measured by PSA decline by more then 50% confirmed 4 weeks later. Two patients (5.3%, 90% CI 1-16%) met criteria for confirmed PSA decline. While both of these patients had previously been treated with docetaxel, neither had confirmed docetaxel-refractory disease. None of the 24 patients with measurable disease had a confirmed partial response. Seventy-three percent of patients had an adverse event leading to dose delay, reduction, or treatment discontinuation. Neurological toxicity and fatigue predominated. Seventeen patients (44.7%) had treatment related grade 3 neurological adverse events including peripheral sensory neuropathy (n = 4, 10.5%), ataxia (n = 3, 7.9%), peripheral motor neuropathy (n = 1, 2.6%), involuntary muscle contractions (n = 1, 2.6%) and neuropathic pain (n = 1, 2.6%). One subject (2.6%) had a grade 4 treatment peripheral motor neuropathy. Further study of this dose and schedule of KOS-862 in this patient population cannot be recommended due to both lack of activity and excessive toxicity.

Background: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer., Methods: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used., Findings: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275)., Interpretation: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Context: Prostate-specific antigen screening has led to an increase in the diagnosis and treatment of localized prostate cancer. However, the role of active treatment of low- and intermediate-risk disease in elderly men is controversial., Objective: To estimate the association between treatment (with radiation therapy or radical prostatectomy) compared with observation and overall survival in men with low- and intermediate-risk prostate cancer., Design and Setting: Observational US cohort from Surveillance, Epidemiology, and End Results Medicare data., Patients: At total of 44,630 men aged 65 to 80 years who were diagnosed between 1991 and 1999 with organ-confined, well- or moderately differentiated prostate cancer and who had survived more than a year past diagnosis. Patients were followed up until death or study end (December 31, 2002). Patients were classified as having received treatment (n=32,022) if they had claims for radical prostatectomy or radiation therapy during the first 6 months after diagnosis. They were classified as having received observation (n=12,608) if they did not have claims for radical prostatectomy, radiation, or hormonal therapy. Patients who received only hormonal therapy were excluded., Main Outcome Measure: Overall survival., Results: At the end of the 12-year study period, 4663 men (37%) in the observational group and 7639 men (23.8%) in the treatment group had died. The treatment group had longer 5- and 10-year survival than the observation group. After using propensity scores to adjust for potential confounders (tumor characteristics, demographics, and comorbidities), there was a statistically significant survival advantage associated with treatment (hazard ratio, 0.69; 95% confidence interval, 0.66-0.72). A benefit associated with treatment was seen in all subgroups examined, including older men (aged 75-80 years at diagnosis), black men, and men with low-risk disease., Conclusions: This study suggests a survival advantage is associated with active treatment for low- and intermediate-risk prostate cancer in elderly men aged 65 to 80 years. Because observational data cannot completely adjust for potential selection bias and confounding, these results must be validated in randomized controlled trials of alternative management strategies in elderly men with localized prostate cancer.

Purpose: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP)., Patients and Methods: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment., Results: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2)., Conclusion: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Increases of individual beta tubulin isotypes in antimicrotubule drug resistant cell lines have been reported by several laboratories. We have previously described elevations in beta(III)and beta(IVa)isotypes in estramustine and paclitaxel resistant human prostate carcinoma cells. To investigate further the function of beta tubulin isotypes in antimicrotubule drug response, human prostate carcinoma cells that normally have very low to undetectable levels of beta(III)were stably transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin (HA) epitope tag was added at the 3' end prior to cloning into the vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids and selected in the presence of Zeocin. Immunofluorescent staining of the transfectant cells have shown significant expression and incorporation of HA-tagged beta(III)tubulin into cellular microtubules. Quantitation of Western blots revealed the HA-tagged beta(III)levels to be approximately 7-fold higher than the vector control cells. RT-PCR analysis confirmed the increase at the transcript level and also revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell viability assays indicated that sensitivity of beta(III)transfected cells to various antimicrotubule agents was similar to vector transfected cells: IC50 values for estramustine, paclitaxel, colchicine and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for both cell lines. Thus, overexpression of beta(III)isotype in human prostate carcinoma cells by stable transfection failed to confer antimicrotubule drug resistance to these cells. Counterregulatory increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these beta(III)transfected cells may be a compensatory mechanism used by the cells to overcome the effects of elevated beta(III)levels on the cellular microtubules. These results highlight the difficulty in isolating the contribution of single tubulin isotypes in drug response studies., (Copyright 2001 Cancer Research Campaign.)

