Prostatic Neoplasms: Regan MM

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.

Daskivich TJ, Regan MM, Oh WK. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. · J Urol. · Pubmed #17070213 No free full text.

Abstract: PURPOSE: Although prostate specific antigen doubling time is widely used to predict outcomes such as time to progression and prostate cancer specific mortality, clinicians may be unaware of the impact of method on prostate specific antigen doubling time calculation. We present a critical review of the literature to assess the diversity of methods used to calculate prostate specific antigen doubling time. We then describe the need for methodological consistency with the literature by showing examples from our clinical experience at our institution. MATERIALS AND METHODS: A comprehensive review of articles evaluating prostate specific antigen doubling time as a prognostic and predictive indicator in various prostate cancer disease states was performed using PubMed. Case examples were drawn from the prostate cancer database at our institution. The database is a registry of 4,651 patients with prostate cancer who have been seen at our institution since 1998. RESULTS: The methodology of prostate specific antigen doubling time calculation is inconsistent in the literature. Based on our experience and data presented in the literature the different methods in the literature are not always interchangeable. Small deviations from the methods outlined in a study can sometimes lead to wide variation in calculated prostate specific antigen doubling time. This variation of up to several months or longer is large enough to cause errors in assessment of prognosis and can even lead to incorrect management. The rules for prostate specific antigen doubling time calculation found in the literature can be categorized into 4 parameter groups, including method, calculation interval, data acquisition rules and data analysis rules. Case examples illustrate the importance of adherence to the literature with regard to each parameter. CONCLUSIONS: Consistency with the literature in methodological elements of prostate specific antigen doubling time calculation is essential for the accurate calculation of prostate specific antigen doubling time. Clinicians and researchers should understand how methodological differences influence the value of calculated prostate specific antigen doubling time for purposes of patient care and research.

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, Xie W, Bubley GJ, Ernstoff MS, Walsh W, Morganstern DE, Regan MM. · Dana-Farber Cancer Institute, Boston, MA 02115, USA. · J Clin Oncol. · Pubmed #17135641 No free full text.

Abstract: PURPOSE: Androgen-deprivation therapy (ADT) is effective for relapsed prostate cancer, but is rarely curative. The purpose of this trial was to determine the feasibility, toxicity, and prostate-specific antigen (PSA) response of chemotherapy and limited ADT for men with PSA relapse. PATIENTS AND METHODS: Eligible men had an increasing PSA and no metastases after prostatectomy and/or radiation for localized disease. Treatment consisted of four cycles of docetaxel (70 mg/m2) every 21 days and estramustine 280 mg tid on days 1 through 5. After chemotherapy, goserelin acetate and bicalutamide were prescribed for 15 months. RESULTS: Sixty-two patients were enrolled. A complete PSA response (CR) was defined as PSA at or below the assay-specific lower limit. The proportion of patients with CR after chemotherapy, after ADT, and at 1 year after completion of ADT was 53%, 63%, and 36%, respectively. Testosterone was more than 100 ng/dL (median, 250 ng/dL) 1 year after completion of ADT in 97% of patients. Patients with a PSA less than 3.0 ng/mL at enrollment had a significantly longer time to progression (TTP; P = .0004). Of 56 patients who were observed at least 1 year after completion of ADT, 23 (41%) have not experienced progression as of their last follow-up. The median TTP is 34 months from treatment initiation (maximum, 74 months free from progression). CONCLUSION: Chemotherapy plus ADT was feasible for early prostate cancer relapse. Forty-one percent of men who are at least 1 year after completion of ADT with recovered testosterone have not experienced progression. This approach is being tested in a randomized trial with investigation of predictors of response.

Spentzos D, Mantzoros C, Regan MM, Morrissey ME, Duggan S, Flickner-Garvey S, McCormick H, DeWolf W, Balk S, Bubley GJ. · Divisions of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. · Clin Cancer Res. · Pubmed #12960113 links to  free full text

