Castration induces autoantibody and T cell responses that correlate with inferior outcomes in an androgen-dependent murine tumor model.

We recently reported that hormone therapy induces antigen-specific autoantibody responses in prostate cancer patients. However, the contribution of autoantibody responses to clinical outcomes is unknown. We used an animal model to test the hypothesis that hormone therapy-induced immune responses may be associated with delayed tumor recurrence. Male DD/S mice bearing established tumors from the androgen-dependent Shionogi carcinoma line were castrated to induce tumor regression. Tumor-specific autoantibody responses were measured by immunoblot, and the underlying antigen was identified by serological screening of a cDNA expression library. T cell responses were assessed by immunohistochemistry and IFN-gamma ELISPOT. Following castration, 97% of mice underwent complete tumor regression. Of these, 72% experienced tumor recurrence 18-79 days postcastration, whereas the remaining 28% remained tumor-free for the duration of the experiment. In 55% of mice, castration induced autoantibody responses to an antigen identified as poly(A) binding protein nuclear 1 (PABPN1). Castration also induced PABPN1-specific T cell responses, which were highly correlated to autoantibody responses, and this was accompanied by dense infiltration of tumors by CD3+ T cells 1-2 weeks after castration. Unexpectedly, mice that developed autoantibody and T cell responses to PABPN1 showed a higher rate and shorter latency of tumor recurrence. In mice with recurrent tumors, T cell responses to PABPN1 were still detectable; however, T cell infiltrates were restricted to the peripheral stroma of tumors. In conclusion, castration-induced immune responses are associated with inferior outcomes in the Shionogi carcinoma model, raising concerns about the influence of treatment-induced immune responses on clinical outcomes in humans.

Does neoadjuvant hormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy?

PURPOSE: To assess outcome and predictive factors in men with prostate cancer who receive post radical prostatectomy (RP) radiotherapy (RT) either in the adjuvant or salvage setting, with or without neoadjuvant androgen deprivation therapy (NADT). METHODS: A retrospective analysis was performed on 175 patients with clinically localized prostate cancer treated with RP who subsequently received RT (dose range 50 Gy-68 Gy). Twenty-two patients received adjuvant RT (ART), 57 received NADT + ART, 15 received salvage RT (SRT), and 81 received NADT + SRT. Outcome was assessed by biochemical disease free survival (BDFS), prostate cancer specific survival and overall survival (OS). RESULTS: Although BDFS favored patients who received NADT with 5 year rates of 67%, 80%, 27% and 62% for the ART, NADT + ART, SRT, and NADT + SRT groups respectively; this was not a significant predictor on multivariable analysis. Significant independent predictive factors of improved BDFS were pre-RT PSA < or = 0.2 ng/ml, low Gleason score and positive surgical margins. Age and Gleason score were independent predictors of OS. CONCLUSIONS: Pre-RT PSA is an important predictor of outcome. NADT appears to benefit patients who presented with a pre-RT PSA > 0.2 ng/ml, particularly for patients receiving SRT. NADT can be considered for patients receiving RT after RP who present with a high pre-RT PSA but may not be necessary for patients without. Results of ongoing randomized studies such as RADICALS will also help clarify the role of hormone therapy in conjunction with RT.

Standard treatments induce antigen-specific immune responses in prostate cancer.

PURPOSE: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. EXPERIMENTAL DESIGN: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. RESULTS: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. CONCLUSION: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.

Hemoglobin levels do not predict biochemical outcome for localized prostate cancer treated with neoadjuvant androgen-suppression therapy and external-beam radiotherapy.