Objectives: To exploit the favorable dose intensity and safety profile of weekly paclitaxel, we conducted a Phase I trial of paclitaxel by 3-hour infusion in combination with estramustine phosphate (EM) in men with hormone-refractory prostate cancer (HRPC). The antimicrotubule drug combination of paclitaxel by 96-hour infusion plus EM is active in HRPC., Methods: Twenty-four patients with metastatic HRPC and progressive tumor after antiandrogen withdrawal were enrolled in this study. Oral EM was taken at a dose of 600 mg/m(2) daily for the initial 21 patients and on a reduced schedule of 280 mg twice daily for the final 3 patients. Paclitaxel was escalated from 60 to 118 mg/m(2)., Results: The major toxicities were gastrointestinal and thromboembolic complications related to daily oral dosing of EM. Of the first 21 patients, one third (n = 7) discontinued therapy within 4 weeks because of protracted nausea and/or thrombotic complications. Dose-limiting toxicities at 118 mg/m(2) paclitaxel were fatigue and hepatotoxicity. Of 13 patients with measurable soft-tissue lesions, 6 had objective partial regressions, and 9 (37.5%) of 24 patients (95% confidence interval 19.1% to 59.1%) with elevated prostate-specific antigen levels had a 50% or greater decline of at least 4 weeks' duration., Conclusions: Weekly paclitaxel at doses of 60 to 107 mg/m(2) were feasible in combination with oral EM, but daily oral EM produced unacceptable toxicity. On the basis of these results, a Phase II trial of weekly paclitaxel with the reduced dose and schedule of EM was initiated by the Eastern Cooperative Oncology Group to assess further the benefits and risks of this treatment in men with metastatic HRPC.

Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer.

Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

Twenty-nine patients with progressive hormone-refractory metastatic adenocarcinoma of the prostate were treated with daily estramustine phosphate at 10 mg/kg, and I.V. doxorubicin 50 mg/m2 every 3 weeks. Twenty-six patients were evaluable. Four of seven patients with nonosseous measurable disease had partial responses lasting 3 to 10 months. Eleven of 19 patients with osseous metastases had stable disease or improvement on bone scan, 6 of these for 7 months or longer. Median time to progression was 20 weeks, and the median survival was 43 weeks.

Dolastatin-10 is a natural, cytotoxic peptide with microtubule-inhibitory and apoptotic effects. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. A Phase II clinical trial was designed in patients with hormone-refractory prostate cancer. Dolastatin-10 was administered at a dose of 400 microg/m2 i.v. every 3 weeks. Dose escalation to 450 microg/m2 was permitted. Toxicity evaluation was conducted every 2 weeks, and assessment of response was done at the end of every two cycles. Sixteen patients were enrolled between October 1998 to December 1999. The median age was 71 years (range, 59-79 years). Median prostate-specific antigen value was 108 ng/ml (range, 15.3-1672 ng/ml). Of the 15 eligible patients, 7 were Caucasian and 8 were African-American. Eight patients had bone-only metastases, and seven had measurable disease with or without bone metastases. A total of 56 cycles have been administered. Only 2 patients required dose adjustment because of toxicity, and in 5 patients, dose escalation was feasible to 450 microg/m2. The major toxicities observed were grade 3 and 4 neutropenia in 8 patients and grade 3 neuropathy in 1 patient. All 15 patients are evaluable for response. Three patients demonstrated stable disease; 2 of these had bone disease, and 1 had nodal metastasis. All others had disease progression. Dolastatin-10 is very well tolerated in this elderly, pretreated population but lacks significant clinical activity as a single agent.

Purpose: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters., Result: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point., Conclusion: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Purpose: To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC)., Patients and Methods: A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m(2) by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m(2) PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V., Results: Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P =.08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P <. 001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with >/= 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P <.0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P <.0001); however, grade 2 or worse nausea (26% v 7%, respectively; P =.0002) and extremity edema (22% v 8%, respectively; P =.005) were more frequent for EM-V., Conclusion: Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.

