Does race affect postoperative outcomes in patients with low-risk prostate cancer who undergo radical prostatectomy?

OBJECTIVES: To assess the magnitude of racial disparities in prostate cancer outcomes following radical prostatectomy for low-risk prostate cancer. METHODS: We retrospectively reviewed our database of 2407 patients who under went radical prostatectomy and isolated 2 cohorts of patients with low-risk prostate cancer. Cohort 1 was defined using liberal criteria, and cohort 2 was isolated using more stringent criteria. We then studied pre- and postoperative parameters to discern any racial differences in these 2 groups. Statistical analyses, including log-rank, chi(2), and Fisher's exact analyses, were used to ascertain the significance of such differences. RESULTS: Preoperatively, no significant differences were found between the white and African-American patients with regard to age at diagnosis, mean prostate-specific antigen, median follow-up, or percentage of involved cores on prostate biopsy. African-American patients in cohort 1 had a greater mean body mass index than did white patients (26.9 vs 27.8, P = .026). The analysis of postoperative data demonstrated no significant difference between white and African-American patients in the risk of biochemical failure, extraprostatic extension, seminal vesicle involvement, positive surgical margins, tumor volume, or risk of disease upgrading. African-American patients in cohort 2 demonstrated greater all-cause mortality compared with their white counterparts (9.4% vs 3.1%, P = .027). CONCLUSIONS: In patients with low-risk prostate cancer treated with radical prostatectomy, there exist no significant differences in surrogate measures of disease control, risk of disease upgrading, estimated tumor volume, or recurrence-free survival between whites and African-Americans.

A heterogeneous algorithm for PDT dose optimization for prostate.

The object of this study is to develop optimization procedures that account for both the optical heterogeneity as well as photosensitizer (PS) drug distribution of the patient prostate and thereby enable delivery of uniform photodynamic dose to that gland. We use the heterogeneous optical properties measured for a patient prostate to calculate a light fluence kernel (table). PS distribution is then multiplied with the light fluence kernel to form the PDT dose kernel. The Cimmino feasibility algorithm, which is fast, linear, and always converges reliably, is applied as a search tool to choose the weights of the light sources to optimize PDT dose. Maximum and minimum PDT dose limits chosen for sample points in the prostate constrain the solution for the source strengths of the cylindrical diffuser fibers (CDF). We tested the Cimmino optimization procedures using the light fluence kernel generated for heterogeneous optical properties, and compared the optimized treatment plans with those obtained using homogeneous optical properties. To study how different photosensitizer distributions in the prostate affect optimization, comparisons of light fluence rate and PDT dose distributions were made with three distributions of photosensitizer: uniform, linear spatial distribution, and the measured PS distribution. The study shows that optimization of individual light source positions and intensities are feasible for the heterogeneous prostate during PDT.

Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study.

PURPOSE: We evaluated the effects of toremifene on bone mineral density, a surrogate for fracture risk, in men receiving androgen deprivation therapy for prostate cancer. MATERIALS AND METHODS: In an ongoing, multicenter, phase 3 fracture prevention study 1,392 men 50 years or older with prostate cancer receiving androgen deprivation therapy were randomized to 80 mg toremifene per day or placebo. Bone mineral density of the lumbar spine, total hip and femoral neck was assessed using dual energy x-ray absorptiometry. In this planned interim analysis of the first 197 subjects we compared bone mineral density changes from baseline to month 12 between the placebo and toremifene groups. RESULTS: Compared with the placebo group men in the toremifene group had significant increases in bone mineral density at each evaluated skeletal site. Lumbar spine bone mineral density decreased 0.7% in the placebo group and increased 1.6% in the toremifene group (between group comparison p <0.001). Total hip bone mineral density decreased 1.3% in the placebo group and increased 0.7% in the toremifene group (p = 0.001). Femoral neck bone mineral density decreased 1.3% in the placebo group and increased 0.2% in the toremifene group (p = 0.009). Between group differences in the change in bone mineral density from baseline to month 12 were 2.3%, 2.0% and 1.5% for the lumbar spine, total hip and femoral neck, respectively. CONCLUSIONS: Toremifene significantly increased hip and spine bone mineral density in men receiving androgen deprivation therapy for prostate cancer. The effect of toremifene on the fracture risk is being assessed in the ongoing randomized, controlled trial.