Abstract: PURPOSE: The effects of a low-fat diet or a low-fat diet with the addition of a soy supplement were investigated in a pilot Phase II study for asymptomatic, hormonally naive prostate cancer patients with rising prostate-specific antigen (PSA) levels. Experimental Design: A two-step intervention was implemented. During step 1 patients were begun on a low-fat diet with a goal to reduce fat intake to 15% of total daily calories. On PSA progression, a soy protein supplement was added to the diet (step 2). The primary end point was PSA reduction by 50%. Secondary end points were PSA doubling time and time to progression (TTP). Serum was analyzed for changes in the sex hormone and insulin-like growth factor (IGF-I) axes. RESULTS: Among 18 evaluable patients, (median follow-up on study 10.5 months), no patient on either step had a PSA reduction by 50% at any time. There was a trend toward a longer PSA doubling time (P = 0.06) and a prolongation in estimated median TTP of approximately 3 months (P = 0.018) during step 2 compared with step 1 of the study. During step 1, free testosterone levels decreased by 5% (P < 0.01), and during step 2, IGF-I levels increased by 22% (P = 0.02). CONCLUSIONS: A low-fat diet with the subsequent addition of a soy supplement did not result in a significant decline in PSA levels. The addition of soy protein had a modest effect on TTP. A potentially undesirable effect associated with the administration of soy was an increase in IGF-I serum levels.

Choueiri TK, Xie W, D'Amico AV, Ross RW, Hu JC, Pomerantz M, Regan MM, Taplin ME, Kantoff PW, Sartor O, Oh WK. · Dana-Farber Cancer Institute/Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Cancer. · Pubmed #19152438 No free full text.

Abstract: BACKGROUND: The objective of this study was to evaluate the relation between the kinetics of prostate-specific antigen (PSA) decline after the initiation of androgen-deprivation therapy (ADT) and overall survival (OS) in men with metastatic, hormone-sensitive prostate cancer (HSPC). METHODS: The authors' institutional database was used to identify a cohort of men with metastatic HSPC who were treated with ADT. Patients were included if they had at least 2 serum PSA determinations before PSA nadir and at least 1 serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN), and PSA decline (PSAD) in relation to OS were analyzed. RESULTS: One hundred seventy-nine patients were identified, and they had a median follow-up after ADT initiation of 4 years. The median OS after ADT initiation was 7 years. The median PSA level at ADT initiation and PSA nadir were 47 ng/mL and 0.28 ng/mL, respectively. On univariate analysis: TTN <6 months, PSAD >52 ng/mL per year, PSA nadir >or=0.2 ng/mL, PSA >or=47.2 ng/mL at ADT initiation, and Gleason score >7 were associated with shorter OS. On multivariate analysis, TTN <6 months, Gleason score >7, and PSA nadir >or=0.2 ng/mL independently predicted shorter OS. CONCLUSIONS: To the authors' knowledge, this was the first report to demonstrate that a faster time to reach a PSA nadir after the initiation of ADT was associated with shorter survival duration in men with metastatic HSPC. These results need confirmation but may indicate that a rapid initial response to ADT indicates more aggressive disease.

Sher DJ, Mantzoros C, Jacobus S, Regan MM, Lee GS, Oh WK. · Harvard Radiation Oncology Program, Boston, Massachusetts, USA. · Urology. · Pubmed #19036418 No free full text.

Abstract: OBJECTIVES: To analyze the relationship between plasma testosterone and estradiol levels on prostate biopsy and radical prostatectomy Gleason scores in a cohort of patients with newly diagnosed prostate cancer. METHODS: Patients with prostate cancer evaluated at the Dana-Farber Cancer Institute from 2001 to 2005 who were enrolled in a prospective sample banking protocol were eligible for this study. Stored plasma was processed for total testosterone, total estradiol, and sex hormone-binding globulin levels using enzyme-linked immunosorbent assays. The frequency of high-grade biopsy and radical prostatectomy Gleason scores (>6) was the primary endpoint. Univariate and multivariate logistic regression analyses were performed to determine the relationship between the hormone levels and high-grade Gleason scores while adjusting for sex hormone-binding globulin, age, body mass index, and prostate-specific antigen. RESULTS: A total of 539 patients were included in this study, 199 of whom underwent radical prostatectomy. The median prostate-specific antigen level was 5.1 ng/dL, and 67% of the cancers were not palpable. The Gleason score was 2-6, 7, and 8-10 in 53%, 37%, and 10% of the cancers, respectively. On univariate analysis of the high-grade biopsy and radical prostatectomy Gleason score, the total testosterone, total estradiol, and estradiol-to-testosterone ratio were not significant as continuous or categorical variables. Adjusting these results for sex hormone-binding globulin level, body mass index, age, and prostate-specific antigen level did not change the conclusions, and these results were unchanged when categorizing high-grade prostate cancer as Gleason score 8-10. CONCLUSIONS: No relationship was found between the circulating steroid hormone levels and the Gleason score in this cohort.

Sher DJ, Oh WK, Jacobus S, Regan MM, Lee GS, Mantzoros C. · Harvard Radiation Oncology Program, Boston, Massachusetts 02115, USA. · Prostate. · Pubmed #18646046 No free full text.

