Prostatic Neoplasms: Kantoff PW

Arlen PM, Bianco F, Dahut WL, D'Amico A, Figg WD, Freedland SJ, Gulley JL, Kantoff PW, Kattan MW, Lee A, Regan MM, Sartor O, Anonymous00032. · Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. · J Urol. · Pubmed #18423743 links to  free full text

Abstract: PURPOSE: Prostate specific antigen is a glycoprotein found almost exclusively in normal and neoplastic prostate cells. Prostate specific antigen doubling time, or the change in prostate specific antigen over time, has emerged as a useful predictive marker for assessing disease outcome in patients with prostate cancer. It is important to agree on definitions and values for the calculation of prostate specific antigen doubling time, and to develop a common approach to outcome analysis and reporting. MATERIALS AND METHODS: In September 2006 a conference was held at the National Cancer Institute in Bethesda, Maryland to define these parameters and develop guidelines for their use. RESULTS: The Prostate Specific Antigen Working Group defined criteria regarding prostate specific antigen doubling time including the calculation of prostate specific antigen doubling time, evidence to support prostate specific antigen doubling time as a predictive factor in the setting of biochemical recurrence and the use of prostate specific antigen doubling time as a stratification factor in clinical trials. CONCLUSIONS: We propose that investigators calculate prostate specific antigen doubling time before enrolling patients in clinical studies and calculate it as an additional measurement of therapeutic activity. We believe we have developed practical guidelines for the calculation of prostate specific antigen doubling time and its use as a measurement of prognosis and outcome. Furthermore, the use of common standards for prostate specific antigen doubling time in clinical trials is important as we determine which treatments should progress to randomized trials in which "hard" end points such as survival will be used.

Ross RW, Kantoff PW. · No affiliation provided · J Clin Oncol. · Pubmed #17704399 No free full text.

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Febbo PG, Kantoff PW. · No affiliation provided · J Clin Oncol. · Pubmed #16822841 No free full text.

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Taplin ME, Kantoff PW. · No affiliation provided · J Clin Oncol. · Pubmed #12913104 No free full text.

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Dall'Era MA, Cooperberg MR, Chan JM, Davies BJ, Albertsen PC, Klotz LH, Warlick CA, Holmberg L, Bailey DE, Wallace ME, Kantoff PW, Carroll PR. · Department of Urology, University of California at San Francisco Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-1695, USA. · Cancer. · Pubmed #18306379 links to  free full text

Abstract: The natural history of prostate cancer is remarkably heterogeneous and, at this time, not completely understood. The widespread adoption and application of prostate-specific antigen (PSA) screening has led to a dramatic shift toward the diagnosis of low-volume, nonpalpable, early-stage tumors. Autopsy and early observational studies have shown that approximately 1 in 3 men aged >50 years has histologic evidence of prostate cancer, with a significant portion of tumors being small and possibly clinically insignificant. Utilizing the power of improved contemporary risk stratification schema to better identify patients with a low risk of cancer progression, several centers are gaining considerable experience with active surveillance and delayed, selective, and curative therapy. A literature review was performed to evaluate the rationale behind active surveillance for prostate cancer and to describe the early experiences from surveillance protocols. It appears that a limited number of men on active surveillance have required treatment, with the majority of such men having good outcomes after delayed selective intervention for progressive disease. The best candidates for active surveillance are being defined, as are predictors of active treatment. The psychosocial ramifications of surveillance for prostate cancer can be profound and future needs and unmet goals will be discussed.

Ross RW, Kantoff PW. · Harvard Medical School, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Oncology (Williston Park). · Pubmed #17396482 No free full text.

Abstract: Hormone-refractory prostate cancer (HRCaP) is both heterogeneous and lethal. Multiple treatment options exist, including secondary hormonal manipulations, chemotherapy, experimental options, and best supportive care. Choosing the appropriate therapy for an individual patient depends on several important clinical factors such as the presence or absence of symptomatic metastatic disease, age and comorbidities, and prostate-specific antigen velocity. While only docetaxel (Taxotere)-based chemotherapy has been proven to improve survival in this setting, a wide range of therapies may be effective for any individual. Palliative maneuvers, such as external-beam radiation, bisphosphonate therapy, radiopharmaceuticals, and pain management are critical for appropriate patient management. Several promising novel therapies are in late-stage testing and will hopefully provide more treatment options for these patients.