PURPOSE: To investigate whether hemoglobin (Hb) levels affect outcome in men with localized prostate adenocarcinoma (LPA) treated with neoadjuvant androgen-suppression therapy (NAST) and external-beam radiotherapy (EBRT). METHODS AND MATERIALS: A total of 563 men with LPA treated with NAST (median: 5.3 months) and EBRT who had Hb levels during treatment were retrospectively reviewed. Patient, tumor, and treatment variables, including the following Hb variables, were subjected to univariate and multivariable analyses to identify factors that predict biochemical control (bNED) and overall survival (OS): pre-EBRT Hb, Hb nadir during EBRT, and change in Hb from pre-EBRT to nadir during EBRT. RESULTS: Median PSA follow-up was 4.25 years. Forty-nine percent of men were anemic during EBRT, with a median Hb of 13.4 g/dL, and 68% experienced a decline in Hb from pre-EBRT to during EBRT of median 0.6 g/dL. Five-year Nadir+2 bNED and OS rates were similar for anemic and nonanemic patients during EBRT. High percent-positive biopsies, PSA and Gleason score, and use of AA monotherapy predicted worse bNED. High stage and age predicted worse OS. Hb variables were not predictive of bNED or OS. CONCLUSIONS: Anemia is a common side effect of NAST and is usually mild. Hb levels, however, do not predict biochemical control or survival.

Prospective evaluation of the prevalence and severity of fatigue in patients with prostate cancer undergoing radical external beam radiotherapy and neoadjuvant hormone therapy.

OBJECTIVE: To prospectively evaluate the prevalence and severity of fatigue and its impact on quality of life (QOL) during and after radical external beam radiotherapy (RT) for prostate cancer. METHOD AND MATERIALS: Twenty-eight men with prostate cancer undergoing RT over 6-8 consecutive weeks were prospectively accrued. The Brief Fatigue Inventory (BFI), a validated fatigue assessment tool, was administered at five time points: baseline (week 1), middle of RT (week 3-4), end of RT (last week of RT), and follow-up (median 6.5 weeks after RT). The BFI contained nine questions, each using 0-10 ratings to quantify fatigue severity and interference with six QOL domains. The prevalence of moderate-severe fatigue was plotted as a function of time. Mean sum and subscale scores at each time point were compared to baseline scores using Wilcoxon tests. Linear regression analyses were performed to assess associations between fatigue scores and age, tumor and treatment characteristics. RESULTS: The median age was 69 years (range 57-84), Gleason score 7 (range 6-10), and presenting PSA 9.0 ng/mL (range 2.5 ng/mL-103.0 ng/mL). Patients were treated once daily to a median dose of 74 Gy (range 60 Gy-78 Gy) over a median of 37 fractions (range 30-39). Hormone therapy was used in all patients (median duration 12.2 months). The prevalence of moderate-severe present fatigue increased from 7% at baseline to 8% at mid-RT and 32% at RT completion. Compared to baseline (mean score 11.5), fatigue increased significantly mid-RT (mean score 14.6, p = 0.03) and peaked at the end of RT (mean score 23.5, p = 0.001). Fatigue significantly interfered with walking ability, normal work, daily chores, and enjoyment of life only at the end of RT. After RT completion, fatigue improved but remained higher compared to baseline at 6.5 weeks of follow-up (mean score 15.0, p = 0.02). On linear regression analysis, age, Gleason score, PSA, T-stage, hormone therapy duration, RT dose and fractions were not significantly associated with mean fatigue scores. CONCLUSION: Patients undergoing 6-8 weeks of RT experienced significant fatigue adversely affecting QOL persisting after therapy completion. Since walking ability was not affected until the end of RT, a walking exercise intervention to combat fatigue is likely feasible and is being investigated.

Neoadjuvant hormone therapy and external-beam radiation for localized high-risk prostate cancer: the importance of PSA nadir before radiation.