Abstract: BACKGROUND: Obesity is associated with prostate cancer (PCA) grade, but the mechanism behind this relationship is not understood. Adiponectin is an adipokine that has been linked with the development of hormonally sensitive carcinomas, including prostate cancer. We evaluated the relationship between serum adiponectin and Gleason score (GS) in a prospective series of patients seen in a single institution. METHODS: Localized PCA patients evaluated at Dana-Farber Cancer Institute between 2001 and 2005 who enrolled in a prospective serum banking protocol were eligible for this study. Patients with prior hormonal therapy and/or metastatic disease were excluded. High-grade disease was defined as biopsy or radical prostatectomy (RP) GS of 7 or higher. Logistic regression models were used to assess the relationship between high-grade disease and adiponectin levels while adjusting for other potential prognostic variables. RESULTS: There were 539 patients included in this study, of whom 199 had undergone RP. Median age was 60 years. Median PSA was 5.1 ng/dl. Biopsy GS of 7 or higher was seen in 46.9% of patients. For biopsy GS, higher PSA, older age, and higher BMI were significantly associated with increased odds of GS 7 or higher, but adiponectin was not. In men undergoing RP, there was a significant inverse relationship between pathologic GS and adiponectin dichotomized at the median, due to a significantly higher rate of upgrading in patients with lower adiponectin (P = 0.014). CONCLUSIONS: Although there was no association between biopsy GS and adiponectin, in patients who had undergone RP, lower adiponectin was independently associated with high-grade prostate cancer.

Ross RW, Xie W, Regan MM, Pomerantz M, Nakabayashi M, Daskivich TJ, Sartor O, Taplin ME, Kantoff PW, Oh WK. · Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #18293426 links to  free full text

Abstract: BACKGROUND: The purpose of this study was to compare predictive factors for the efficacy of androgen deprivation therapy (ADT) in men with hormone-sensitive prostate cancer (HSPC) either with (M+) or without (M-) metastases. METHODS: A cohort of prostate cancer patients was identified from a medical oncology practice treated with ADT for presumed nonlocalized prostate cancer, evaluated the efficacy of ADT using prostate-specific antigen (PSA) time to progression (TTP) and compared factors associated with TTP in M- and M+ patients. RESULTS: In this 553 patient cohort 51% were M- and 49% M+. The median TTP on ADT for the M- group was 33.2 months, versus 15.9 months in the M+ group (P<.0001). In multivariate analyses, lower biopsy Gleason score (GS), the absence of metastases, and lower serum PSA at ADT initiation all were associated with the efficacy of ADT. The association between GS and TTP was confined to M+ patients, whereas the association between PSA at ADT initiation and TTP was confined to M- patients. Use of ADT as part of local treatment was associated with a shortened TTP in both groups (hazard ratio [HR], 1.45, 95% confidence interval [CI], 1.10-1.91). CONCLUSIONS: In this large, retrospective study of HSPC patients in a medical oncology practice treated with ADT for nonlocalized prostate cancer, we found factors predicting efficacy of this treatment differed based on whether metastases were present at ADT initiation. The use of ADT as a part of local therapy was associated with a significantly decreased TTP, regardless of metastatic disease status.

Ross RW, Oh WK, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin ME, Regan MM, Kantoff PW, Freedman M. · Dana-Farber Cancer Institute, Dana 710-C, 44 Binney St, Boston, MA 02115, USA. · J Clin Oncol. · Pubmed #18281655 No free full text.

Abstract: PURPOSE: Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. PATIENTS AND METHODS: A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. RESULTS: Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001). CONCLUSION: This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual's response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic -genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic -these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. · BJU Int. · Pubmed #18184327 No free full text.

Abstract: OBJECTIVES: To evaluate the efficacy of docetaxel/carboplatin (DC)-based chemotherapy as first- and second-line chemotherapy for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: We retrospectively identified all patients with HRPC treated with DC-based chemotherapy at the Dana-Farber Cancer Institute. Regimens either included estramustine (EDC) or not (DC). We identified patients who received EDC as first-line chemotherapy and patients who received DC as second-line or subsequent chemotherapy. Patients treated with EDC received 20-70 mg/m(2) docetaxel every 1-4 weeks, estramustine 140 mg three times daily and carboplatin (area under the curve, AUC), (4-6) every 3-4 weeks. Patients treated with DC received docetaxel 50-70 mg/m(2) and carboplatin AUC (4-6) every 3-4 weeks. RESULTS: In all, the study included 54 patients; 24 received EDC and 30 DC (median age 62.8 and 66.9 years, respectively); their prostate-specific antigen (PSA) level at the start of chemotherapy was 112.7 and 213.3 ng/mL, respectively. There were declines of >or=50% in PSA level in 88% and 20% in the two groups, respectively. The median overall survival was 17.7 and 14.9 months in the EDC and DC groups, respectively. The most common reversible grade 4 toxicity with either regimen was neutropenia (4% and 7% in EDC and DC, respectively). CONCLUSIONS: DC-based chemotherapy is well tolerated and active in HRPC. Adding carboplatin to docetaxel provides an additional activity in 20% of patients as a second-line or subsequent chemotherapy.