Carroll PR, Chan JM, D'Amico AV, Gelmann EP, Iversen P, Klotz L, Nelson JB, Nelson PS, Nelson WG, Oh WK, Rosen N, Rubin MA, Sandler H, Sellers WR, Smith MR, Xu J, McMann MC, Kantoff PW. · Department of Urology, University of California School of Medicine, San Francisco 94115-1711, USA. · J Urol. · Pubmed #15535434 No free full text.

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Rubin MA, Kantoff PW. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · J Cell Biochem. · Pubmed #14755678 No free full text.

Abstract: The Prostate Cancer Prevention Trial (PCPT) reported conclusively that finasteride prevents or delays the detection of prostate cancer. One perplexing finding was that more high-grade tumors were detected in the finasteride treated group. It is hard to put this into perspective because of the limited published data on the effects of finasteride on prostate cancer. The strong possibility exists that the increase in high-grade tumors may be due to a treatment effect, which causes intermediate grade cancers to appear to be high-grade or aggressive tumors. Confirmation of a spurious tumor grade "inflation" will make the conclusions of this study clearer and define the benefits of finasteride chemoprevention in a more favorable light.

Carroll PR, Benaron DA, Blackledge G, Coakley FV, D'Amico AV, Higano CS, Iversen P, Kattan M, Nanus DM, Nelson JB, Oh WK, Roach M, Sellers WR, Smith MR, McMann MC, Kantoff PW. · Department of Urology, University of California School of Medicine, San Francisco 94115-1711, USA. · J Urol. · Pubmed #14610403 No free full text.

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Leibowitz SB, Kantoff PW. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. · Semin Oncol. · Pubmed #14571417 No free full text.

Abstract: Much interest has developed recently in the use of differentiating agents in the management of solid tumors, specifically prostate cancer. Two classes of drugs that have shown particularly intriguing results are vitamin D(3) and its analogs and the peroxisome proliferator-activated receptor gamma (PPARgamma) ligands. Both the vitamin D(3) receptor and the PPARs are members of the nuclear receptor superfamily of ligand-dependent transcription factors and both are widely expressed by prostate cancer cells. This article reviews in detail the preclinical and clinical data available supporting the use of these agents in the treatment of prostate cancer. The proposed mechanisms of action of these agents and potential future therapeutic roles for these drugs are discussed as well.

Gilligan T, Kantoff PW. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. · Urology. · Pubmed #12231060 No free full text.

Abstract: Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Carroll PR, Kantoff PW, Balk SP, Brown MA, D'amico AV, George DJ, Grossfeld GD, Johnson CS, Kelly WK, Klotz L, Lee WR, Lubeck DP, Mcleod DG, Oh WK, Pollack A, Sartor O, Smith MR, Hart C, Anonymous00147. · Department of Urology, University of California School of Medicine, San Francisco, San Francisco, California, USA. · Urology. · Pubmed #12231036 No free full text.

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Smith MR, Kantoff PW. · Massachusetts General Hospital, Boston 02114, USA. · Invest New Drugs. · Pubmed #12099579 No free full text.

Abstract: Peroxisome proliferator activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARgamma is expressed at high levels in adipose tissue and plays a central role in adipocyte differentiation. Recent studies have implicated PPARgamma in the pathogenesis of several human malignancies. Here we review the evidence that PPARgamma contributes to prostate carcinogenesis and the potential for PPARgamma as a novel therapeutic target for prostate cancer.

Oh WK, Kantoff PW. · Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · Semin Oncol. · Pubmed #10604270 No free full text.

Abstract: Treatment of hormone-refractory prostate cancer (HRPC) historically has shown limited efficacy. However, taxane-based chemotherapy regimens recently have demonstrated more promising results. Several groups have reported significant efficacy and minimal toxicity in patients with hormone-refractory disease receiving estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA). Others have demonstrated single-agent activity of platinum compounds in HRPC. Therefore, the combination of estramustine, docetaxel, and carboplatin is currently being tested in two separate trials of HRPC. The first is a Dana-Farber/Partners Cancer Care phase I study of estramustine, carboplatin, and escalating doses of weekly docetaxel. The second study is a Cancer and Leukemia Group B multicenter phase II study evaluating the combination of estramustine, docetaxel, carboplatin, and granulocyte colony-stimulating factor. The promise of taxane-based regimens in the treatment of hormone-refractory disease has led to consideration of treating patients at high risk for developing metastatic disease earlier in their clinical course. At Dana-Farber/ Partners Cancer Care, we are evaluating neoadjuvant weekly docetaxel alone followed by surgery in patients with high-risk localized prostate cancer using pathologic response as the primary end point. Adding carboplatin to the active combination of estramustine and docetaxel may improve the response rate in HRPC. Furthermore, the use of promising chemotherapy agents earlier in high-risk localized disease may improve clinical outcomes in these patients by decreasing their risk for systemic relapse.