Association of obesity with tumor characteristics and treatment failure of prostate cancer in African-American and European American men.

PURPOSE: The impact of body mass index on tumor characteristics and treatment failure in prostate cancer is not well understood in diverse ethnic groups. We evaluated the effect of body mass index in African-American and European American patients from a radical prostatectomy cohort between 1995 and 2004 with regard to tumor histopathological characteristics and biochemical relapse-free survival. MATERIALS AND METHODS: A total of 924 patients were studied to evaluate whether obese men (body mass index greater than 30) had different preoperative and postoperative tumor characteristics or biochemical relapse-free survival compared to nonobese men. There were 784 European American and 140 African-American patients analyzed using failure time models, adjusted for age, preoperative prostate specific antigen, tumor stage and race. RESULTS: Mean and median followup was 42 and 36 months, respectively. African-American men were significantly more obese than European American men. Mean body mass index was 29.0 in African-American and 28.1 in European American men (p = 0.003). African-American men (OR 2.30, 95% CI 1.04-5.1) were more likely to have higher tumor stage on final pathology. Obesity was a risk factor for biochemical failure in African-American men (adjusted hazard ratio 5.49, 95% CI 2.16-13.9) but not in European American men (HR 1.41, 95% CI 0.96-2.08), and this difference was statistically significant (p value for interaction 0.036). CONCLUSIONS: Obesity is associated with poorer tumor prognostic characteristics and decreased biochemical relapse-free survival, particularly in African-American men. These data suggest that obesity may in part explain the poorer prostate cancer prognosis seen in African-American men compared to other racial and ethnic groups.

A method to improve reconstruction of the distribution of hemoglobin, oxygenation, and MLu concentration in the human prostate before and after photodynamic therapy.

Explicit dosimetry of photodynamic therapy requires detailed knowledge of the light, drug, and oxygenation distributions within the target tissue. We present a method for the optical detection and three-dimensional reconstruction of hemoglobin concentration and oxygenation and sensitizer concentration within the human prostate. Spectrally resolved diffuse transmission measurements were made using a small isotropic fiber-based white light source and an isotropic detector inserted into the prostate via parallel closed transparent catheters. The spectra were modeled using the diffusion approximation appropriate for infinite media. The optical absorption of the prostate was assumed to be a linear combination of the absorption spectra of oxy- and deoxyhemoglobin and MLu, and the scattering was assumed to be of the form A(λ/λ0)-b. The separation of absorption and scattering coefficients was accomplished based on the spectral shape of the diffuse transmission, rather than the spatial variation in intensity. By making multiple measurements at various source-detector separations, we investigate the signal-to-noise sensitivity of our algorithm. In addition, the redundancy in our source-detector position matrix creates several positions in which the tissue parameters can be reconstructed from multiple independent measurements, allowing an assessment of the repeatability of the algorithm. We find significant heterogeneity in the reconstructed optical properties; however the recovery of spectrally consistent absorption and scattering spectra is improved compared to wavelength-wise reconstruction algorithms.

Preliminary results of interstitial motexafin lutetium-mediated PDT for prostate cancer.

BACKGROUND AND OBJECTIVES: Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed. STUDY DESIGN/MATERIALS AND METHODS: We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed. RESULTS: We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate. CONCLUSIONS: PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.

Association of prostate cancer family history with histopathological and clinical characteristics of prostate tumors.