Xie W, Nakabayashi M, Regan MM, Oh WK. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #17960608 links to  free full text

Abstract: BACKGROUND: Higher prostate-specific antigen (PSA) and alkaline phosphatase (ALK-P) levels predicted worse survival in men with metastatic hormone-refractory prostate cancer (HRPC). In the current study, the authors evaluated the combined effects of PSA and ALK-P on survival. METHODS: Two hundred twenty-four men who had HRPC with bone metastases and who were receiving chemotherapy were identified, and 143 of those men had data available on both ALK-P and PSA levels at chemotherapy initiation. The primary endpoint of the study was overall survival (OS) after chemotherapy. The men were dichotomized into normal and abnormal ALK-P groups according to levels based on institutional normal ranges. The effect of PSA was evaluated as both a categorical value and a continuous value using Cox regression. RESULTS: Eighty-nine of 143 patients (62%) had elevated ALK-P levels. The median PSA was 147 ng/mL (93 ng/mL in patients with normal ALK-P, 171 ng/mL in patients with elevated ALK-P). At a median follow-up of 30 months after chemotherapy initiation, 93 patients had died. The median OS after chemotherapy was 15.8 months (95% confidence interval, 12.8-18.4 months) and was significantly longer if ALK-P was in the normal range (21.3 months vs 14 months; P = .005). For the group with normal ALK-P levels, the median OS was 12.5 months, 24.5 months, and 36.9 months for patients with low, medium, and high PSA levels, respectively. In contrast, the effect of PSA on survival was not as evident in the group with elevated ALK-P levels (16.5 months vs 11.9 months vs 12.1 months, respectively; P = .14 for interaction). Age-adjusted multivariate analysis demonstrated statistically significant interactions of PSA and ALK-P with OS (P = .02). CONCLUSIONS: ALK-P significantly predicted OS in men with HRPC who had bone metastases. In patients with normal ALK-P levels, higher PSA levels were associated with improved survival.

Daskivich TJ, Regan MM, Oh WK. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. · Urology. · Pubmed #17905110 No free full text.

Abstract: OBJECTIVES: To investigate whether the prostate-specific antigen doubling time (PSADT) and velocity (PSAV) at the emergence of androgen-independent prostate cancer (AIPC) provide independent prognostic information. METHODS: Patients treated with chemotherapy were identified in an institutional prostate cancer database. The PSADT was calculated using PSA values from the first increase greater than the PSA nadir during androgen deprivation therapy until the start of the next treatment. The PSAV was calculated using the same PSA values over time. The association with overall survival (OS) from the date of AIPC was analyzed using the Cox proportional hazards regression model. RESULTS: PSADT and PSAV at the emergence of AIPC were calculated in 91 patients. On univariate analysis, a shorter PSADT and greater PSAV were associated with decreased OS. On multivariate analysis, a PSADT of 12 weeks or less (hazard ratio 3.2), PSAV greater than 10 ng/mL/yr (hazard ratio 2.8), PSA nadir greater than 0.2 with ADT, low hemoglobin, and type of chemotherapy persisted as significant predictors of decreased OS (each P <0.01). A rapid PSADT (12 weeks or less) and high PSAV (greater than 10 ng/mL/yr) predicted for the worst prognosis (25 months median OS, unadjusted). A slow PSADT (greater than 12 weeks), and low PSAV (10 ng/mL/yr or less) predicted for the best prognosis (75 months); other combinations had intermediate prognoses (49 and 50 months). CONCLUSIONS: The PSAV at the start of AIPC contributes prognostic information independent of the PSADT in patients receiving chemotherapy. Future studies should investigate the relative contribution of each of these factors in predicting survival.

Nakabayashi M, Ling J, Xie W, Regan MM, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Cancer J. · Pubmed #17476141 No free full text.

