Prostatic Neoplasms: Eisenberger MA

Montie JE, Clark PE, Eisenberger MA, El-Galley R, Greenberg RE, Herr HW, Hudes GR, Kuban DA, Kuzel TM, Lange PH, Lele SM, Michalski J, Patterson A, Pohar KS, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00046. · University of Michigan Comprehensive Cancer Center. · J Natl Compr Canc Netw. · Pubmed #19176203 No free full text.

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Montie JE, Abrahams NA, Bahnson RR, Eisenberger MA, El-Galley R, Herr HW, Hudes GR, Kuzel TM, Lange PH, Patterson A, Pollack A, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00097. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17112448 No free full text.

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Eisenberger MA, Walsh PC. · No affiliation provided · N Engl J Med. · Pubmed #10588970 No free full text.

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Walsh PC, DeWeese TL, Eisenberger MA. · James Buchanan Brady Urological Institute, the Sidney Kimmel Comprehensive Cancer Center, the Department of Urology, Radiation Oncology and Molecular Radiation Sciences, and Johns Hopkins Medical Institutions, Baltimore, MD 21287-2101, USA. · N Engl J Med. · Pubmed #18160689 No free full text.

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Antonarakis ES, Blackford AL, Garrett-Mayer E, Eisenberger MA. · Prostate Cancer Research Program, and the Division of Oncology Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA. · J Clin Oncol. · Pubmed #17971600 No free full text.

Abstract: PURPOSE: We aimed to describe disease-free survival (DFS) and overall survival (OS) in men with localized or locally advanced prostate cancer receiving immediate hormone therapy as adjunct to radiation therapy, adjunct to radical prostatectomy, or stand-alone therapy. MATERIALS AND METHODS: A systematic literature search of MEDLINE, EMBASE, CancerLit, the Cochrane Library, and Current Contents (from 1986 to September 2006) yielded 35 high-quality clinical trials (n = 11,105 patients) which formed the evidence base. Selected studies were required to address early hormone therapy in nonmetastatic prostate cancer only. Data on DFS and OS were extracted from individual trials, summarized statistically, and displayed in graphic form. RESULTS: Survival probabilities were extracted from 16 trials (n = 5,987 patients) addressing hormone therapy as an adjunct to radiation therapy, 11 trials (n = 1,885 patients) investigating hormone therapy as an adjunct to prostatectomy, and 10 trials (n = 3,233 patients) evaluating hormone therapy alone. In men receiving hormones and radiation, estimated 5-year DFS and OS were 52% and 82%, whereas median DFS and OS were 5.4 years and more than 7 years, respectively. In men receiving hormones and surgery, 5-year DFS and OS were 64% and 90%, whereas median DFS and OS were more than 6 years and more than 7 years, respectively. In men receiving hormones alone, 5-year DFS and OS were 57% and 70%, whereas median DFS and OS were 6.0 years and more than 7 years, respectively. CONCLUSION: This systematic review provides a new baseline for expected DFS and OS in patients treated with hormone therapy for nonmetastatic prostate cancer. Survival in these men may be longer than estimated previously.

Sandler HM, Eisenberger MA. · Departments of Radiation Oncology and Urology, University of Michigan, Ann Arbor, Michigan 48109, USA. · J Urol. · Pubmed #17644123 No free full text.

Abstract: PURPOSE: In patients who undergo local treatment for clinically localized prostate cancer evidence of increasing serum prostate specific antigen usually antedates the development of clinically evident metastasis by many years. Prostate specific antigen is used to guide subsequent salvage strategies, such as postoperative radiotherapy, androgen ablation or active surveillance with delayed intervention. We discuss options for management in patients who have increasing prostate specific antigen after radical prostatectomy. MATERIALS AND METHODS: The current status of treatment approaches was reviewed to provide an update on frequently used management strategies. RESULTS: Increasing prostate specific antigen values of 0.2 to 0.4 ng/ml are used to indicate recurrent disease after surgery. Restaging is recommended to determine whether metastatic disease can be detected, although many patients with low prostate specific antigen values will have no detectable metastases. Local therapy should be used for select patients in the absence of metastases but the results are most satisfactory for relatively slowly increasing prostate specific antigen with values below 1.0 ng/ml and lower Gleason score neoplasms because these tumors are more likely to have localized recurrences. CONCLUSIONS: Current knowledge about patients with biochemical relapse after radical prostatectomy is primarily related to their natural history. Although approximately 70% of these patients are unlikely to die of the disease, they remain at risk for the development of metastasis and disease related morbidity. Currently no general consensus exists regarding standard systemic treatment approaches for these patients and inclusion in clinical trials remains the most important priority.

Eisenberger MA, Sinibaldi VW. · The Johns Hopkins University, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-1000, USA. · Oncology (Williston Park). · Pubmed #16922258 No free full text.