PURPOSE: To examine the impact of various patient, disease, and treatment characteristics on outcome in patients treated with neoadjuvant hormone therapy (NAHT) and external-beam radiation therapy (EBRT) for clinically localized, high-risk prostate adenocarcinoma (initial prostate-specific antigen [PSA] level >20, Gleason score 8-10 or Stage > or = T3). METHODS AND MATERIALS: A retrospective chart review was conducted on 407 patients treated between 1991 and 2001 with NAHT and EBRT for high-risk prostate cancer. The effect of tumor (PSA level, Gleason score, and T stage) and treatment (NAHT duration, total-hormone duration, preradiation PSA) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival, and overall survival were examined. RESULTS: Median follow-up time was 78 months (range: 5-140 months). Actuarial bDFS at 5 years was 52% (95% confidence interval [CI], 46% to 57%) for the entire group. On multivariate analysis, initial PSA level (p = 0.004), Gleason score (p = 0.005), and preradiation PSA level (p < 0.001) were predictive of bDFS, whereas age, T stage, duration of NAHT, and duration of total hormone therapy were not predictive of outcomes. Gleason score and preradiation PSA level were also predictive of prostate cancer-specific survival rates. CONCLUSION: Improved bDFS in patients with high-risk prostate cancer was associated with lower initial PSA level, lower Gleason score, and lower preradiation PSA level. The duration of NAHT did not have an impact on outcomes, but the preradiation PSA was an important predictor of bDFS in high-risk patients.

Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer.

PURPOSE: To evaluate the effect of 3 months vs. 8 months of neoadjuvant hormonal therapy before conventional dose radiotherapy (RT) on disease-free survival using prostate-specific antigen PSA and biopsies as end points for clinically localized prostate cancer. METHODS AND MATERIALS: Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before conventional-dose RT (66 Gy) at four participating centers. The median patient age was 72 years (range, 50-84 years). The stage distribution was 17% T1c, 35% T2a, 34% T2b-T2c, 13% T3-T4. The Gleason score (GS) was < or =6 in 51%, 7 in 38%, and 8-10 in 11%. The median baseline PSA level was 9.7 ng/mL (range, 1.3-189 ng/mL). Of the 378 men, 26% were low risk (Stage T1c-T2a, GS < or =6, PSA <10 ng/mL), 43% were intermediate risk (Stage T2b or GS 7 or PSA 10-20 ng/mL), and 31% were high risk (Stage T3 or GS 8-10 or PSA >20 ng/mL). The two arms were balanced in terms of age, GS, T stage, risk group, and presenting PSA level. The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation. RESULTS: The 8-month arm achieved a lower PSA level before starting RT (0.37 vs. 0.74 ng/mL, p < or =0.001) and had a greater downsizing of the prostate (mean volume 26.6 cm(3) vs. 30.5 cm(3), p < or =0.001). However, the actuarial freedom from failure rate (biochemical by American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. 8-month arms at 3 years was 66% vs. 68% and by 5 years was 61% vs. 62%, respectively (p = 0.36). No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical, 22.2% vs. 22.3%; local, 10.2% vs. 6.5%; and distant, 3.4% vs. 4.4% (p = 0.61). Two-year post-RT biopsies were done in 57% (n = 205). Negative biopsies were obtained in 68% of the 3-month and 77% of the 8-month patients; 18% and 14% had indeterminate biopsies and 14% and 9% were positive for residual cancer (p = 0.34) in the two arms, respectively. The median PSA level for nonfailing patients was 0.50 ng/mL in both the 3-months and 8-month arms. A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs. 52%) but did not achieve statistical significance. CONCLUSION: A longer period of neoadjuvant hormonal therapy before standard-dose RT does not appear to confer a benefit in terms of disease-free survival or to alter failure patterns. Failure was delayed in the 8-month arm, but this advantage was lost by 5 years of follow-up. A suggestion of benefit was noted with a longer period of hormonal therapy for high-risk patients.

Tumor-associated autoantibodies correlate with poor outcome in prostate cancer patients treated with androgen deprivation and external beam radiation therapy.

Standard cancer treatments trigger immune responses that may influence tumor control. The nature of these responses varies depending on the tumor and the treatment modality. We previously reported that radiation and androgen-deprivation therapy (ADT) induce tumor-associated autoantibody responses in prostate cancer patients. This follow-up analysis was conducted to assess the relationship between autoantibody responses and clinical outcome. Patients with non-metastatic prostate cancer received external beam radiation therapy (EBRT) plus neoadjuvant and concurrent androgen deprivation. Treatment-induced autoantibodies were detected in almost a third of patients receiving combinatorial ADT and EBRT. Unexpectedly, patients that developed autoantibody responses to tumor antigens had a significantly lower 5-year biochemical failure-free survival (BFFS) than patients that did not develop an autoantibody response. Thus, tumor-reactive autoantibodies may be associated with increased risk of biochemical failure and immunomodulation to prevent autoantibody development may improve BFFS for select, high-risk prostate cancer patients receiving both ADT and EBRT.