Abstract: BACKGROUND: Vinorelbine (VRL) in combination with estramustine has known efficacy in the initial chemotherapeutic management of hormone-refractory prostate cancer (HRPC). However, little is known about the efficacy of VRL as second-line chemotherapy in HRPC. METHODS: We retrospectively identified patients with HRPC treated in a single institution with VRL as second-line chemotherapy with or without estramustine. Patient baseline characteristics, declines in prostate-specific antigen, performance status, toxicities, and survival were assessed. RESULTS: Thirty-nine patients were treated with VRL between 1999 and 2005. Twenty-one patients (54%) received single-agent VRL and 18 patients (46%) had concomitant estramustine. Seven patients (17.9%, 95% confidence interval 7.5%-33.6%) treated with VRL experienced prostate-specific antigen declines >or=50%. Median duration of therapy was 1.4 months (range 0.2-14.0 months). Median overall survival was 6.9 months (range 1.4-29.9 months); it was 16.1 month in responders and 5.5 months in nonresponders. Median survival was significantly longer in patients with VRL and estramustine than in patients who received VRL alone (8.5 months versus 4.1 months, P=0.05). The most common reversible adverse effect of VRL was grade 1 or 2 fatigue observed in 36% of patients. CONCLUSIONS: As a second-line chemotherapy, VRL demonstrated moderate activity and was well tolerated in patients with HRPC. Patients treated with the combination of VRL and estramustine experienced a longer survival than those receiving VRL alone.

Nakabayashi M, Xie W, Regan MM, Jackman DM, Kantoff PW, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #16862573 links to  free full text

Abstract: BACKGROUND: High-dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen-independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low-dose ketoconazole (LDK). To the authors' knowledge, relatively little is known regarding the efficacy of LDK in AIPC. The efficacy of LDK and of subsequent dose escalation from LDK to HDK was evaluated as secondary hormonal therapy in patients with AIPC. METHODS: In a single institution, patients with AIPC treated with LDK (at a dose of 200 mg orally 3 times daily) as secondary hormonal therapy with or without concomitant steroids were retrospectively identified. In addition, patients were identified who received dose escalation to HDK (400 mg orally 3 times daily) after experiencing a rising prostate-specific antigen (PSA) level. RESULTS: Thirty-nine of 138 eligible patients (28.3%, 95% confidence interval [95% CI], 20.9-36.6%) treated with LDK experienced PSA declines > or =50%. The median time to disease progression or dose escalation on LDK was 3.2 months (range, 0.1(+)-61 months). Dose escalation to HDK was subsequently performed in 55 patients (39.9%), 7 of whom (12.7%) demonstrated a subsequent PSA decline > or =50%. A longer duration of primary androgen deprivation therapy and total duration of all previous hormonal therapies was associated with a longer time to progression with LDK (P < .05). The most common reversible adverse effect of LDK was NCI Common Toxicity Criteria Grade 1 or 2 fatigue (12.3%). CONCLUSIONS: LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, but with less toxicity. Although uncommon, additional durable responses occurred in some patients after dose escalation.

San Francisco IF, Regan MM, Dewolf WC, Olumi AF. · Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. · J Urol. · Pubmed #16515994 No free full text.

Abstract: PURPOSE: We determined the relationship between age adjusted free T, and stage, grade and the biochemical-free survival rate in patients with surgically treated prostate cancer. MATERIALS AND METHODS: A retrospective cohort study was done between 1995 and 2001 in 333 patients treated for clinically localized prostate cancer with radical retropubic prostatectomy by a single surgeon at our institution. The study cohort consisted of 279 patients (84%) who had free T levels available. Free T was assessed by single cutoff value of 1.5 ng/dl or less, as suggested by the assay manufacturer, or by age adjusted free T. The relationship of low free T as a single cutoff value and age adjusted reference ranges with clinical and pathological measures of disease progression were assessed using the Fisher exact and Wilcoxon rank sum tests with the outcome assessed by the log rank test. RESULTS: Using the assay manufacturer suggested single cutoff value of 1.5 ng/dl or less to define low free T 57% of patients with prostate cancer in the cohort were categorized as hypogonadal. However, using age adjusted free T reference ranges only 2.5% of patients with prostate cancer were categorized as hypogonadal, which is more logical and representative of clinically significant hypogonadism in the general population. Poorly differentiated prostate cancer was associated with low free T when measured by a single cutoff value of 1.5 ng/dl or less, or by age adjusted free T (p = 0.017 and 0.04, respectively). CONCLUSIONS: Low age adjusted free T as well as single cutoff free T correlates with poorly differentiated prostate cancer in surgically treated patients.