Abstract: In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.

Eisenberger MA. · Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Semin Urol Oncol. · Pubmed #12198634 No free full text.

Abstract: The management of patients with high-risk, early-stage, prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. Definition of the natural history of this disease, including the identification of key prognostic factors, in addition to the availability of active systemic therapeutic modalities for patients with advanced disease, are among the basic requirements that allow for early intervention in high-risk patients. Emerging new antiprogression approaches, targeted at various known stages of the metastatic cascade with the potential benefit of altering the natural history of early prostate cancer are attractive alternatives for early interventions with innovative programs. Studies on the natural history of patients with evidence of biochemical relapse following local treatment provide the basis for appropriate estimation of the risk ratio for development of clinical metastasis and selection of candidates for aggressive implementation of early treatment. The study of new candidate biomarkers of disease activity should be included in the context of clinical trials. Genotypic and phenotypic characterization of patients in clinical trials may enhance future therapeutic prospects in this disease.

Laufer M, Denmeade SR, Sinibaldi VJ, Carducci MA, Eisenberger MA. · Departments of Oncology and Urology, Johns Hopkins University, Baltimore, Maryland, USA. · J Urol. · Pubmed #10840412 No free full text.

Abstract: PURPOSE: We summarized and critically assessed all available data from phase III clinical trials on complete androgen blockade versus surgical or medical castration alone. MATERIALS AND METHODS: Published results in journals and abstracts of phase III trials, and published meta-analyses were reviewed. We also reviewed quality of life and toxicity issues associated with the addition of antiandrogens to medical or surgical castration. Finally, we discuss the original rationale for complete androgen blockade in the context of current knowledge. RESULTS: A total of 27 clinical trials using various combinations of androgen deprivation were identified, of which 3 showed a statistically significant benefit for the complete androgen blockade arm. There were 5 publications of meta-analyses that each used different selection criteria for the inclusion of studies in the final analysis. Toxicity and quality of life have not been widely investigated in prospective fashion but the available data suggest a higher toxicity rate and decreased quality of life with complete androgen blockade. CONCLUSIONS: The extensive body of data does not support routine use of antiandrogens in combination with medical or surgical castration as first line hormonal therapy in patients with metastatic prostate cancer.

Laufer M, Pound CR, Carducci MA, Eisenberger MA. · Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-8936, USA. · Urology. · Pubmed #10699599 No free full text.

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Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Anonymous00048. · Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. · J Clin Oncol. · Pubmed #18309951 No free full text.

Abstract: PURPOSE: To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. METHODS: A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. RESULTS: The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. CONCLUSION: PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.

Rathkopf D, Carducci MA, Morris MJ, Slovin SF, Eisenberger MA, Pili R, Denmeade SR, Kelsen M, Curley T, Halter M, Collins C, Fleisher M, Heller G, Baker SD, Scher HI. · Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #18565882 No free full text.

Abstract: PURPOSE: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. PATIENTS AND METHODS: Noncastrate patients with <or= 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m(2)), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m(2)), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; <or= 0.05, <or= 0.5, or <or= 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. RESULTS: A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles. CONCLUSION: The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.

Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA, Chatta GS, Nelson JB, DiPaola RS, Roth BJ, Cookson MS, Wilding G, Jarrard DF, Beer TM, Ryan CW, Petrylak DP, Benson MC, Partin AW, Garrett-Mayer E, Eisenberger MA. · Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63105, USA. · J Urol. · Pubmed #17437819 No free full text.

Abstract: PURPOSE: Patients with adverse pathological features are at high risk for recurrence following radical prostatectomy. To improve outcomes in this population we performed a phase II study of adjuvant docetaxel in these high risk patients. MATERIALS AND METHODS: Patients with nonmetastatic radical prostatectomy at greater than 50% risk for recurrence by 3 years were eligible. Pathological findings were centrally reviewed and risk assessment was based on a validated multivariate Cox proportional hazards model. Treatment consisted of 6 cycles of 35 mg/m(2) docetaxel weekly given 4 to 12 weeks following surgery. Progression was defined as a prostate specific antigen of 0.4 ng/ml or greater, radiological/pathological evidence of recurrent disease or death from any cause. To screen for the potential benefit of adjuvant weekly docetaxel we used nomogram predicted progression-free survival as a historical control. RESULTS: A total of 77 patients were registered between April 2002 and January 2004. Two patients had grade IV hyperglycemia and 20 had grade III toxicity. At a median followup of 29.2 months (range 1.6 to 39.2) 46 of 76 evaluable cases (60.5%) progressed. Observed median progression-free survival was 15.7 months (95% CI 12.8-25.1). Predicted median progression-free survival in a matched population was 10 months. Seven patients died, including 4 of prostate cancer, 1 with intra-abdominal bleeding during treatment and 2 of pneumonia and sudden cardiac death, respectively, following treatment. CONCLUSIONS: Adjuvant docetaxel for prostate cancer is feasible with significant reversible but acceptable toxicity. The actual median progression-free survival of 15.7 months was longer than the nomogram predicted rate for this patient population. Adjuvant docetaxel treatment should be further evaluated in phase III trials in patients with high risk prostate cancer.