Objectives: To compare the accuracy of a bone marrow magnetic resonance imaging (MRI) protocol in patients at high risk of metastatic disease with radioisotopic bone scans, the standard method for detection of bony metastases in patients with prostate cancer., Methods: The study group consisted of 19 men with prostate cancer who underwent a bone marrow MRI between November 1993 and February 1996. This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and femurs. Indications for MRI included an equivocal bone scan and/or staging of locally advanced or recurrent disease. The findings on MRI and bone scan were compared and the results correlated with the subsequent clinical patient outcome., Results: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13 patients with negative bone scans. Four patients had an indeterminate bone scan: 2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on the basis of subsequent clinical follow-up. Two patients with positive bone scans had true-positive MRIs., Conclusions: Although not recommended for routine staging, MRI was useful in this study for clarifying an equivocal bone scan. The bone marrow MRI protocol images a high yield volume of the bony skeleton and is fast and economical compared with obtaining many focused MRI scans of these areas separately. These preliminary data suggest that further investigation of its clinical utility for staging locally advanced or recurrent disease is justified.

This report is a multi-institutional phase II study designed to obtain the response rate, survival, and toxicity profile for patients having hormone-refractory prostate cancer. Patients who had bidimensionally measurable prostate carcinoma in first or second remission after previous hormonal therapy but no history of chemotherapy were eligible. Patients were treated with leucovorin, 20 mg/m2 intravenously, followed by 5-fluorouracil (5-FU), 425 mg/m2 intravenously daily for 5 days, with cycles repeated every 28 days. Of 38 eligible patients, 3 (7.9%) had partial responses to therapy and 20 (52.6%) had stable disease. Median survival was 11.6 months for all 38 patients and median time to progression was 4.4 months. Most of the serious side effects were gastrointestinal or hematologic and overall, 23 of 38 patients (60.5%) experienced at least one grade 3 or 4 treatment-related toxicity of any type, as measured by the National Cancer Institute common toxicity criteria. Five patients (13.2%) withdrew from the study because of adverse reactions from chemotherapy. We conclude that treatment of hormone-refractory prostate cancer patients with 5-FU and leucovorin chemotherapy produced few responses at the cost of significant side effects. Further investigation of this combination is not warranted in this setting.

To investigate the role of beta-tubulin isotype composition in resistance to paclitaxel, an anti-microtubule agent, human prostate carcinoma (DU-145) cells were intermittently exposed to increasing concentrations of paclitaxel. Cells that were selected and maintained at 10 nM paclitaxel (Pac-10) were fivefold resistant to the drug. Pac-10 cells accumulated radiolabelled paclitaxel to the same extent as DU-145 cells and were negative for MDR-1. Analysis of Pac-10 and DU-145 cells by flow cytometry showed similar cell cycle patterns. Immunofluorescent staining revealed an overall increase of alpha- and beta-tubulin levels in Pac-10 cells compared with DU-145 cells. Examination of beta-tubulin isotype composition revealed a significant increase in betaIII isotype in the resistant cells, both by immunofluorescence and by western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the isotypes confirmed the increase observed for the betaIII by exhibiting ninefold higher betaIII mRNA levels and also showed fivefold increase of the betaIVa transcript. In addition, analysis of paclitaxel-resistant cells that were selected at increasing levels of the drug (Pac 2, 4, 6, 8 and 10) exhibited a positive correlation between increasing betaIII levels and increasing resistance to paclitaxel. Increased expression of specific beta-tubulin isotypes and subsequent incorporation into microtubules may alter cellular microtubule dynamics, providing a defence against the anti-microtubule effects of paclitaxel and other tubulin-binding drugs.