Nakabayashi M, Regan MM, Lifsey D, Kantoff PW, Taplin ME, Sartor O, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Haber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. · BJU Int. · Pubmed #16153200 No free full text.

Abstract: OBJECTIVE: To evaluate the activity of nilutamide as secondary hormonal therapy in patients with androgen-independent prostate cancer (AIPC), as treatment options are limited for these patients and secondary hormonal therapy with antiandrogens has advantages, including low toxicity, oral administration and high patient acceptance. PATIENTS AND METHODS: We retrospectively identified 45 patients with AIPC who were treated with nilutamide as secondary hormonal therapy in two institutions. The decrease in prostate-specific antigen (PSA) levels, side-effects of treatment, and the relationship between baseline characteristics, type and duration of previous therapy and response to nilutamide were assessed. Most patients received oral nilutamide at 150 mg/day. RESULTS: Eighteen of 45 evaluable patients (40%) had a PSA level decrease of > or = 50%. Responders (PSA decline > or = 50%) had a median (range) time to progression of 4.4 (0.31-44.7) months. There were responses to nilutamide whether used as the second to fifth line of hormonal therapy. There were no differences in response to nilutamide based on clinical stage, type of local therapy, PSA level at diagnosis or initiation of nilutamide, or type of previous antiandrogen therapy. Responders were more likely to have received monotherapy with luteinizing hormone-releasing hormone analogues or orchidectomy as first-line hormonal treatment (P = 0.02). The most common reversible adverse effects were mild to moderate visual adaptation effects, reported in 20% of patients. CONCLUSIONS: Nilutamide appears to be an effective secondary hormonal therapy in patients with AIPC and is associated with a mild toxicity profile.

Tay MH, Kaufman DS, Regan MM, Leibowitz SB, George DJ, Febbo PG, Manola J, Smith MR, Kaplan ID, Kantoff PW, Oh WK. · Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Ann Oncol. · Pubmed #15151957 links to  free full text

Abstract: BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

San Francisco IF, Regan MM, Olumi AF, DeWolf WC. · Division of Urologic Surgery and Biometrics Center (MMR), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. · J Urol. · Pubmed #15017206 No free full text.

Abstract: PURPOSE: We examined the prognostic significance of clinical and pathological variables on outcome following radical retropubic prostatectomy (RRP) in a cohort of patients in the post-prostate specific antigen (PSA) era. MATERIALS AND METHODS: We reviewed the clinical and pathological data on a cohort of 476 patients who underwent RRP for localized prostate cancer between January 1990 and July 2001 by 1 urologist (WCD). Median age, preoperative PSA and followup were 61 years, 5.8 ng/ml and 49 months, respectively. We used Cox proportional hazard modeling to evaluate the prognostic significance of clinical and pathological variables for cancer recurrence, defined as 2 successive PSA determinations 0.3 ng/ml or greater. RESULTS: Of the 476 patients 53 (11%) had recurrence. Estimated cancer nonprogression probability was 86% (95% CI 83 to 90) and 76% (95% CI 68 to 86) at 5 and 10 years, respectively. Two multivariate analyses were performed. The first analysis, using only preoperative indicators, found that the percent of biopsy cores positive for cancer and biopsy Gleason score were the best predictive indicators of recurrence. The second multivariate analysis, using preoperative and postoperative indicators, found that the percent of biopsy cores positive for cancer, RRP Gleason score and the combined pathological stage/margin status variable were the best predictive indicators of recurrence. PSA was not found to be an important predictor of recurrence on either multivariate analysis. Patients with a percent of biopsy cores in the upper half of the distribution (greater than 28% positive) were at significantly increased risk for recurrence compared with those in the lower half of the distribution (28% or less positive) (HR 3.86, p <0.001). CONCLUSIONS: The percent of cores positive for cancer was a better predictor of cancer recurrence than PSA in this post-PSA era RRP series. In addition, surgical Gleason score and pathological stage/surgical margins were also independent predictors of cancer recurrence after RRP. These 3 predictors are displayed in a nomogram-type format to summarize estimated 5 and 10-year recurrence-free probabilities.

George DJ, Regan MM, Oh WK, Tay MH, Manola J, Decalo N, Duggan S, Dewolf WC, Kantoff PW, Bubley GJ. · Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Urology. · Pubmed #14972483 No free full text.