Bajaj GK, Zhang Z, Garrett-Mayer E, Drew R, Sinibaldi V, Pili R, Denmeade SR, Carducci MA, Eisenberger MA, DeWeese TL. · Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Urology. · Pubmed #17382158 No free full text.

Abstract: OBJECTIVES: Patients with biochemical recurrence of prostate cancer after definitive or salvage local therapy in the absence of metastatic disease represent a group well suited to a novel therapeutic intervention. Imatinib mesylate (Gleevec) is a protein-tyrosine kinase inhibitor that has previously been tested in men with androgen-independent and metastatic prostate cancer. This Phase II study was undertaken to determine the safety and efficacy of imatinib mesylate in men with biochemical relapse of nonmetastatic, androgen-sensitive prostate cancer after local therapy. METHODS: Twenty-seven patients were treated with imatinib mesylate 400 mg twice daily for up to 12 months. Three patients (11%) completed less than 4 weeks of therapy and were included in the intent-to-treat analysis of the response to therapy. RESULTS: Of the 27 patients treated, 5 (18.5%) had a stable prostate-specific antigen (PSA) during the course of treatment; 2 patients (7.4%) experienced a partial response. The remaining 20 patients (74.1%) demonstrated PSA progression. The median progression-free survival was 3 months. The proportion of patients achieving a partial PSA response during therapy did not significantly differ from the null rate of 5% (P = 0.394). Seven patients (25.9%) discontinued therapy secondary to grade 1 to 3 toxicities. No irreversible National Institutes of Health Common Toxicity Criteria grade 3 or 4 toxicities occurred. Grade 3 and 4 toxicity included leukopenia (3.7%), serum glutamic-oxaloacetic transaminase (3.7%) and serum glutamic-pyruvic transaminase (3.7%) elevation, and rash (18.5%). CONCLUSIONS: The results of our study have demonstrated that imatinib mesylate delivered at a dose of 400 mg twice daily is associated with a moderate degree of toxicity and a limited PSA response in this patient population.

Sinibaldi VJ, Elza-Brown K, Schmidt J, Eisenberger MA, Rosenbaum E, Denmeade SR, Pili R, Walczak J, Baker SD, Zahurak M, Carducci MA. · Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. · Am J Clin Oncol. · Pubmed #16891869 No free full text.

Abstract: OBJECTIVES: In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. METHODS: Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. RESULTS: All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added. CONCLUSIONS:: Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

Rosenbaum E, Zahurak M, Sinibaldi V, Carducci MA, Pili R, Laufer M, DeWeese TL, Eisenberger MA. · Department of Radiation Oncology and Molecular Sciences, Division of Medical Oncology and Biostatistics and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. · Clin Cancer Res. · Pubmed #15958628 links to  free full text

Abstract: PURPOSE: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. EXPERIMENTAL DESIGN: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. RESULTS: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). CONCLUSION: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.

Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Anonymous00262. · Department of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada. · N Engl J Med. · Pubmed #15470213 links to  free full text

Abstract: BACKGROUND: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease. METHODS: From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. RESULTS: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. CONCLUSIONS: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.

Eisenberger MA, Laufer M, Vogelzang NJ, Sartor O, Thornton D, Neubauer BL, Sinibaldi V, Lieskovsky G, Carducci MA, Zahurak M, Raghavan D. · Johns Hopkins Medical Institutions, Baltimore, Maryland 21231-1000, USA. · Urology. · Pubmed #14751361 No free full text.