Antimicrotubule drugs are used as chemotherapeutic agents due to their effects on essential cellular functions such as mitosis, organelle transport and maintenance of cell shape. When used in combination, paclitaxel with estramustine or vinblastine has demonstrated activity against hormone refractory prostate cancer. To understand the mechanism of resistance that develops in patients as a result of antimicrotubule drug therapy, we exposed human prostate carcinoma cells to IC20 and IC40 doses of estramustine, paclitaxel or vinblastine for 48 h and examined the beta-tubulin (the cellular target) isotype composition. The results revealed an increase in the betaIII-tubulin isotype as a result of drug treatment both at protein and message levels. In addition, examination of human brain cell lines with different intrinsic levels of betaIII showed that cell lines with higher betaIII levels were more resistant to paclitaxel. These results are in agreement with our previous findings in human prostate carcinoma cell lines that were made resistant to estramustine or paclitaxel and suggest an important function for betaIII in antimicrotubule drug resistance. Also, the complete coding sequence of human betaIII tubulin reported here will provide molecular tools for future investigations.

Purpose: To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC)., Patients and Methods: Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously., Results: Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks., Conclusion: The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.

Background: beta-tubulin, the intracellular target of several antimicrotubule agents, is encoded by at least six genes and exists as multiple isotypes with tissue-specific expression. Previous in vitro studies indicated that tubulin isotype composition may affect polymerization properties, dynamics, and sensitivity to drugs., Methods: To investigate the isotype composition of beta-tubulin in human prostate, tissues were collected from 26 patients after radical prostatectomy and sections were stained with isotype-specific antibodies., Results: beta IV tubulin is the predominant isotype in benign prostatic hyperplasia (BPH) and adenocarcinoma, showing significantly stronger immunohistochemical expression than beta II and beta III, particularly in Gleason's grade 3 and 4 cancers. Staining for the beta II isotype was invariably weak and often absent in BPH and normal glands. There was a marked increase in beta II isotype stain from BPH to cancer in 77% of the patients, suggesting that the expression of this isotype is related to malignant status., Conclusions: The beta II tubulin isotype is a potential marker for prostate adenocarcinoma. The possibility that tumor beta-tubulin isotype composition may effect the response to antimicrotubule drug therapy in prostate cancer and other tumors merit investigation.

Long misclassified as an alkylating agent, estramustine phosphate is a stable conjugate of estradiol and nornitrogen mustard with antimitotic properties. Binding of the drug to microtubule-associated proteins, tubulin, and proteins of the nuclear matrix are presently considered to be the most likely mechanisms underlying the cytotoxicity of estramustine in androgen-independent prostatic carcinoma. Identification of these mechanisms of action has led to clinical reevaluation of estramustine phosphate (EMP) in several rationally designed drug combinations. Combination of EMP with either vinblastine, paclitaxel or etoposide has produced antitumor responses in 30% to 60% of patients with metastatic hormone-refractory prostate carcinoma as determined by reduction in bidimensionally measurable soft tissue disease, pain, and serum prostate-specific antigen. Whereas the antitumor activity of the combinations has been greater than additive for the single agents, the toxicities of treatment have not been greater than predicted for the individual drugs. The promising results of EMP-based chemotherapy encourage additional laboratory and clinical investigations to develop more effective therapy for hormone-refractory disease and for selected patients with earlier stages of prostate cancer.

Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with beta-tubulin isotype-specific antibodies showed an approximately 6-fold increase in the beta(III)-tubulin levels and moderate increase in overall beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of beta(III) isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using beta-tubulin isotype-specific primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific beta-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.

Purpose: The patterns of failure (local and/or regional v metastatic) have been determined for patients with prostate cancer and pretreatment prostate-specific antigen (PSA) levels > or = 20 ng/mL treated with radiation alone with the purpose to design appropriate multimodal treatments., Materials and Methods: One hundred twenty patients with pretreatment PSA levels > or = 20 ng/mL were treated with external-beam radiation alone between February 1988 and October 1993. They were arbitrarily divided by PSA levels, 20 to 29.9 ng/mL, 30 to 49.9 ng/mL, and > or = 50 ng/mL, and analyzed in terms of freedom from any failure (no evidence of biochemical disease [bNED], and PSA level < 1.5 ngm/mL and not increasing), as well as freedom from imaging evidence of distant metastasis (fdm)., Results: There was no significant difference in short-term outcome by pretreatment PSA level, and thus all patients were pooled for analysis. At 4 years, 81% were fdm and 28% were free of any failure. This suggests that approximately 50% have recurred with local and/or regional disease or undetectable metastatic disease. Multivariate analysis indicated that low palpation stage and higher center of prostate dose were associated with better bNED survival. Multivariate analysis indicated that increasing stage and younger age are significantly associated with increasing distant metastasis., Conclusion: Patients with pretreatment PSA levels > or = 20 ng/mL are not optimally treated by irradiation alone. The pattern of failure suggests improvement may come from systemic treatment of metastatic disease and high-dose radiation to improve locoregional disease. To evaluate this, we have begun a multimodal trial of chemohormonal therapy followed by extended-field irradiation.

