Testosterone loss and estradiol administration modify memory in men.

PURPOSE: Little is known about the effect of androgen deprivation therapy on the brain despite the fact that sex steroid receptors are abundant in cortical brain regions that mediate memory and other cognitive functions. We characterized the impact of androgen deprivation and of subsequent estradiol therapy on the long-term and working memory of patients with prostate cancer. MATERIALS AND METHODS: Long-term memory (immediate and delayed paragraph recall tests), working memory (SOP and Trails tests) and Profile of Mood States were assessed at baseline and 4 weeks later in 18 patients with androgen independent prostate cancer beginning second line hormonal therapy with transdermal estradiol 0.6 mg/24 hours. The same assessments were performed in 2 age matched control groups of 18 patients with prostate cancer undergoing androgen deprivation continuing on hormonal therapy and 17 community dwelling healthy men. RESULTS: Immediate and delayed verbal memory were significantly worse in patients with prostate cancer on androgen deprivation than in age matched healthy controls. In addition, men with prostate cancer took more time to complete the Trails A task, indicating slower processing speed, but did not differ significantly from healthy controls in working memory tasks. In individual repeated measures analyses, verbal memory performance improved with estradiol therapy but did not change in the 2 control groups. CONCLUSIONS: Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory performance caused by androgen deprivation.

Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer is now used in earlier disease stages and as adjuvant treatment. Recognizing and reducing the toxicity of this therapy, including worsened lipid levels and cardiovascular disease (CVD) risks, has become an important clinical concern. Oral estrogen therapy induces hypogonadism and mitigates many side effects of ADT, but has a high thrombosis risk. Transdermal estrogen therapy (TDE) has a lower thrombosis risk than oral estrogen and may improve CVD risk compared with ADT. This prospective pilot study of 18 men with androgen-independent prostate cancer receiving ADT measured effects of TDE on lipid and inflammatory CVD risk factors before and after 8 weeks of TDE (estradiol 0.6 mg/day). During treatment, estradiol levels rose 17-fold; total cholesterol, LDL cholesterol, and apolipoprotein B levels decreased. HDL2 cholesterol increased, with no changes in triglyceride or VLDL cholesterol levels. Dense LDL cholesterol decreased and LDL buoyancy increased in association with a decrease in HL activity. Highly sensitive C-reactive protein levels and other inflammatory markers did not worsen. Compared with ADT, short-term TDE therapy of prostate cancer improves lipid levels without deterioration of CVD-associated inflammatory markers and may, on longer-term follow-up, improve CVD and mortality rates.

Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer.

OBJECTIVE: To characterize the clinical outcomes of androgen deprivation therapy (ADT) as the sole therapy for localized prostate cancer, and to determine independent predictors of disease progression, as recent studies indicate an increasing use of ADT. PATIENTS AND METHODS: The records of all patients with cT1-4NXM0 adenocarcinoma of the prostate treated with ADT as the primary initial therapy at the Portland Veterans Affairs Medical Center between 1993 and 2000 were reviewed. Age, race, Charlson Health Index, family history, prostate-specific antigen (PSA) level, PSA density, digital rectal examination (DRE) findings, Gleason score, and percentage of positive biopsy cores at diagnosis were recorded for 81 patients. Patients had a median (SD, range) age of 73 (5.6, 58-84) years, a PSA level of 14.3 (34.6, 1.4-252) ng/mL and tumours were classified as Gleason score < or = 5 in 9% of patients, 6 in 31%, 7 in 31% and 8-10 in 30%. Outcomes extracted were PSA progression, PSA nadir, bone fractures, local progression, distant progression and overall survival. RESULTS: With a median (range) follow-up of 54 (6-115) months, the incidence of local progression, distant progression, bone fractures, PSA progression, and death were 10%, 7%, 25%, 21% and 41% respectively. The percentage of positive biopsy cores > or = 83%, age < 70 years, Gleason score > or = 7, abnormal DRE, and PSA nadir > or = 0.2 ng/mL were significantly associated with PSA progression by univariate analysis. The multivariate analysis identified age < 70 years (hazard ratio 6.52, 95% confidence interval 2.29-18.55) and Gleason score > or = 6 (4.0, 2.0-12.0) as independent risk factors for PSA progression. CONCLUSIONS: ADT resulted in modest control of localized prostate cancer, but younger patients and those with Gleason > or = 6 cancers were at higher risk of treatment failure. Toxicity, principally in the form of bone fractures, was high.

High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study.

PURPOSE: We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. MATERIALS AND METHODS: Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. RESULTS: A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. CONCLUSIONS: High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.

Phase II study of transdermal estradiol in androgen-independent prostate carcinoma.

BACKGROUND: Oral estrogen therapy has activity in patients with hormone-naive and androgen-independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids "first pass" liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC. METHODS: Patients with prostate carcinoma progressing after primary hormonal therapy received TDE 0.6 mg per 24 hours (administered as six 0.1 mg per 24-hour patches replaced every 7 days). Serum prostate-specific antigen (PSA) and hormone levels, coagulation factors, markers of bone turnover, bone density measurements, and a hot flash diary were collected at regular intervals. RESULTS: Three of 24 patients (12.5%; 95% confidence interval [CI], 0-26%) had a confirmed PSA reduction >50%. The Kaplan-Meier estimate of median time to disease progression was 12 weeks (95% CI, 4.6-19.4 weeks). Toxicity was modest and no thromboembolic complications occurred. The mean (+/-95% CI) serum estradiol level increased from 17.2 pg.mL (range, 14.8-19.6 pg/mL) to 460.7 pg/mL (range, 334.6-586.7 pg/mL). The total testosterone level remained stable in the anorchid range during treatment, but the free testosterone level decreased as a result of increased sex hormone binding globulin. No change in factor VIII activity, F 1.2, or resistance to activated protein C was observed, whereas a modest decrease in the protein S level was observed. CONCLUSIONS: In patients with APIC, TDE was well tolerated and produced a modest response rate, but was not associated with thromboembolic complications or clinically important changes in several coagulation factors.

Targeting FSH in androgen-independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy.

OBJECTIVES: To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy and to measure its effect on serum follicle-stimulating hormone (FSH). METHODS: Sixteen patients with prostate cancer progressing after orchiectomy received abarelix-depot 100 mg by intramuscular injection on days 1, 15, and 29 and then every 28 days for up to 24 weeks (52 weeks in patients who met the criteria for a prostate-specific antigen [PSA] response after 24 weeks). PSA response was the primary endpoint and was defined as a 50% reduction confirmed 4 weeks later. The time to progression and effect of therapy on serum FSH were secondary endpoints. RESULTS: No patient met the criteria for a PSA response. Five patients (31%, 95% confidence interval 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% confidence interval 6 to 18). The mean serum FSH concentration declined after 4 weeks of study treatment by nearly 90% from a baseline of 45.1 IU/L (95% confidence interval 34.0 to 56.2) and remained suppressed throughout the observation period. Treatment was well tolerated, with one grade 3 allergic reaction. CONCLUSIONS: Treatment with abarelix in patients with androgen-independent prostate cancer after orchiectomy results in marked reduction in circulating FSH. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients.

Polymorphisms of GSTT1 and related genes in head and neck cancer risk.

BACKGROUND: Glutathione S-transferase T1 detoxifies some environmental carcinogens while activating others and is deleted in 15% to 38% of humans. We sought to determine whether GSTT1 genotype and genotypes of several related genes are associated with risk of squamous cell carcinoma of the head and neck (HNSCC). METHODS: Somatic genotypes for GSTT1, GSTM1, GSTP1, and CYP1A1 were determined in 283 individuals with HNSCC and 208 population-based controls. RESULTS: The OR for presence of GSTT1 was 1.6 (CI, 1.1-2.5, p = 0.03). HNSCC risk was not associated with GSTM1 null genotype, the presence of the GSTP1 Val/Val genotype, or the Val/Val homozygous genotype for CYP1A1. Stratified analysis revealed disparate ORs for women (OR, 3.0; CI, 1.5-6.3) and men (OR, 1.2; CI, 0.7-2.1) for the presence of GSTT1. CONCLUSIONS: In this population, the presence of GSTT1 gene was associated with a significant increase in the risk of HNSCC. This association was particularly robust in women.

Weekly docetaxel in elderly patients with prostate cancer: efficacy and toxicity in patients at least 70 years of age compared with patients younger than 70 years.

We sought to determine whether age was significantly associated with efficacy and toxicity of weekly docetaxel in patients with metastatic androgen-independent prostate cancer (AIPC). Individual patient data were pooled from 2 phase II clinical trials of weekly docetaxel 36 mg/m(2) for 6 of every 8 weeks in men with metastatic AIPC. Baseline characteristics and outcome measures of men > 70 years of age (n = 52) were compared with patients < 70 of age (n = 34) using Pearson c2 test for categoric variables, Mann-Whitney U test for continuous variables, and log-rank test of Kaplan-Meier estimates for time-dependent variable. Multivariate analysis was used to adjust for any imbalances in baseline characteristics. At baseline, older patients had a lower hemoglobin level (P = 0.05) and a higher serum prostate-specific antigen (PSA; P = 0.04). The PSA response rate was 47% (95% CI, 33%-62%) in older patients and 40% (95% CI, 23%-59%) in younger patients (P = 0.75). Similarly, measurable disease response rate (P = 0.43), time to progression (P = 0.28), and survival (P = 0.52) were not affected by age in both univariate and multivariate analyses. There was also no difference in overall hematologic and nonhematologic toxicity > grade 2. This comparison of pooled individual patient data from 2 phase II studies of weekly docetaxel in AIPC did not reveal significant differences in efficacy or toxicity in men aged > 70 years compared with younger patients. These findings are consistent with the hypothesis that docetaxel chemotherapy in patients with AIPC is equally well tolerated and effective across a wide range of ages.