Optimizing cancer treatments to induce an acute immune response: radiation Abscopal effects, PAMPs, and DAMPs.

Clinical results indicate improved survival in poorly differentiated prostate cancer patients following a treatment schedule that maximizes hormone therapy prior to radiation. This may be because of a systemic immune response, called an abscopal effect. A literature review showed an association between acute infection and abscopal cancer remission. This led to the theory that, in the presence of endogenous cancer-specific antigens exposed by cancer necrosis, an innate immune response can adapt to respond to those antigens via a cross-talk mechanism. This theory was validated in an animal model. An acute innate immune T-cell response was stimulated using cluster vaccination with Poly(I:C). In the presence of exogenous cancer-specific antigens, this immune response became adaptive, creating an abscopal effect that resulted in cancer resolution. These concepts may be of clinical value, improving outcomes by inducing systemic abscopal effects.

Extreme-risk prostate adenocarcinoma presenting with prostate-specific antigen (PSA)>40 ng/ml: prognostic significance of the preradiation PSA nadir.

PURPOSE: To examine the impact of patient, disease, and treatment characteristics on survival outcomes in patients treated with neoadjuvant androgen deprivation therapy (ADT) and radical external-beam radiotherapy (RT) for clinically localized, extreme-risk prostate adenocarcinoma with a presenting prostate-specific antigen (PSA) concentration of >40 ng/ml. METHODS AND MATERIALS: A retrospective chart review was conducted of 64 patients treated at a single institution between 1991 and 2000 with ADT and RT for prostate cancer with a presenting PSA level of >40 ng/ml. The effects of patient age, tumor (presenting PSA level, Gleason score, and T stage), and treatment (total ADT duration and pre-RT PSA level) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were examined. RESULTS: Median follow-up time was 6.45 years (range, 0.09-15.19 years). Actuarial bDFS, PCSS, and OS rates at 5 years were 39%, 87%, and 78%, respectively, and 17%, 64%, and 45%, respectively, at 10 years. On multivariate analysis, the pre-RT PSA level (≤0.1 versus >0.1 ng/ml) was the single most significant prognostic factor for bDFS (p=0.033) and OS (p=0.018) rates, whereas age, T stage, Gleason score, and ADT duration (≤6 versus >6 months) were not predictive of outcomes. CONCLUSION: In prostate cancer patients with high presenting PSA levels, >40 ng/ml, treated with combined modality, neoadjuvant ADT, and RT, the pre-RT PSA nadir, rather than ADT duration, was significantly associated with improved survival. This observation supports the use of neoadjuvant ADT to drive PSA levels to below 0.1 ng/ml before initiation of RT, to optimize outcomes for patients with extreme-risk disease.

Prospective evaluation of a 12-week walking exercise program and its effect on fatigue in prostate cancer patients undergoing radical external beam radiotherapy.