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.

Although prostate specific antigen (PSA) density appears to be an important discriminator between benign and malignant prostatic disease, conflicting data exist concerning its prognostic value. The present study was undertaken to confirm whether PSA density represents a new prognostic indicator of disease-free survival for prostate cancer treated with conformal radio-therapy. Between April 1989 and December 1992, 186 patients with organ confined prostate cancer were treated with definitive irradiation according to previously published conformal guidelines. The PSA density was defined as the ratio of the pretreatment serum PSA (ng./ml.) to the prostate volume (ml.) as determined from treatment planning computerized tomography. The median PSA density was 0.15 with a range of 0.02 to 2.12. A statistically significant advantage in actuarial freedom from biochemical relapse was noted for patients with pretreatment PSA levels less than 15 ng./ml. when compared to those with higher pretreatment PSA levels (3-year freedom from biochemical relapse 85% versus 28%, p < 0.001). Also, patients with PSA density of 0.15 or less had statistically superior freedom from biochemical relapse compared to their counterparts with higher PSA density (3-year freedom from biochemical relapse 88% versus 28%, p < 0.001). In a multivariate analysis only the baseline PSA (p < 0.002) and the Gleason score (p < 0.002) emerged as significant predictors of prolonged freedom from biochemical relapse. The PSA density had no impact on freedom from biochemical relapse whether it was entered into this multivariate model as a continuous or a dichotomous variable. In our data base baseline PSA levels remain the most powerful independent discriminant of response to conformal irradiation. PSA density is only a surrogate for baseline PSA levels and does not refine the ability to predict prolongation of freedom from biochemical relapse following conformal radiotherapy.

Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1-1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease. One of 13 patients (7.6%) with measurable soft tissue disease had a PR in nodal sites. Of 21 patients with only osseous metastases, 1 (4.7%) had improvement in bone scan. Six of the 34 evaluable patients (17.6%) had the serum PSA decrease by > or = 50% and 2 (5.8%) had PSA decreases of > or = 75%. Toxicity was chiefly hematologic with 66% of patients experiencing Grade 3 or 4 granulocytopenia. Thirty-nine percent of cycles required a delay to allow for hematologic recovery and ten patients required red cell transfusions. Non-hematologic toxicity, mainly nausea and alopecia, was mild. Topotecan administered at this dose and schedule has limited activity in patients with HRPC. Further trials of topo I inhibition in HRPC should utilize alternative schedules of topotecan (e.g., prolonged infusion) or other camptothecin analogs with more potent topo I inhibitory activity.

Purpose: Estramustine phosphate (EMP) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro. Their modest single-agent activities in hormone-refractory prostate cancer, nonoverlapping toxicities, and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer., Patients and Methods: Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously (IV) once a week for 6 weeks. Courses were repeated every 8 weeks. Response assessment was based on a change in serum prostate-specific antigen (PSA) levels and was correlated with change in pain scores., Results: PSA decreased from baseline by at least 50% in 22 patients (61.1%) and by > or = 75% in eight patients (22.2%). A 50% or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score, performance status, and measurable soft tissue disease (if present) was required for a partial response (PR), which occurred in 11 patients for an overall response rate of 30.5% (95% confidence interval, 15.6% to 45.6%). In seven patients with measurable nonosseous disease, there was one PR (14%) and one minor response (MR). In 28 patients with assessable pain, major pain responses occurred in 12 (42.9%). PSA response (> or = 50% decrease times three measurements) was predictive of major pain response with a 93.7% specificity, a 50% sensitivity, and a positive predictive value of 85.7%., Conclusion: We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer.