The prognostic value of hemoglobin change after initiating androgen-deprivation therapy for newly diagnosed metastatic prostate cancer: A multivariate analysis of Southwest Oncology Group Study 8894.

BACKGROUND: The objective of this study was to characterize changes in hemoglobin (HGB) levels after the initiation of androgen-deprivation therapy (ADT) in patients with previously untreated, metastatic prostate cancer who were enrolled in a large clinical trial. METHODS: The multivariate associations between 3-month change in HGB and baseline characteristics were evaluated with a linear regression model. The associations between 3-month change in HGB level and time-to-event outcomes, including overall survival and progression-free survival, were evaluated by using proportional hazards regression models. RESULTS: Quartiles of baseline HGB levels were < or =12.0 g/dL, from 12.1 to 13.7 g/dL, from 13.8 to 14.7 g/dL, and >14.7 g/dL. Overall, 3 months after initiating ADT, the mean HGB level declined 0.54 g/dL (standard deviation [SD], 1.68 g/dL); however, the mean HGB level increased by 0.99 g/dL (SD, 1.83 g/dL) in patients who had baseline HGB levels <12 g/dL and decreased 1.04 g/dL (SD, 1.28 g/dL) in patients who had baseline HGB levels > or =12 g/dL. After adjusting for potential confounders, including baseline HGB level, a decline in HGB after 3 months of ADT was associated independently with shorter survival (hazards ratio [HR], 1.10 per 1 g/dL decline; P = .0035) and shorter progression-free survival (HR, 1.08 per 1 g/dL decline; P = .013). An unexpected finding was that the effect of baseline HGB on overall and progression-free survival varied significantly by race. CONCLUSIONS: In a sample of men with newly diagnosed, metastatic prostate cancer, a decline in HGB level after 3 months of ADT was associated with shorter survival and progression-free survival after adjusting for disease status and other baseline covariates. Although race alone was not a strong predictor of death or disease progression, the effect of the baseline HGB level on overall and progression-free survival varied significantly by race.

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.

Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?

Androgen deprivation therapy (ADT) is the mainstay of management of advanced-stage prostate cancer and recently has been shown to improve survival when administered in earlier stages of the disease. The oncologic benefits of ADT might be partially offset, however, by a reduction in quality of life because of adverse effects. In addition to the well-recognized adverse consequences of ADT, recent evidence suggests that ADT is associated with dyslipidemia, impaired glucose metabolism, adverse body compositional changes, and osteoporosis. Therefore, there is a pressing need to develop less toxic forms of ADT. A novel approach to this problem is the use of estrogen to induce androgen suppression. Whereas oral estrogen therapy is known to be associated with thromboembolic complications, studies of parenteral estrogen in men with prostate cancer suggest that the use of parenteral estrogen achieves target androgen suppression, does not adversely affect prothrombotic protein levels, and is not associated with adverse metabolic, skeletal, and body compositional changes when compared with conventional ADT. Herein, we review the data for parenteral estrogen use in prostate cancer, the antineoplastic mechanisms of action of estrogen in prostate cancer, the potential advantages of parenteral estrogen compared with conventional ADT, and the remaining barriers in the use of parenteral estrogen in prostate cancer.

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.

Prognostic value of anemia in newly diagnosed metastatic prostate cancer: a multivariate analysis of southwest oncology group study 8894.

PURPOSE: Previously reported association of anemia with shorter survival in newly diagnosed metastatic prostate cancer may simply reflect extent of disease. The impact of anemia on response to androgen deprivation is not known. We examined the prognostic value of anemia in a multivariate analysis that included disease extent and other tumor and demographic covariates in 957 patients starting hormonal therapy for metastatic prostate cancer as part of Southwest Oncology Group study 8894. MATERIALS AND METHODS: The multivariate associations of disease and patient measures with anemia (hemoglobin less than 12 gm/dl) were evaluated with a logistic regression model. The associations between hemoglobin and survival and progression-free survival (PFS) were evaluated using a proportional hazards model, and included indicators for quartiles of hemoglobin and baseline covariates. Prostate specific antigen (PSA) normalization (PSAN, or PSA of 4 ng/ml or less) was evaluated with a logistic model. RESULTS: Quartiles of hemoglobin were 10.1 or less, 10.2 to 12.0, 12.1 to 13.4 and greater than 13.4 gm/dl. In a multivariate model anemia was significantly associated (p <0.02) with being black, performance status 2 to 3 (vs 0 to 1), extensive disease and higher PSA. Anemia was inversely associated with prior therapy with curative intent and with Gleason score 6 to 7 (vs 5 or less), and was not associated with age or bone pain. After adjusting for potential confounders, lower hemoglobin was associated with shorter survival and PFS, and lower likelihood of PSAN with hormonal therapy (p <0.01). CONCLUSIONS: In this newly diagnosed metastatic prostate cancer sample, anemia was common and was associated with shorter survival, shorter PFS, and lower likelihood of PSAN with hormonal therapy after adjustment for disease status and other covariates.

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.