OBJECTIVE: To evaluate tolerability and compliance to a walking exercise program and its effect on fatigue during and after radical external beam radiation therapy (EBRT) for prostate cancer. METHODS: A total of 50 subjects with prostate cancer undergoing EBRT over 6 to 8 weeks were prospectively accrued to an exercise intervention group, matched for age and clinical characteristics to 30 subjects in a historical control group who underwent EBRT with no specific exercise intervention. Starting 1 week before EBRT, exercise participants performed moderate-intensity walking targeting 60% to 70% age-predicted maximum heart rate, at least 20 min/d, 3 d/wk over 12 weeks. The Brief Fatigue Inventory was administered at baseline, mid-EBRT (week 3-4), end-EBRT (week 6-8), and 6 months post-EBRT. RESULTS: Of 50, 42 (84%) of exercise participants completed the walking program. There were no cardiovascular complications, musculoskeletal injuries, or other adverse events. A total of 89% subjects reported "Good-Excellent" satisfaction during and up to 6 months post-EBRT. Fatigue in control subjects escalated from baseline to end-EBRT, remaining high at 6 months post-EBRT (P[r] = 0.03). In contrast, mean total fatigue scores in exercise subjects were stable from baseline up to 6 months post-EBRT (P = 0.52). Trends for higher fatigue interference with quality of life were observed in the control group as compared with the exercise group. CONCLUSIONS: Moderate-intensity walking exercise during radical EBRT is safe and feasible. The high convenience and satisfaction ratings, in conjunction with the observed fatigue trends, indicate that this activity has the potential to attenuate fatigue and improve quality of life for patients with localized prostate cancer undergoing curative therapy.

Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- versus 8-month randomized trial.

PURPOSE: To ascertain whether biochemical response to neoadjuvant androgen-deprivation therapy (ADT) before radiotherapy (RT), rather than duration, is the critical determinant of benefit in the multimodal treatment of localized prostate cancer, by comparing outcomes of subjects from the Canadian multicenter 3- vs 8-month trial with a pre-RT, post-hormone PSA (PRPH-PSA) < or =0.1 ng/ml vs those >0.1 ng/ml. METHODS AND MATERIALS: From 1995 to 2001, 378 men with localized prostate cancer were randomized to 3 or 8 months of neoadjuvant ADT before RT. On univariate analysis, survival indices were compared between those with a PRPH-PSA < or =0.1 ng/ml vs >0.1 ng/ml, for all patients and subgroups, including treatment arm, risk group, and gleason Score. Multivariate analysis identified independent predictors of outcome. RESULTS: Biochemical disease-free survival (bDFS) was significantly higher for those with a PRPH-PSA < or =0.1 ng/ml compared with PRPH-PSA >0.1 ng/ml (55.3% vs 49.4%, p = 0.014). No difference in survival indices was observed between treatment arms. There was no difference in bDFS between patients in the 3- and 8-month arms with a PRPH-PSA < or =0.1 ng/ml nor those with PRPH-PSA >0.1 ng/ml. bDFS was significantly higher for high-risk patients with PRPH-PSA < or =0.1 ng/ml compared with PRPH-PSA >0.1 ng/ml (57.0% vs 29.4%, p = 0.017). Multivariate analysis identified PRPH-PSA (p = 0.041), Gleason score (p = 0.001), initial PSA (p = 0.025), and T-stage (p = 0.003), not ADT duration, as independent predictors of outcome. CONCLUSION: Biochemical response to neoadjuvant ADT before RT, not duration, appears to be the critical determinant of benefit in the setting of combined therapy. Individually tailored ADT duration based on PRPH-PSA would maximize therapeutic gain, while minimizing the duration of ADT and its related toxicities.

Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer.

PURPOSE: To evaluate the effect of 3 vs. 8 months of neoadjuvant hormonal therapy before conventional-dose radiotherapy (RT) on disease-free survival for localized prostate cancer. METHODS AND MATERIALS: Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before 66 Gy RT at four participating centers. The median baseline prostate-specific antigen level was 9.7 ng/mL (range, 1.3-189). Of the 378 men, 26% had low-, 43% intermediate-, and 31% high-risk disease. The two arms were balanced in terms of age, Gleason score, clinical T category, risk group, and presenting prostate-specific antigen level. The median follow-up for living patients was 6.6 years (range, 1.6-10.1). Of the 378 patients, 361 were evaluable, and 290 were still living. RESULTS: The 5-year actuarial freedom from failure rate for the 3- vs. 8-month arms was 72% vs. 75%, respectively (p = 0.18). No difference was found in the failure types between the two arms. The median prostate-specific antigen level at the last follow-up visit for patients without treatment failure was 0.6 ng/mL in the 3-month arm vs. 0.50 ng/mL in the 8-month arm. The disease-free survival rate at 5 years was improved for the high-risk patients in the 8-month arm (71% vs. 42%, p = 0.01). CONCLUSION: A longer period of NHT before standard-dose RT did not alter the patterns of failure when combined with 66-Gy RT. High-risk patients in the 8-month arm had significant improvement in the 5-year disease-free survival rate.