Oh WK, Kantoff PW. · Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. · J Clin Oncol. · Pubmed #10550165 No free full text.

Abstract: PURPOSE: Management of locally advanced prostate cancer remains controversial. Various single and combination modality approaches have been advocated, but an accepted standard of care remains undefined. The purpose of this review is to define the current knowledge in managing locally advanced prostate cancer and to propose new treatment approaches based on current knowledge. MATERIALS AND METHODS: A MEDLINE search to detect all relevant articles on the management of locally advanced prostate cancer was performed. A review of the staging, natural history, and prognosis of this disease was also performed. RESULTS: The lack of a clearly defined treatment approach to patients with locally advanced prostate cancer stems from multiple factors, including ambiguities in clinical staging, inadequate knowledge of the natural history of the cancer, and a dearth of comparative randomized trials evaluating efficacy of different therapies. Single modality treatment, including radical prostatectomy (RP) or external-beam radiotherapy alone, is associated with high rates of failure. The use of adjuvant hormonal ablation therapy in combination with external-beam radiotherapy has shown improvement in progression-free and overall survival, although similar improvements have not been clearly demonstrated for surgical patients treated with hormonal therapy. New advances in chemotherapy for hormone-refractory prostate cancer suggest that response rates may be as high as 50% or more, and current trials are evaluating the addition of chemotherapy to hormonal ablation in either surgery or radiation therapy in locally advanced prostate cancer. CONCLUSION: Optimal management of locally advanced prostate cancer remains undefined. Standard treatment options include RP, external-beam radiotherapy, or hormonal ablation therapy, alone or in combination. New approaches being tested include improved methods for delivering radiation or combining hormonal ablation with surgery or radiation. It is possible that other forms of systemic therapy, including chemotherapy, may become important components of multimodality treatment. Clinical trials designed to test this hypothesis are ongoing.

George DJ, Kantoff PW. · Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Urol Clin North Am. · Pubmed #10361553 No free full text.

Abstract: Prognostic factors in hormone refractory prostate cancer currently are of limited use to clinicians. Although studies have identified several factors that predict for poor survival in patients, most are either retrospective, or nonrandomized. Therefore, large prospective, randomized trials are needed to validate the significance of these factors. In addition, these indicators are largely descriptive of the patients' condition or the extent of disease. As more treatment options are developed for these patients, functionally relevant and prognostic molecular markers are needed to direct their care.

Dror Michaelson M, Regan MM, Oh WK, Kaufman DS, Olivier K, Michaelson SZ, Spicer B, Gurski C, Kantoff PW, Smith MR. · Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. · Ann Oncol. · Pubmed #19403935 No free full text.

Abstract: BACKGROUND: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC). METHODS: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured. RESULTS: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin. CONCLUSIONS: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.

Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M, Barb D, Mantzoros C, Gelmann EP, Balk SP. · Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. · BJU Int. · Pubmed #18399827 No free full text.

Abstract: OBJECTIVE: To evaluate mifepristone (RU-486) in patients with castration-resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites PATIENTS AND METHODS: The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3 alpha-diol G, were measured at baseline and during therapy. RESULTS: Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31-338) days. The median prostate-specific antigen (PSA) level at enrollment was 22.0 (3.0-937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline. CONCLUSION: Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.

D'Amico AV, Halabi S, Vollmer R, Loffredo M, McMahon E, Sanford B, Archer L, Vogelzang NJ, Small EJ, Kantoff PW, Anonymous00198. · Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. · Urology. · Pubmed #18291508 No free full text.

Abstract: OBJECTIVES: It has been hypothesized that abnormal p53 protein expression is associated with a worse prognosis after radiation (RT) and androgen suppression therapy (AST). This hypothesis was prospectively tested. METHODS: Between May 1997 and April 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered on a study evaluating whether the endorectal magnetic resonance imaging (eMRI)-defined change in tumor volume (TV) during neoadjuvant (n) AST was associated with prostate-specific antigen (PSA) outcome. Of these, 141 had sufficient tissue to perform immunohistochemical detection of the p53 protein expression status and 113 had complete eMRI information. Multivariable Cox regression analysis was used to assess whether p53 protein expression status predicted time to PSA failure adjusting for known prognostic factors. RESULTS: After a median follow-up of 6.9 years and adjusting for PSA level, Gleason score, clinical stage, and eMRI-defined TV change during nAST, men with abnormal compared with normal p53 expression were at increased risk of PSA failure (hazard ratio [HR]: 2.8; 95% confidence interval [CI]: 1.3-5.9; P = 0.008 for the 141; HR: 2.4; 95% CI: 1.1-5.4; P = 0.03 for the 113). Adjusted estimates of PSA failure were significantly higher (P = 0.03) in men with abnormal compared with normal p53 expression. At 5 years, these respective estimates were 33% and 18%. CONCLUSIONS: Maximizing local control and randomized trials evaluating the impact on survival of adding novel agents to maximal local therapy are warranted in men whose prostate cancer demonstrates abnormal p53 expression.