Genetic factors may be used not only to assess risk of prostate cancer development but also to evaluate prostate cancer outcomes including clinical prognosis, treatment methods, and treatment response. To assess the role of family history on prostate cancer outcomes, we evaluated tumor characteristics, diagnostic precursors and biochemical (prostate specific antigen) relapse-free survival in men with and without a family history of prostate cancer. A total of 684 prostate cancer cases unselected for family history were identified from an ongoing hospital based prostate cancer case-control study between 1995 and 2002. Self-reported family history was grouped within the following categories: none, any, moderate (one affected first or second degree relative) and high (2 or more affected first or second degree relatives). We further considered groups defined by early (before age 60) and late (after age 60) age at diagnosis. Overall, tumor stage was not significantly associated with any (odds ratio [OR] = 1.43 95% confidence interval [CI] = 1.00-2.05) or moderate (OR = 1.48, 95% CI = 1.0-2.19) family histories. Men diagnosed before age 60, however, had higher tumor stages if they had any (OR = 2.19, 95% CI = 1.28-3.75) or moderate (OR = 2.15, 95% CI = 1.2-3.9) family histories. Men diagnosed after age 60 with any family history were significantly more likely to experience biochemical (PSA) failure (Hazard ratio [HR] = 2.60, 95%CI = 1.08-6.25). Men with any and moderate family histories were at significantly increased risk of biochemical failure (HR = 2.49, 95%CI = 1.25-4.95 and HR = 2.46, 95% CI = 1.17-5.16, respectively). Moderate family history increased probability of seminal vesicle invasion (OR = 2.14, 95%CI = 1.06-4.34). Our results suggest that a family history of prostate cancer may be associated with predictors of clinical outcome in prostate cancer cases unselected for a family history of prostate cancer.

Clinical characteristics of prostate cancer in African Americans, American whites, and Senegalese men.

OBJECTIVES: To describe the clinical features of prostate cancer in Senegalese men and compare these features with those found in African-American and white American men. METHODS: We identified an unselected series of 121 patients with prostate cancer diagnosed at two hospitals in Dakar, Senegal between 1997 and 2002. Medical record abstractions were undertaken to evaluate the prostate tumor characteristics, patient age at diagnosis, prostate-specific antigen (PSA) levels, and reason for referral. In addition, these characteristics were compared with a sample of 455 U.S. white men and 60 African-American men with prostate cancer who were studied as part of a prostate cancer case-control study. RESULTS: Senegalese men had a significantly worse tumor stage than Americans (41.3% versus 18.8%, P <0.001), a significantly worse mean PSA level at diagnosis (mean PSA 72.7 ng/mL versus 9.0 ng/mL in Americans; P <0.001), and were diagnosed at a significantly later age than U.S. men (69 years versus 61 years, P <0.001). U.S. men were most likely to be diagnosed with prostate cancer after an elevated PSA test, and Senegalese men were most often diagnosed after presenting for prostate-related symptoms. CONCLUSIONS: These observations are not unexpected given the differences in the patterns of prostate cancer screening and health care in the United States compared with Senegal. However, our data provide descriptive information about the characteristics of prostate cancer diagnosed in Senegal and highlight differences in the characteristics and detection of these tumors across populations with very different healthcare systems.

KIAA1096, a gene on chromosome 1q, is amplified and overexpressed in bladder cancer.

Chromosomal gain on 1q23-24 is a cytogenetic finding found in approximately 30% of bladder tumors. Currently, no defined or candidate tumor-associated genes from this region have been identified. The objective of this study was to identify and quantitate the expression of putative cancer genes located at this chromosome locus in normal urothelium, superficial, and muscle invasive bladder tumors. We examined both normal and bladder cancer tissue specimens (N = 40-80 RNA, DNA, and protein) by semiquantitative RT/PCR, genomic PCR, and by Western blotting. The KIAA1096 gene is located at 1q23-24 with no overexpression or amplification in normal urothelium, but was significantly upregulated in 30% of tumors (P = 0.0001). There was a trend towards increased expression in invasive compared to superficial lesions (P = 0.06). A significant increase in gene copy was also found in a 38% of TCC of the bladder compared to normal bladder mucosa or peripheral blood lymphocytes. Immunohistochemistry (IHC) demonstrated KIAA1096 expression in nonmalignant bladder mucosa tissue but apparent upregulation in invasive transitional cell carcinoma. Two other genes, CH1 and RGS5, which are situated in the same region of chromosome 1q, demonstrated disparate patterns of expression. In summary, KIAA1096 is a gene situated at 1q23-24, which demonstrated a pattern of RNA and DNA expression consistent with the 38% expression of cytogenetic amplification noted on previous studies. This gene may, therefore, be a putative marker for this cytogenetic phenomenon and provide an opportunity to evaluate the clinical significance of previous cytogenetic findings.

Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4.

OBJECTIVES: Ethnic differences in prostate cancer incidence are well documented, with African-Americans having among the highest rates in the world. Ethnic differences in genotypes for genes associated with androgen metabolism including SRD5A2 and CYP3A4 also may exist. The aim of this study was to evaluate differences in these genotypes by ethnicity. METHODS: We studied cancer-free controls representative of four groups: 147 African Americans, 410 Caucasian-Americans, 129 Ghanaians, and 178 Senegalese. PCR-based genotype analysis was undertaken to identify two alleles (V89L, A49T) at SRD5A2 and *1B allele at CYP3A4. RESULTS: Differences were observed for V89L (variant frequency of 30% in Caucasians, 27% in African Americans, 19% in Ghanaians, and 18% in Senegalese, p = 0.002) and were observed for CYP3A4*1B (variant frequencies of 8% in Caucasians, 59% in African Americans, 81% in Ghanaians, and 78% in Senegalese, p = 0.0001). Pooled data combining the present data and previously published data from from Asian, Hispanic, and Arab cancer-free controls showed significant ethnic differences for SRD5A2 and CYP3A4 polymorphisms. Overall, Asians were least likely to have alleles associated with increased prostate cancer risk, while Africans were most likely to have those alleles. CONCLUSIONS: These results suggest that ethnicity-specific differences in genotype frequencies exist for SRD5A2 and CYP3A4. Africans and African-Americans have the highest frequency of those alleles that have previously been associated with increased prostate cancer risk. Future studies should address whether allele frequency differences in part explain differences in prostate cancer incidence in these populations.

Predicting prostate specific antigen outcome preoperatively in the prostate specific antigen era.

PURPOSE: We evaluated the ability of previously defined risk groups to predict prostate specific antigen (PSA) outcome 10 years after radical prostatectomy in patients diagnosed with clinically localized prostate cancer during the PSA era. MATERIALS AND METHODS: Between 1989 and 2000, 2,127 men with clinically localized prostate cancer underwent radical prostatectomy, including 1,027 at Hospital of the University of Pennsylvania (study cohort) and 1,100 at Brigham and Women's Hospital (validation cohort). Cox regression analysis was done to calculate the relative risk of PSA failure with the 95% confidence interval (CI) in patients at intermediate and high versus low risk. The Kaplan-Meier actuarial method was used to estimate PSA outcome 10 years after radical prostatectomy. RESULTS: Compared with low risk patients (stages T1c to 2a disease, PSA 10 ng./ml. or less and Gleason score 6 or less) the relative risk of PSA failure in those at intermediate (stage T2b disease or PSA greater than 10 to 20 ng./ml. or less, or Gleason score 7) and high (stage T2c disease, or PSA greater than 20 ng./ml. or Gleason score 8 or greater) risk was 3.8 (95% CI 2.6 to 5.7) and 9.6 (95% CI 6.6 to 13.9) in the study cohort, and 3.3 (95% CI 2.3 to 4.8) and 6.3 (95% CI 4.3 to 9.4) in the validation cohort. The 10-year PSA failure-free survival rate in the 1,020 patients in the low, 693 in the intermediate and 414 in the high risk groups was 83%, 46% and 29%, respectively (p <0.0001). CONCLUSIONS: Based on 10-year actuarial estimates of PSA outcome after radical prostatectomy 3 groups of patients were identified using preoperative PSA, biopsy Gleason score and 1992 clinical T category.