Twenty-four-month postradiation prostate biopsies are strongly predictive of 7-year disease-free survival: results from a Canadian randomized trial.

BACKGROUND: The objective of this study was to evaluate the predictive value of prostate biopsies that were obtained 24 months after the completion of radiotherapy (RT) with respect to disease-free survival (DFS) in a randomized trial that compared 3 months versus 8 months of neoadjuvant hormone therapy before conventional dose external RT. METHODS: From February 1995 to June 2001, 378 men were randomized to receive either 3 months or 8 months of combined flutamide and goserelin before they received 66 Gray of RT at 4 participating centers. By risk group, 26% of patients were categorized as low risk, 43% were categorized as intermediate risk, and 31% were categorized as high risk. The 2 treatment arms were balanced in terms of age, Gleason score, clinical tumor classification, risk group, and presenting prostate-specific antigen level. The median follow-up for the patients who remained alive was 6.6 years (range, 1.6-10.1 years). Of 361 evaluable patients, 290 patients remained alive. Post-RT prostate biopsies were performed between 24 and 30 months after the completion of RT in 3 of the 4 centers. Biopsies that had residual tumor with severe treatment effect were considered indeterminate, and biopsies that had minimal or no treatment effect were considered positive. RESULTS: The 5-year rate of actuarial freedom from any failure for the 3-month arm versus the 8-month arm was 72% versus 75% (P = .18). The DFS for patients who had negative and indeterminate biopsies was similar. Two-year post-treatment biopsy status was a strong predictor of 5-year DFS rate (82% and 83% for negative and indeterminate biopsies, respectively, vs 27% for positive biopsies; P < .0001). Multivariate analysis indicated that biopsy status (P < .0001) and Gleason score (P < .0001) were the strongest determinates of biochemical DFS. CONCLUSIONS: Two-year post-RT prostate biopsies were strongly predictive of subsequent DFS. Biopsies with severe treatment effect were considered negative.

Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions.

PURPOSE: We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of androgen suppression therapy (AST). PATIENTS AND METHODS: The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Gray's regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Gray's k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST. RESULTS: Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not receive AST (P = .017) and men younger than 65 years (P = .016). No significant difference (P = .97) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of AST compared with 3 months of AST. CONCLUSION: The use of AST is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST.

Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters.

BACKGROUND: This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation. METHODS: Patients who demonstrated a rising serum prostate-specific antigen (PSA) level after they received radiotherapy and who were without evidence of distant metastasis were accepted into the study. Treatment in each cycle consisted of cyproterone acetate given as lead-in therapy for 4 weeks, followed by a combination of leuprolide acetate and cyproterone acetate, which ended after a total of 36 weeks. RESULTS: Of 109 patients registered, 103 patients were eligible for interruption of treatment, yielding a PSA response rate of 95%. The study continued for 6 years with a mean follow-up of 3.7 years (median follow-up, 4.2 years). The time off treatment averaged 53% of the total cycle time but, in absolute terms, decreased with each succeeding cycle, ranging from 63.7 weeks in Cycle 1 to 25.6 weeks in Cycle 5. Prostate volume was reduced by 40% in Cycle 1 and by 34% in Cycle 2, and there were no decreases in Cycle 3 or Cycle 4. At the end of the trial, 38.5% of patients still were receiving treatment, 23.9% of patients had failed, and 15.6% of patients had died. Only 2% of deaths were cancer-specific. CONCLUSIONS: Biochemical recurrence after irradiation for localized prostate cancer was amenable to cyclic androgen withdrawal therapy and showed a high response rate. Despite progressively shorter treatment cycles, the off-treatment interval remained appreciable, ranging from 65% in Cycle 1 to 46% in Cycle 5.