Pomerantz M, Manola J, Taplin ME, Bubley G, Inman M, Lowell J, Beard C, Kantoff PW, Oh WK. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. · J Urol. · Pubmed #17509304 No free full text.

Abstract: PURPOSE: Although estrogens have known antitumor activity in androgen independent prostate cancer, the best studied agent, diethylstilbestrol, is no longer commercially available in the United States. We tested 2 doses of the conjugated estrogen Premarin(R) in patients with androgen independent prostate cancer to determine the efficacy and safety of this widely available medication. MATERIALS AND METHODS: A total of 45 patients with progressive androgen independent prostate cancer were randomly assigned to receive Premarin 1.25 mg once (17) or 3 times (28) daily. Warfarin 1 mg daily was administered to all patients to minimize risk of thromboembolism. Low dose prophylactic breast irradiation was administered to most patients. RESULTS: Of the patients receiving high dose Premarin 25% achieved a 50% or greater reduction in prostate specific antigen. No patients treated with low dose Premarin reached a 50% reduction in prostate specific antigen. After 3 months of treatment, 11 patients (39.3%) on the high dose arm and 6 patients (35.3%) on the low dose arm showed no signs of progression. Three patients (6.7%) had a thromboembolic event. No significant gynecomastia was noted. A significant difference in dehydroepiandrosterone sulfate levels was detected between those who did and did not respond to Premarin (p = 0.03). CONCLUSIONS: High dose Premarin resulted in prostate specific antigen decreases of 50% or greater in 25% of patients with androgen independent prostate cancer. More than a third of patients receiving high or low dose Premarin maintained stable disease for at least 3 months. With concurrent warfarin 1 mg treatment, 6.7% experienced thromboembolic complications. Premarin 1.25 mg 3 times daily is a reasonable therapeutic option for patients with androgen independent disease.

Febbo PG, Richie JP, George DJ, Loda M, Manola J, Shankar S, Barnes AS, Tempany C, Catalona W, Kantoff PW, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts 02115, USA. · Clin Cancer Res. · Pubmed #16033841 links to  free full text

Abstract: PURPOSE: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. EXPERIMENTAL DESIGN: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. RESULTS: The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. CONCLUSIONS: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.

Oh WK, Hagmann E, Manola J, George DJ, Gilligan TD, Jacobson JO, Smith MR, Kaufman DS, Kantoff PW. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Massachusetts 02115, USA. · Clin Cancer Res. · Pubmed #15671557 links to  free full text

Abstract: PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.

Smith MR, Manola J, Kaufman DS, George D, Oh WK, Mueller E, Slovin S, Spiegelman B, Small E, Kantoff PW. · Division of Hematology and Medical Oncology, Massachusetts General Hospital, Boston 02114, USA. · Cancer. · Pubmed #15468186 links to  free full text

Abstract: BACKGROUND: The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. METHODS: Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases. RESULTS: One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups. CONCLUSIONS: Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting.

D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. · Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Mass 02215, USA. · JAMA. · Pubmed #15315996 links to  free full text

Abstract: CONTEXT: Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events. OBJECTIVE: To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer. DESIGN, SETTING, AND PATIENTS: A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of AST (n = 102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease. MAIN OUTCOME MEASURES: Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival. RESULTS: After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P =.04), lower prostate cancer-specific mortality (P =.02), and higher survival free of salvage AST (P =.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group. CONCLUSION: The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.

Oh WK, Kantoff PW, Weinberg V, Jones G, Rini BI, Derynck MK, Bok R, Smith MR, Bubley GJ, Rosen RT, DiPaola RS, Small EJ. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · J Clin Oncol. · Pubmed #15289492 No free full text.

Abstract: PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC). PATIENTS AND METHODS: A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES. RESULTS: Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots. CONCLUSION: PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.