The role of imaging studies and molecular markers for selecting candidates for radical prostatectomy.

For the typical patient who has newly diagnosed prostate cancer, clinically organ-confined disease of moderate grade, and a PSA less than 10 ng/mL, the current role of imaging studies and molecular biomarkers is limited. Bone scans are not necessary for newly diagnosed men with a PSA less than 10 ng/mL in the absence of bone pain. Similarly, abdominal and pelvic CT scanning rarely provides any useful diagnostic or staging information when the PSA is less the 20 ng/mL and is indicated rarely. Endorectal coil MR imaging adds staging information for patients with a PSA between 10 and 20 ng/mL, a Gleason score of 7 or less, and 50% or more positive biopsies on a sextant sampling. Indium 111 capromab pendetide scanning (ProstaScint) is FDA-approved to evaluate newly diagnosed patients at high risk for metastases. These patients have a Gleason score of 7 or greater and a PSA greater than 20 ng/mL, a Gleason score of 8 to 10 regardless of the PSA value, or clinical stage T3 disease and a Gleason score of 6 or greater. RT-PCR testing of blood or bone marrow for prostate-specific or prostate cancer-specific gene expression, or "molecular staging," is a promising technique whose current use is still investigational. Much useful information may be gained by careful study of prostate needle biopsy material. Aside from current Gleason grading and the number or percentage of cores involved with cancer, no molecular biomarker is approved for clinical use. p27, p53, bcl-2, Ki-67 (MIB-1), and the assessment of neovascularity hold promise, but prospective multicenter studies are needed. In the long-term, multiple gene expression profiling of biopsy material using gene chips may revolutionize the care of patients with prostate cancer and those who elect radical prostatectomy.

Using the receiver operating characteristic curve to select pretreatment and pathologic predictors for early and late postprostatectomy PSA failure.

OBJECTIVES: Pretreatment prostate-specific antigen (PSA), prostatectomy Gleason score, margin status, and pathologic T stage are known explanatory variables for the postprostatectomy PSA outcome. We used the receiver operating characteristic (ROC) curve to select those factors that were optimal for predicting early and late postoperative PSA failure. METHODS: We designed and implemented a clinical outcome prediction expert that performs, assesses, and optimizes the actuarial prediction on individual cases. A postprostatectomy database of 1022 patients was divided into 60% for training and 40% for validation. The ROC areas of the predictors were calculated over a range of cutoff time from 24 to 60 months. RESULTS: Multivariate pathologic T stage/prostatectomy Gleason score/margin status had the highest ROC area of 0.900. Patients with Stage T disease less than T3, negative surgical margins, and Gleason score of 6 or less had a 90% probability to be PSA failure free at 4 years versus 36% otherwise. The pathologic T stage/margin status accurately predicted PSA failure at 24 months or less after prostatectomy with an ROC area of 0.800. Lower risk patients (less than Stage T3, negative surgical margins) had a 94% probability to be PSA failure free at 2 years versus 46% otherwise. CONCLUSIONS: A combination of actuarial analysis and ROC optimization accurately identified the individual patients at high risk of early and late postprostatectomy PSA failure.

Estimating the impact on prostate cancer mortality of incorporating prostate-specific antigen testing into screening.