Abstract: OBJECTIVES: To measure the change in plasma vascular endothelial growth factor (VEGF) levels after radical prostatectomy (RP) and to examine the association of pre-RP VEGF levels with known prognostic factors. METHODS: Plasma was collected from patients in two separate cohorts. The first cohort included 86 patients who consented to give blood before and after RP. The second cohort consisted of 280 plasma samples, obtained from untreated patients with clinically localized prostate cancer. Plasma VEGF levels were measured by enzyme-linked immunosorbent assay. The change in plasma VEGF before and 6 to 8 weeks after RP was analyzed using a Wilcoxon signed rank test. The associations between the pre-RP VEGF levels and prognostic factors were assessed with the Spearman correlation coefficient and the Kruskal-Wallis test. RESULTS: In a cohort of 86 patients with clinically localized prostate cancer, the median preoperative VEGF level was 49.8 pg/mL. The median level 1 month after surgery was significantly lower at 39.1 pg/mL (P = 0.006, 20% decrease). A repeat analysis 6 months or more after surgery demonstrated that the percentage of decrease in the plasma VEGF levels persisted. Plasma VEGF levels were also measured in a separate cohort of 280 patients with localized prostate cancer and demonstrated no statistically significant association with risk groups or known tumor-associated prognostic factors. CONCLUSIONS: These results suggest that the prostate gland itself may be a significant source of systemic VEGF and raises the possibility that elevated plasma VEGF levels could be a reflection of prostatic VEGF production.

San Francisco IF, Olumi AF, Yoon JH, Regan MM, DeWolf WC. · Division of Urologic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. · BJU Int. · Pubmed #14632848 No free full text.

Abstract: OBJECTIVE: To examine the utility and prognostic significance of enzymatic serum acid phosphatase (total acid phosphatase, TAP, and prostatic fraction of acid phosphatase, PFAP) and alkaline phosphatase (ALP) for staging, grading and outcome of patients who underwent radical retropubic prostatectomy (RRP) after the introduction of prostate-specific antigen (PSA) testing. PATIENTS AND METHODS: In all, 180 consecutive patients with clinically localized prostate cancer who underwent RRP with standard obturator lymph-node dissection between 1 January 1990 and 31 December 1995 were evaluated. Levels of TAP of > 5.4 IU/L, PFAP of > 1.2 IU/L and ALP of > 120 IU/L were classified as abnormally high. The relationship between abnormally high values and prostate cancer stage, grade and time to recurrence after RRP were calculated. The median follow-up was 86 months (approximately 7 years). RESULTS: Of the 180 patients, information about preoperative TAP, PFAP and ALP were available in 164, 163 and 154, respectively; TAP was abnormal in seven (4%), PFAP in 33 (20%) and ALP in only 13 (8%). None of the markers examined was associated with any variables of disease severity, as measured by pathological stage, Gleason score, perineural invasion, capsular penetration, positive margins, seminal vesicle involvement, and lymph node involvement. Abnormal TAP, PFAP or ALP were not associated with recurrence (P = 0.96, 0.45 and 0.41, respectively). In contrast, a PSA level of > 4 ng/mL was predictive of recurrence after RRP (P < 0.001). In the sample overall, 25 (14%) of the patients had recurrence and only one died from prostate cancer. CONCLUSIONS: Preoperative enzymatic serum TAP, PFAP and ALP levels are not predictors of the severity of disease or PSA disease-free recurrence after RRP.

Oh WK, Tully P, Kantoff PW, Regan MM. · Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #12712468 links to  free full text

Abstract: BACKGROUND: Attitudes toward the use of chemotherapy in patients with prostate carcinoma have changed as new therapeutics have demonstrated efficacy. This is important as randomized trials using chemotherapy are proposed. The authors used a questionnaire to investigate the attitudes of physicians in the New England area who care for patients with advanced prostate carcinoma. METHODS: A 15-question survey was developed and mailed in the year 2000. No monetary incentives were used to encourage return of surveys. Baseline demographic data were obtained, including type of practice and number of patients with prostate carcinoma seen. Urologists, radiation oncologists, and medical oncologists were asked whether they had recommended chemotherapy for patients with prostate carcinoma, what they perceived as the effectiveness of specific drugs, what concerns they had regarding chemotherapy, and the appropriateness of chemotherapy in three hypothetical patient scenarios. RESULTS: Of 1068 surveys that were delivered to practicing physicians, 232 surveys (22%) were returned and evaluable. Forty-six percent of respondents were urologists, 41% were medical oncologists, and 10% were radiation oncologists. Eighty-seven percent of respondents had recommended cytotoxic chemotherapy to their patients. Four agents were rated as moderately effective to very effective by 41-60% of respondents who rated effectiveness: estramustine, mitoxantrone, paclitaxel, and docetaxel. In three hypothetical patient scenarios of hormone-refractory prostate carcinoma, only one patient was judged as an appropriate candidate for chemotherapy. In a multivariate analysis, female physicians and physicians with practices comprised of > 25% patients with hormone-refractory prostate carcinoma were more likely to recommend chemotherapy. Concerns regarding severe toxicity and lack of benefit were among the most influential on respondent decisions to use chemotherapy. CONCLUSIONS: Most physicians who cared for patients with prostate carcinoma had recommended chemotherapy for patients with hormone-refractory disease. There were differences between specialties regarding the likelihood of recommending chemotherapy and clinical judgment regarding which patients were appropriate candidates for chemotherapy.

Ung JO, San Francisco IF, Regan MM, DeWolf WC, Olumi AF. · Department of Urologic Surgery and Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · J Urol. · Pubmed #12478120 No free full text.

Abstract: PURPOSE: We investigated the relationship between prostate volume and cancer detection by needle biopsy, and determined the effect of an increased number of cores on the sampling error of needle biopsy on large prostate glands. MATERIALS AND METHODS: The study cohort included 750 consecutive patients who underwent first time transrectal ultrasound guided prostate needle biopsy from January 1995 to August 2001. Prostate volumes were divided into quartiles (13 to 34, 34.1 to 45, 45.1 to 64 and 64.1 to 244 cc). Multivariate analysis controlling for age, prostate specific antigen (PSA) and biopsy indication was performed to determine the effect of the number of cores and prostate volume on prostate cancer detection. RESULTS: Patients diagnosed with prostate cancer were older (p = 0.0035) and had higher PSA levels (p = 0.0002) than those with no cancer on biopsy. Decreasing cancer detection rates were seen with increasing prostate volume (p = 0.0074). The OR of detection for each additional core was 0.99 (95% CI 0.93, 1.06), suggesting that increasing the number of biopsy cores did not increase the rate of prostate cancer detection. Multivariate analysis revealed that patients with larger prostates had the same, or possibly lower, cancer detection rate as the number of biopsy cores was increased. Patients with larger prostates were older (p <0.0001), had higher PSA levels (p <0.0001) and were even more likely to have undergone biopsy for increased PSA rather than abnormal digital rectal examination alone (p <0.0001). CONCLUSIONS: Our study suggests that the lower cancer detection rate for men with large prostates may be due to a decrease in the use of increased serum PSA for prostate cancer detection in larger prostates in addition to other factors such as sampling error. Increased serum PSA levels in cases of larger prostates, although a risk factor for prostate cancer warranting biopsy, may also be due to nonmalignant sources such as benign prostatic hyperplasia.

Bubley GJ, Balk SP, Regan MM, Duggan S, Morrissey ME, Dewolf WC, Salgami E, Mantzoros C. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. · J Urol. · Pubmed #12394769 No free full text.

Abstract: PURPOSE: Elevated serum levels of insulin-like growth factor-1 (IGF-1) have been consistently shown to be a risk factor for prostate cancer. Alterations in serum IGF-1 binding proteins 1 to 3 have also been associated with prostate cancer risk. A potentially important complication in these studies is that prostate tissue, perhaps especially malignant prostate tissue, may secrete IGF-1 and its binding proteins into serum. In fact, it is possible that altered levels of these proteins observed in subjects at risk for prostate cancer are the result of prostate cancer rather than related to its cause. MATERIALS AND METHODS: The contribution of prostate cancer to serum levels of IGF-1 and IGF-1 binding proteins was determined by analyzing serum samples from 86 patients with prostate cancer 2 weeks before and 8 weeks after radical prostatectomy. Preoperative and postoperative values for IGF-1 and its 3 major binding proteins were analyzed using univariate and multivariate analysis models. RESULTS: On univariate analysis significant increases and not decreases in IGF-1, IGF binding protein-1 and 3 were observed after prostatectomy. On multivariate analysis a significant post-prostatectomy increase was observed for IGF-1 binding proteins 1 and 3 but the increase in IGF-1 was not significant. CONCLUSIONS: Increased levels of IGF-1 and IGF-1 binding proteins were unexpected after prostatectomy. This result makes it extremely unlikely that secretion from the prostate, even if it contains cancer, affects serum levels of these proteins. The implication of these findings is that endocrine production of IGF-1 is a factor in prostate cancer risk. Therefore, strategies to lower serum IGF-1 may be potentially useful.