Roohollah Sharifi

Radical Prostatectomy versus Observation for Localized Prostate Cancer

BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

Randomized Prospective Study Comparing Radical Prostatectomy Alone Versus Radical Prostatectomy Preceded by Androgen Blockage in Clinical Stage B2 (T2bNxM0) Prostate Cancer

AbstractPurpose: Nonrandomized clinical trials have suggested that preoperative androgen deprivation can decrease the likelihood of positive surgical margins in patients with clinically localized prostate cancer. A multicenter prospective randomized trial compared radical prostatectomy alone to radical prostatectomy after 3 months of leuprolide acetate depot and flutamide in patients with stage cT2bNxM0 prostate cancer and a serum prostate specific antigen level less than 50 ng./ml.Materials and Methods: We randomized 149 patients to undergo androgen deprivation and 138 to undergo lymphadenectomy with (137) or without (1) prostatectomy. Of the 154 patients randomized to the surgery alone group 144 underwent pelvic node dissection with (138) or without (6) prostatectomy.Results: There was no statistically significant difference between the 2 groups in operating time, blood loss, need for transfusion, postoperative morbidity or length of hospital stay. There were 4 rectal and 2 ureteral injuries in the surg...

Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis.

As part of a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage in men with prostate cancer, a nonrandomized 5th arm using tomato sauce was included and reported here. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical prostatectomy. Prostate tissue was obtained as biopsies at baseline and as resected tissue at the time of the prostatectomy. Serum and prostate lycopene, serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH-deoxyguanosine/deoxyguanosine (80HdG) were measured at baseline and at the end of the intervention. Cancer cells in paraffin sections of prostate biopsies and postintervention resected tissue were compared for 80HdG staining and for apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6% of the intended dose, and serum and prostate lycopene concentrations increased 1.97- and 2.92-fold (P< 0.001), respectively. Mean serum PSA concentrations decreased by 17.5% (P< 0.002) and leukocyte 80HdG decreased by 21.3% (P< 0.005) after tomato sauce consumption. Resected tissues from tomato sauce-supplemented patients had 28.3% lower prostate 80HdG compared with the nonstudy control group (P < 0.03). Cancer cell 80HdG staining of Gleason Score-matched resected prostate sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic index was higher in hyperplastic and neoplastic cells in the resected tissue after supplementation. These data taken as a whole indicate significant uptake of lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and prostate tissue. Whether reduction in DNA. damage to prostate cancer cells is beneficial awaits further research, although reduction in serum PSA concentrations is promising.

Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: Final report of a double-blind, randomized, multicenter trial

OBJECTIVES To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer. METHODS This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS The median times to progression and death were 97 and 180 weeks for the bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group. CONCLUSIONS With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Clinical Study of Leuprolide Depot Formulation in the Treatment of Advanced Prostate Cancer

In a phase III, open, multicenter study we evaluated the safety and efficacy of the depot formulation of leuprolide (7.5 mg. injected intramuscularly every 4 weeks) in patients with stage D2 prostate cancer who had not previously received systemic treatment. Serum testosterone, luteinizing hormone and plasma leuprolide levels were monitored during the 24-week study period. Median interval to onset of castrate testosterone levels was 21 days and mean testosterone levels decreased to within the castrate range by week 3 of treatment. After onset of castrate levels there were no escapes (defined as 2 consecutive values of greater than 50 ng./dl.) of testosterone levels during the 24 weeks. Suppression of testosterone did not differ significantly from that observed in patients receiving the daily subcutaneous injection of leuprolide acetate in the first 24 weeks of another study. Objective response (no progression) to treatment occurred in 81% of 53 evaluable patients and adverse (related and unrelated) events were reported in 45 of the 56 patients. The response rate and incidence of adverse events in this study did not differ significantly from those occurring with the daily formulation. We conclude that the depot formulation of leuprolide is safe and effective in the treatment of advanced prostatic cancer, and that the safety and efficacy of this formulation do not differ significantly from those of the daily subcutaneous formulation.

Effects of Tomato Sauce Consumption on Apoptotic Cell Death in Prostate Benign Hyperplasia and Carcinoma

Population studies have suggested that lycopene, which is mostly found in tomato and tomato products, may reduce the risk of prostate cancer. We previously found that tomato sauce consumption prior to prostatectomy for prostate cancer decreased serum prostate specific antigen, decreased oxidative DNA damage, and increased lycopene concentrations in prostate tissue (Chen et al., 2001). Here, we extended those investigations to determine whether apoptotic cell death and associated Bcl-2 and Bax proteins were modulated by tomato sauce intervention. Thirty-two patients diagnosed by biopsy with prostate carcinoma were given tomato sauce pasta entrees (30 mg lycopene/day) for 3 wk before prostatectomy. Thirty-four patients with prostate cancer who did not consume tomato sauce and underwent prostatectomy served as controls. When tumor areas with the most apoptotic cells were compared in the biopsy (before) and resected prostate tissue (after), tomato sauce consumption increased apoptotic cells in benign prostate hyperplasia (BPH) from 0.66 ± 0.10% to 1.38 ± 0.31% (P = 0.013) and in carcinomas from 0.84 ± 0.13% to 2.76 ± 0.58% (P = 0.0003). When comparable morphological areas were counted, apoptotic cell death in carcinomas increased significantly with treatment, from 0.84 ± 0.13% to 1.17 ± 0.19% (P = 0.028), and apoptotic cell death in BPH showed a tendency toward an increase from 0.66 ± 0.10% to 1.20 ± 0.32% (P = 0.20). When the values of apoptotic cells in BPH and carcinomas of patients who consume tomato sauce were compared with corresponding control lesions of the patients who did not consume tomato sauce in resected prostate tissue, the differences of values were not significant [BPH 1.38 ± 0.31% vs. 1.14 ± 0.32% (P= 0.97); carcinomas 2.76 ± 0.58% vs. 1.91 ± 0.32% (P = 0.24)]. Tomato sauce consumption did not affect Bcl-2 expression but decreased Bax expression in carcinomas. These data provide the first in vivo evidence that tomato sauce consumption may suppress the progression of the disease in a subset of patients with prostate cancer by increasing apoptotic cell death. However, because of the relatively small number of control and tomato sauce-supplemented patients and the variability in the values of apoptotic cells in BPH and carcinomas, a much larger number of patients needs to be examined to support the data generated in this study.

Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer

Two open-label, multicenter studies were conducted to evaluate the efficacy and safety of a long-acting depot formulation of leuprolide acetate (22.5 mg) administered intramuscularly every 12 weeks to patients with stage D2 prostate cancer. Clinical evaluations were performed every 12 weeks, and serum testosterone levels were monitored biweekly or weekly for 24 weeks. Onset of castrate levels (< or = 50 ng/dL) of testosterone was achieved within 30 days of the initial depot injection in 87 (95%) of the 92 assessable patients enrolled in the two studies. Mean testosterone levels remained well within the castrate range throughout each dosing interval. Two patients experienced a transient escape (testosterone levels > 50 ng/dL on two consecutive determinations). Delay of an injection of up to 2 weeks did not have an effect on testosterone suppression: in 16 patients in whom the depot injection was delayed by 3 to 14 days, testosterone values remained within the castrate range. A favorable objective tumor response (no progression) to treatment occurred in 85% of the patients. Prostate-specific antigen and prostatic acid phosphatase decreased by 50% or more in 96% and 84% of patients, respectively, with elevated pretreatment values and at least one treatment value. Assessment of local disease status and overall performance status showed improvement or stability in most patients. The most common adverse events were hot flashes (59%), pain (27%), and testicular atrophy (21%). The 22.5-mg depot formulation of leuprolide, which acts in a manner similar to the monthly 7.5-mg depot formulation, was shown to be effective and safe in treating patients with advanced prostate cancer.

Evaluation of an implant that delivers leuprolide for 1 year for the palliative treatment of prostate cancer

OBJECTIVES To evaluate the Viadur implant, which delivers leuprolide acetate for the palliative treatment of advanced prostate cancer. METHODS Inserted subcutaneously, the 4 x 45-mm implant uses osmotic pressure to deliver leuprolide continuously at a controlled rate for 1 year. This 19-center open-label study enrolled patients with prostate cancer who had had no prior therapy or showed biochemical evidence of treatment failure after prostatectomy or radiotherapy. Each patient received one implant. After 1 year, that implant was removed, another was inserted, and patients were followed up for 2 additional months. The primary efficacy measure was suppression of testosterone to less than the castrate threshold (50 ng/dL). RESULTS Eighty patients were enrolled. The implant effectively suppressed testosterone in 79 patients (99%) within 2 to 4 weeks and maintained that suppression through the study period. In 1 patient, the testosterone was suppressed to less than 100 ng/dL within 4 weeks but was not less than 50 ng/dL until week 24. Prostate-specific antigen levels normalized (4 ng/mL or less) or a clinically significant decrease occurred in all patients. Leuprolide was rapidly absorbed, resulting in mean serum concentrations of 16.8 ng/mL 4 hours after implant insertion and 2.4 ng/mL at 24 hours; steady mean serum leuprolide concentrations were then maintained throughout the year, at approximately 0.9 ng/mL. Investigators were satisfied with the insertion and removal procedures. All patients reported satisfaction after 1 year of treatment. The safety profile of the implant was consistent with androgen ablation therapy. Most adverse events were mild, and the most common event was hot flashes. CONCLUSIONS The leuprolide implant effectively suppressed testosterone concentrations to less than the castrate threshold and maintained that suppression throughout the study period.

Antioxidant Effects of Lycopene in African American Men with Prostate Cancer or Benign Prostate Hyperplasia: A Randomized Controlled Trial

Consumption of tomato products is associated with a decreased risk of developing prostate cancer, and lycopene, the red carotenoid in the tomato, is a potent antioxidant that might contribute to this chemoprevention activity. A double-blind, randomized, placebo-controlled trial of 105 African American men veterans, recommended for prostate biopsy to detect cancer, was carried out to investigate whether oral administration of lycopene increases lycopene levels in blood and prostate tissue and lowers markers of oxidative stress. Urology patients were randomly assigned to receive 30 mg/d of lycopene as a tomato oleoresin or placebo for 21 days prior to prostate biopsy for possible diagnosis of prostate cancer. A total of 47 men had a diagnosis of prostate cancer, and 58 men had a diagnosis of benign prostate hyperplasia. Diet, smoking, and drinking habits were assessed. For the men receiving lycopene, the mean lycopene concentration increased from 0.74 ± 0.39 to 1.43 ± 0.61 μmol/L in plasma (P < 0.0001) and from 0.45 ± 0.53 to 0.59 ± 0.47 pmol/mg in prostate tissue (P = 0.005). No significant changes in the DNA oxidation product 8-oxo-deoxyguanosine and the lipid peroxidation product malondialdehyde were observed in prostate tissue and plasma, respectively, as a result of lycopene administration. Cancer Prev Res; 4(5); 711–8. ©2011 AACR.

Ethanolamine Sclerotherapy of a Renal Cyst

We report the effective use of 5% ethanolamine oleate to sclerose a large simple renal cyst. The comparative advantages of ethanolamine versus other sclerosants are discussed in terms of adverse effects, availability and convenience. Guidelines to optimize sclerotherapy with ethanolamine are provided.