OBJECTIVES: Whether early detection using prostate-specific antigen (PSA) and digital rectal examination (DRE) compared with DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the impact that early detection could have on prostate cancer-specific survival can be estimated by assuming that PSA failure after radical prostatectomy (RP) will translate into death from prostate cancer. METHODS: The study population consisted of 1274 men with clinically localized prostate cancer who underwent RP in Boston, Massachusetts or Philadelphia, Pennsylvania between 1989 and 2000 and had a preoperative PSA level greater than 4 but not more than 10 ng/mL. The primary endpoint was actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk of PSA failure after RP for patients diagnosed with a PSA of greater than 4 to 5, 5 to 6, 6 to 7, or 7 to 8 ng/mL compared with greater than 8 up to 10 ng/mL was 0.3 (95% confidence interval [CI] 0.2 to 0.5), 0.5 (95% CI 0.4 to 0.8), 0.6 (95% CI 0.4 to 0.9), or 0.9 (95% CI 0.6 to 1.3), respectively. On the basis of the estimates of the 5-year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781 of 1274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 4 to 7 ng/mL compared with greater than 8 to 10 ng/mL (93% versus 78%, P <0.0001). A benefit to early detection was not found for the vast majority (266 of 312; 88%) of patients who had a biopsy Gleason score of 7 or higher. CONCLUSIONS: Early detection using both PSA and DRE-based screening may benefit men who present with biopsy Gleason score 5 or 6 prostate cancer and a PSA level greater than 4 to 7 ng/mL compared with greater than 8 up to 10 ng/mL. This finding awaits validation from ongoing prospective randomized trials.

The role of diethylstilbestrol in the treatment of prostate cancer.

OBJECTIVES: Diethylstilbestrol administration was a classic form of androgen deprivation therapy (ADT) that gradually fell out of favor because of its cardiovascular toxicity, economic disinterest on the part of manufacturers, and the emergence of novel therapeutic agents with a superior safety profile. The cost of contemporary agents and the efficacy of diethylstilbestrol (DES) have perpetuated the evaluation of this agent, especially in the circumstance of early hormone-refractory (clinical stage D2.5) disease. The objective of this study is to evaluate the status of DES-based therapies, and assess their efficacy and toxicity as a viable form of ADT. METHODS: Current research from single-institution and group studies, as well as basic scientific investigations related to DES, were assessed with regard to the population studied, dosage, criteria for response, response rate, duration of response, and toxicity. RESULTS: Contemporary basic research has demonstrated a direct apoptotic effect of DES on prostate cancer cells. There is also evidence to support the ability of DES to suppress testosterone production at extratesticular sites and inhibit dihydroepiandrosterone sulfate serum levels. Contemporary cooperative group trials for stage D2 disease incorporating a DES arm have demonstrated therapeutic efficacy and equivalence to orchiectomy, which is marred by significant cardiovascular toxicity. In smaller single-institution studies (n = 17 to 38) of patients with D2.5 disease, an average response rate of 55% is noted with a mean time to clinical progression of 6.4 months (2 to 18). Cardiovascular toxicity occurred in 10% to 30% of patients, with events including deep vein thrombosis, myocardial infarction, and transient ischemic attack. Edema and gynecomastia was also noted. Strategies to reduce thromboembolic events, such as dose reduction or the use of warfarin sodium were unsuccessful, whereas the use of low-dose aspirin (100 mg daily) resulted in only 1 of 38 vascular events. CONCLUSIONS: In contemporary studies of DES as an agent for ADT in D2.5 patients, a reasonable response rate (40% to 60%) of modest duration (5 to 8 months) is noted. Cardiovascular complications still persist, requiring the development of safe, effective antithrombolic therapy to take advantage of this phenomenon.

Recent developments in chemotherapy for bladder cancer.

Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials.

Effects of Bowman-Birk inhibitor concentrate (BBIC) in patients with benign prostatic hyperplasia.

BACKGROUND: The Bowman-Birk inhibitor is a soybean-derived protease inhibitor that has anti-inflammatory and anticarcinogenic activities. METHODS: A Phase I trial of Bowman-Birk inhibitor concentrate (BBIC) in 19 male subjects with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) has been performed. RESULTS: The results of the trial indicated that there was no dose-limiting toxicity of BBIC. There was a statistically significant decrease in serum PSA levels in all BBIC-treated patients. Some BBIC-treated patients exhibited a relatively large reduction in serum PSA levels, ranging up to a 43% reduction. There was also a statistically significant decrease in serum triglyceride levels and a decrease in prostate volume in the treated patients. The scores recorded in response to a urinary symptom questionnaire indicated improved urinary activities in the BBIC-treated patients; however, the control subjects exhibited similar improvements in urinary activities during the course of the trial. CONCLUSIONS: The data obtained in this trial, particularly the data suggesting that BBIC treatment may lead to reduced serum PSA levels and reduced prostate volumes, suggest that a Phase II clinical trial of BBIC for the therapy of BPH is warranted.

Phase II trial of toremifene in androgen-independent prostate cancer: a Penn cancer clinical trials group trial.

Toremifene has antiestrogenic and estrogenic properties in vitro and in vivo. In addition, it may have antiangiogenesis and antimicrotubule properties at higher doses. Studies have demonstrated the efficacy of this agent in the treatment of metastatic breast cancer. We performed a phase II trial of toremifene in patients with androgen-independent prostate cancer (AIPC). Patients with an increasing prostate-specific antigen level despite castrate testosterone levels and antiandrogen withdrawal were eligible. Patients could not have received prior salvage hormonal therapy or chemotherapy. Patients received toremifene at 300 mg/m2/d orally (maximum dose 640 mg/d). Fifteen patients were treated. Patients received treatment for a median of 13 weeks (range, 4-30 weeks). The median age was 72 years (range, 58-80 years). The median Eastern Cooperative Oncology Group performance status was 0. The treatment was well tolerated and toxicity was mild. Two patients had grade III hepatic toxicity; one had grade III hyperglycemia. There were no treatment-related deaths. No objective responses were demonstrated. In summary, toremifene is not effective therapy for AIPC at the dose and schedule evaluated in this trial.

Growth inhibitory effect of p21 and p53 containing adenoviruses on transitional cell carcinoma cell lines in vitro and in vivo.

Altered p53 expression has been demonstrated in the majority of advanced transitional cell carcinoma (TCC) of the bladder tumors. The objective of this investigation was to examine the effect of the introduction of a p53 or p21((WAF1/CIP1)) adenovirus on the proliferation and apoptosis of various human TCC cell lines in vitro and in vivo. Proliferation was measured by 3H-thymidine incorporation. Apoptosis was measured by DNA fragmentation and bax expression. We also examined the effect of ex vivo introduction of the p21((WAF1/CIP1)) or the p53 gene on growth of the T24 TCC cells and UMUC-3 TCC cells introduced subcutaneously into athymic nude mice. We found that although the effect of the p21-adenovirus on the proliferation of various TCC lines varied with each individual cell line, there was a substantial growth inhibition observed (greater than 80% growth inhibition) in seven of the eight TCC cell lines at the highest viral dosage. In contrast, after 24 h, the highest dosage of the p53-adenovirus produced only a heterogeneous decrease in proliferation compared to the highest dose of the p21((WAF1/CIP1))-adenovirus (40-90%). In ex vivo experiments, no tumors were found in nude mice injected subcutaneously with either TCC cell line exposed in vitro to the AdSCMV-p21((WAF1/CIP1)) or AdSCMV-p53 viruses before three weeks. There was a threefold decrease in tumor square area at week 5 in the Ad5CMV-p21((WAF1/CIP1)) or Ad5CMV-p53 TCC cells injected mice (p<0.001, p<0.009) compared to either mock or Ad5CMVLacZ TCC bladder tumor cells. These data suggest that significant portion of the effect of altered p53 on TCC phenotype may be mediated through the p21((WAF1/CIP1)) pathway. Thus, the restoration of p21((WAF1/CIP1)) function in this tumor system may be a beneficial therapeutic strategy.