Abstract: OBJECTIVES: To study the safety, pharmacokinetics, biologic activity, and preliminary efficacy of the bispecific 5-alpha-reductase inhibitor (LY320236) in prostate cancer. METHODS: Fifty-one patients with recurrent or metastatic prostate cancer were sequentially (nonrandomly) assigned in cohorts to receive one of five single daily oral doses of LY320236 (10, 50, 150, 250, and 500 mg). Serial evaluations included serum testosterone, dihydrotestosterone, androstenediol glucuronide, estradiol, and pharmacokinetics on days 1, 29, and 57. Toxicity assessments, x-rays/scans, and blood tests, including serum prostate-specific antigen (PSA) determination, were done at regular intervals. RESULTS: Overall, treatment was well tolerated, with 3 of 51 patients developing reversible grade 3-4 toxicity (one diarrhea, two elevated liver enzymes). Peak blood levels (2 to 3 hours after drug administration) were greater for doses of 150 mg or greater compared with less than 150-mg doses with slow accumulation. Serum levels of testosterone, dihydrotestosterone, and androstenediol glucuronide did not change significantly during treatment; however, a statistically significant increase occurred in serum estradiol levels in both the castration and noncastration groups. One of 26 in the noncastration group and 4 (27%) of 15 in the castration group with baseline PSA levels of 5 ng/mL or greater had a 50% or greater PSA decline for 4 weeks or longer. CONCLUSIONS: LY320236 treatment is associated with modest reversible toxicity. An elevation of estradiol levels was seen in both castration and noncastration groups, although PSA declines were primarily seen in the castration group. The absence of cardiovascular toxicity suggests that this agent may be a promising alternative to exogenous estrogens in patients with prostate cancer who demonstrate evidence of disease progression after initial androgen deprivation treatment.

Carducci MA, Nelson JB, Bowling MK, Rogers T, Eisenberger MA, Sinibaldi V, Donehower R, Leahy TL, Carr RA, Isaacson JD, Janus TJ, Andre A, Hosmane BS, Padley RJ. · Division of Medical Oncology, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · J Clin Oncol. · Pubmed #11956279 No free full text.

Abstract: PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Sinibaldi VJ, Carducci MA, Moore-Cooper S, Laufer M, Zahurak M, Eisenberger MA. · Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. · Cancer. · Pubmed #11920502 links to  free full text

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

Carducci MA, Gilbert J, Bowling MK, Noe D, Eisenberger MA, Sinibaldi V, Zabelina Y, Chen TL, Grochow LB, Donehower RC. · Division of Medical Oncology, The Johns Hopkins Oncology Center, 1 M88 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA. · Clin Cancer Res. · Pubmed #11595694 links to  free full text

Abstract: PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.

Kucuk O, Fisher E, Moinpour CM, Coleman D, Hussain MH, Sartor AO, Chatta GS, Lowe BA, Eisenberger MA, Crawford ED. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA. · Urology. · Pubmed #11445479 No free full text.

Abstract: OBJECTIVES: To determine the efficacy and tolerability of bicalutamide in patients with advanced prostate cancer with progression after conventional hormonal therapy. METHODS: Fifty-two patients received bicalutamide, 150 mg once daily, as second-line therapy after progressing following treatment with orchiectomy or luteinizing hormone-releasing hormone analogue or diethylstilbestrol, alone or in combination. Patients had measurable (n = 8) or assessable (n = 44) disease, a Southwest Oncology Group performance status of 0 to 2, and no prior antiandrogen therapy or chemotherapy. The objective response to treatment was assessed every 12 weeks; symptoms and pain were assessed monthly with questionnaires for 6 months. RESULTS: There was evidence of palliation with three measures of pain and, to a lesser extent, with a measure of overall symptom status after 3 months of taking bicalutamide. No complete or partial responses occurred. However, 9 (20%) of 44 subjects with adequate prostate-specific antigen data had a 50% or higher decrease in their prostate-specific antigen levels, which did not correlate with symptom improvement. The median survival time was 15 months. The most common side effects were hot flashes (23%) and nausea (21%). CONCLUSIONS: These data suggest that bicalutamide decreases pain and improves symptom status in patients with prostate cancer in whom first-line hormonal therapy failed.

Pienta KJ, Fisher EI, Eisenberger MA, Mills GM, Goodwin JW, Jones JA, Dakhil SR, Crawford ED, Hussain MH. · University of Michigan Medical Center, Ann Arbor, Michigan, USA. · Prostate. · Pubmed #11241547 No free full text.

Abstract: BACKGROUND: The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS: Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy. RESULTS: Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS: This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.

Hussain M, Fisher EI, Petrylak DP, O'Connor J, Wood DP, Small EJ, Eisenberger MA, Crawford ED. · Department of Medicine, Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. · J Clin Oncol. · Pubmed #10694555 No free full text.

Abstract: PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment. PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity. RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity. CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

Antonarakis ES, Eisenberger MA. · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD 21231,USA. · Nat Clin Pract Oncol. · Pubmed #18957947 No free full text.

Abstract: This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate (an inhibitor of the androgen-regulating enzyme CYP17) in the treatment of castration-resistant prostate cancer. This open-label, dose-escalation study by Attard et al. showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone (a mineralocorticoid receptor antagonist). Abiraterone is a potent suppressor of adrenal androgen synthesis, and produced lasting prostate-specific antigen responses in approximately half of the patients. A few patients had partial regression of distant metastases. Although promising, these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy. Multi-institutional, prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach.