Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer

OBJECTIVE: To evaluate, in the ongoing Early Prostate Cancer (EPC) trial programme, the efficacy and tolerability of bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer. PATIENTS AND METHODS: The EPC programme comprises three randomized, double-blind, placebo-controlled trials designed for combined analysis. Following standard care, 8113 men with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) received oral bicalutamide 150 mg once daily or oral placebo. The primary endpoints were progression-free survival (PFS) and overall survival. RESULTS: The large EPC trial programme is defining men who benefit or do not from early or adjuvant antiandrogen therapy. At a median follow-up of 7.4 years, in localized disease there is no benefit to PFS by adding bicalutamide to standard care, and there is a trend (hazard ratio, HR, 1.16; 95% confidence intervals, CI, 0.99-1.37; P = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting. However, in locally advanced disease, bicalutamide significantly improved PFS irrespective of standard care. Bicalutamide significantly improved overall survival in patients receiving radiotherapy (HR 0.65; 95% CI 0.44-0.95; P = 0.03); this was driven by a lower risk of prostate cancer-related deaths. Bicalutamide produced a trend towards improved overall survival in patients with locally advanced disease otherwise undergoing watchful waiting (HR 0.81; 95% CI 0.66-1.01; P = 0.06). No survival difference was evident in the prostatectomy subgroup. CONCLUSIONS: This ongoing programme is clarifying the role of early or adjuvant antiandrogen therapy in prostate cancer. Patients with localized disease do not appear to derive clinical benefit from added bicalutamide. However, adding bicalutamide 150 mg to standard care provides significant clinical benefits in patients with locally advanced prostate cancer, irrespective of primary therapy.     

The impact of prior radical prostatectomy in men with metastatic castration recurrent prostate cancer: a pooled analysis of 9 Cancer and Leukemia Group B Trials

PURPOSE: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy. MATERIALS AND METHODS: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes. RESULTS: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9-16.7) and 14.5 months (95% CI 13.5-15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90-1.19, p = 0.65) in men with vs without prostatectomy. CONCLUSIONS: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer.     

Predictors of overall and cancer-free survival of patients with localized prostate cancer treated with primary androgen suppression therapy: results from the prostate cancer outcomes study

PURPOSE: Primary androgen suppression therapy for clinically localized prostate cancer is increasingly common in the United States despite a lack of supportive evidence for its use. We determined which demographic and clinical factors predict overall and cancer specific survival with this treatment strategy in patients enrolled in the Prostate Cancer Outcomes Study. MATERIALS AND METHODS: In 1994 to 1995 the Prostate Cancer Outcomes Study recruited 3,533 men diagnosed with prostate cancer. Clinical and treatment information was abstracted from medical records and demographic characteristics were obtained from patient surveys 6, 12, 24 and 60 months after diagnosis. Overall and cancer specific mortality was analyzed through December 2002 using the Kaplan-Meier method and Cox regression. RESULTS: A total of 276 patients had organ confined (cT1-2) prostatic adenocarcinoma and received primary androgen suppression therapy within 1 year of diagnosis. Median followup for censored patients was 7.6 years (range 1.1 to 8.1). Five-year overall and cancer specific survival was 66% (95% CI 59-72) and 91% (95% CI 86-94), respectively. Independent predictors of shorter overall survival were patient age 75 years or older, prostate specific antigen 20 ng/ml or greater, Gleason score 7 or greater and abnormal digital rectal examination. Gleason score 7 or greater, prostate specific antigen 20 ng/ml or greater and a low comorbidity index were independent predictors of shorter cancer specific survival. CONCLUSIONS: The use of primary androgen suppression therapy in the Prostate Cancer Outcomes Study data set resulted in 91% 5-year cancer specific survival. Advanced age, and factors that reflect tumor burden and biology were predictive of overall survival, while cancer specific survival was predicted by tumor factors and the burden of comorbid conditions. A nomogram for predicting overall survival at 5 years was constructed.     

The association between total and positive lymph node counts, and disease progression in clinically localized prostate cancer

PURPOSE: We examined the association between the number of LNs removed, the number of positive LNs and disease progression in patients undergoing pelvic lymph node dissection and radical retropubic prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS: We analyzed 5,038 consecutive patients who underwent radical retropubic prostatectomy between 1983 and 2003. Clinicopathological parameters, including the administration of neoadjuvant hormonal therapy, preoperative prostate specific antigen, specimen Gleason score, surgeon and pathological stage, were collected prospectively in our prostate cancer database. We excluded men treated with radiation or chemotherapy before surgery. BCR was defined as 2 postoperative prostate specific antigen increases greater than 0.2 ng/ml. Cox models were used to determine whether the number of nodes removed or the number of positive nodes predicted freedom from BCR after adjustment for prognostic covariates. RESULTS: The 4,611 eligible patients had a median of 9 LNs (IQR 5 to 13) removed. Positive nodes were found in 175 patients (3.8%). Overall the number of LNs removed did not predict freedom from BCR (HR per additional 10 nodes removed 1.02, 95% CI 0.92 to 1.13, p = 0.7). Results were similar in patients receiving and not receiving neoadjuvant hormonal therapy. Finding any LN involvement was associated with a BCR HR of 5.2 (95% CI 4.2 to 6.4, p <0.0005). However, in men without nodal involvement an increased number of nodes removed correlated significantly with freedom from BCR (p = 0.01). CONCLUSIONS: Nodal disease increased the risk of progression. Extensive lymphadenectomy enhances the accuracy of surgical staging. However, we were unable to determine that removing more nodes improves freedom from BCR uniformly. Since the proportion of patients with prostate cancer with positive nodes is low, the value of extensive lymphadenectomy requires a multi-institutional, randomized clinical trial.     

Association of body mass index with response and survival in men with metastatic prostate cancer: Southwest Oncology Group trials 8894 and 9916

PURPOSE: We evaluated the effect of body mass index on prostate specific antigen response, and progression-free and overall survival in men with androgen dependent or androgen independent metastatic prostate cancer. MATERIALS AND METHODS: We examined the prognostic impact of body mass index in patient cohorts from phase III randomized studies coordinated by the Southwest Oncology Group. The first study included 1,006 men treated with androgen deprivation for metastatic prostate cancer. The second study included 671 patients treated with chemotherapy for metastatic, androgen independent prostate cancer. RESULTS: Among men with androgen dependent disease, higher body mass index was associated with longer overall (p <0.001) and progression-free (p = 0.009) survival, as well as with an increased likelihood of achieving a prostate specific antigen nadir less than 4 ng/ml (p = 0.008). In multivariate analysis adjusting for risk factors, increasing body mass index was positively correlated with overall survival (p <0.01) and overweight but not obese patients (body mass index 27 to 29.9) had a significantly improved outcome compared to normal weight patients, with hazard ratios for risk of progression and death of 0.82 (95% CI 0.69, 0.98) and 0.75 (95% CI 0.63, 0.89), respectively. Among men with androgen independent prostate cancer, no clear association could be detected between body mass index and progression-free survival, overall survival or prostate specific antigen response. CONCLUSIONS: This study revealed higher body mass index to be associated with better overall and progression-free survival in patients with androgen dependent metastatic prostate cancer. Among men who had androgen independent disease, no significant association was found between body mass index and survival.     

Clinical outcomes by age in men with hormone refractory prostate cancer: a pooled analysis of 8 Cancer and Leukemia Group B (CALGB) studies

PURPOSE: We determined if age is a prognostic factor of clinical outcomes, specifically overall survival, disease-free survival and progression-free survival in men with hormone refractory prostate cancer. MATERIALS AND METHODS: Data from 8 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive adenocarcinoma of the prostate after androgen ablation, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate hematological, renal and hepatic function. The proportional hazards model stratified by study was used to assess the prognostic importance of age for predicting clinical outcomes. RESULTS: Of 1,194 men 132 (11%) were 50 to 60 years old and 120 (10%) were 80 to 89 years old. Median survival was 12.2 months (95% CI 10.6 to 13.8) in men 50 to 59 years old, 15.9 months (95% CI 14.2 to 17.6) in men 60 to 69 years old, 15.6 months (95% CI 13.8 to 16.9) in men 70 to 79 years old and 8.9 months (95% CI 6.6 to 12.1) in men 80 to 89 years old. Compared to 70 to 79-year-old men the HR for death in octogenarians was 1.3 (95% CI 1.0 to 1.6, p = 0.015). Furthermore, the HR for prostate cancer death in octogenarians was 1.3 (95% CI 1.1 to 1.7, p = 0.010) and in 50 to 59-year-old men it was 1.3 (95% CI 1.0 to 1.6, p = 0.042) compared to men 70 to 79 years old. Black men were at lower risk for death than white men (HR 0.77, 95 CI% 0.65 to 0.92, p = 0.004). CONCLUSIONS: Octogenarians and white men are at increased risk for death compared to other men with hormone refractory prostate cancer.     

Race and survival of men treated for prostate cancer on radiation therapy oncology group phase III randomized trials

PURPOSE: We assessed the impact of race on survival in men treated with external beam radiotherapy with or without hormonal therapy for localized prostate cancer in Radiation Therapy Oncology Group randomized trials. MATERIALS AND METHODS: Between 1975 and 1992, 2,048 men were treated for clinically localized prostate cancer in 1 of 4 consecutive prospective phase III randomized trials. After excluding nonblack and nonwhite men 2,012 remained for analysis. Patients were included in this analysis if they were deemed evaluable and eligible for the trial, and followup information and centrally reviewed pathological results were available. Short-term hormonal therapy consisted of goserelin acetate and flutamide administered 2 months before and during radiotherapy. Long-term hormonal therapy consisted of adjuvant goserelin acetate, which was generally given for 2 years or more. Pretreatment prostate specific antigen (PSA) findings were available in 430 cases (21%), including 213 treated with radiotherapy alone, 60 treated with short-term hormonal therapy and 157 on long-term hormonal therapy. Mean pretreatment PSA was 68.8 and 35.2 ng./ml. in black and white patients, respectively. Cox proportional hazards models were used to identify the impact of previously defined risk groups on overall and disease specific survival. Multivariate analysis was done for the significance of race using a stratified Cox model. Median followup in patients treated in early and late studies exceeded 11 and 6 years, respectively. RESULTS: On univariate analysis black race was associated with lower overall and disease specific survival (p = 0.04, RR = 1.24 and p = 0.016, RR = 1.41, respectively). After adjusting for risk group and treatment type (with or without short-term or long-term hormonal therapy) race was no longer associated with outcome (p >0.05). The trend for a persistent difference in survival was likely due to the higher tumor burden in black men, as reflected in higher PSA. CONCLUSIONS: As previously reported, tumor grade (Gleason score), palpation T stage, lymph node status, pretreatment PSA and treatment type are major predictors of overall and disease specific survival. We noted no evidence that race has independent prognostic significance in patients treated for prostate cancer in Radiation Therapy Oncology Group prospective randomized trials.     

Surrogate end point for prostate cancer specific mortality in patients with nonmetastatic hormone refractory prostate cancer

PURPOSE: We determined whether prostate specific antigen (PSA) velocity can serve as surrogate end point for prostate cancer specific mortality (PCSM) in patients with nonmetastatic, hormone refractory prostate cancer. MATERIALS AND METHODS: The study cohort comprised 919 men treated from 1988 to 2002 at 1 of 44 institutions with surgery (560) or radiation therapy (359) for clinical stages T1c-4NxMo prostate cancer, followed by salvage hormonal therapy for PSA failure. All patients experienced PSA defined recurrence while on hormonal therapy. Prentice criteria require that the surrogate should be a prognostic factor and the treatment used did not alter time to PCSM following achievement of the surrogate end point. These criteria were tested using Cox regression. All statistical tests were 2-sided. RESULTS: PSA velocity greater than 1.5 ng/ml yearly was statistically significantly associated with time to PCSM and all cause mortality following PSA defined recurrence while undergoing hormonal therapy (Cox p <0.0001). While initial treatment was statistically associated with time to PCSM and all cause mortality (Cox p = 0.001 and 0.01), this association became insignificant when PSA velocity and potential confounding variables were included in the Cox model (p = 0.22 and 0.93, respectively). The adjusted HR for PCSM in patients who experienced a greater than 1.5 ng/ml increase in PSA within 1 year while on hormonal therapy was 239 (95% CI 10 to 5,549). CONCLUSIONS: These data provide evidence to support PSA velocity greater than 1.5 ng/ml yearly as a surrogate end point for PCSM in patients with nonmetastatic, hormone refractory prostate cancer. Enrolling these men onto clinical trials evaluating the impact of chemotherapy on time to bone metastases and PCSM is warranted.     

Use of hormonal therapy in men with metastatic prostate cancer

PURPOSE: Bilateral orchiectomy or luteinizing hormone releasing hormone agonists represent the standard of care for metastatic prostate cancer. In this population based study we assessed the use rates of these therapies in men who died of prostate cancer. MATERIAL AND METHODS: A total of 9,110 men 65 years or older who died of prostate cancer in 1991 to 2000 were identified through the population based Surveillance, Epidemiology and End Results, and Medicare linked database to determine hormonal therapy use rates. A modified Poisson regression model was used to estimate the adjusted effects of various factors associated with hormone use. RESULTS: Approximately 38% of black and 25% of white men did not receive hormonal therapy before dying of prostate cancer. After adjusting for cancer status at diagnosis and other potential confounding factors black race and residence in low income areas were associated with lower hormonal therapy use (relative risk 0.73, 95% CI 0.67 to 0.80 and 0.91, 95% CI 0.85 to 0.98, respectively). Hormonal therapy use was most comprehensive in the Northeast. CONCLUSIONS: A substantial number of men who die as a consequence of prostate cancer never receive hormonal therapy. The use of hormonal therapy varies significantly. Further studies are warranted to determine factors that may be associated with the incomplete use of hormonal therapy for metastatic prostate cancer.     

Mortality After Prostate Cancer Treatment with Radical Prostatectomy,External-Beam Radiation Therapy,or Brachytherapy in Men Without Comorbidity

Background

Medical comorbidity is a confounding factor in prostate cancer (PCa) treatment selection and mortality. Large-scale comparative evaluation of PCa mortality (PCM) and overall mortality (OM) restricted to men without comorbidity at the time of treatment has not been performed.

Objective

To evaluate PCM and OM in men with no recorded comorbidity treated with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT).

Design, setting, and participants

Data from 10 361 men with localized PCa treated from 1995 to 2007 at two academic centers in the United States were prospectively obtained at diagnosis and retrospectively reviewed. We identified 6692 men with no recorded comorbidity on a validated comorbidity index. Median follow-up after treatment was 7.2 yr.

Intervention

Treatment with RP in 4459 men, EBRT in 1261 men, or BT in 972 men.

Outcome measurements and statistical analysis

Univariate and multivariate Cox proportional hazards regression analysis, including propensity score adjustment, compared PCM and OM for EBRT and BT relative to RP as reference treatment category. PCM was also evaluated by competing risks analysis.

Results and limitations

Using Cox analysis, EBRT was associated with an increase in PCM compared with RP (hazard ratio [HR]: 1.66; 95% confidence interval [CI], 1.05–2.63), while there was no statistically significant increase with BT (HR: 1.83; 95% CI, 0.88–3.82). Using competing risks analysis, the benefit of RP remained but was no longer statistically significant for EBRT (HR: 1.55; 95% CI, 0.92–2.60) or BT (HR: 1.66; 95% CI, 0.79–3.46). In comparison with RP, both EBRT (HR: 1.71; 95% CI, 1.40–2.08) and BT (HR: 1.78; 95% CI, 1.37–2.31) were associated with increased OM.

Conclusions

In a large multicenter series of men without recorded comorbidity, both forms of radiation therapy were associated with an increase in OM compared with surgery, but there were no differences in PCM when evaluated by competing risks analysis. These findings may result from an imbalance of confounders or differences in mortality related to primary or salvage therapy.     

p53 immunochemistry is an independent prognostic marker for outcome in conservatively treated prostate cancer

OBJECTIVE

To determine whether p53 is an independent biomarker of prostate cancer outcome against currently used biomarkers in a cohort of conservatively treated prostate cancers with long‐term follow‐up available.

PATIENTS AND METHODS

We examined p53 expression by immunohistochemistry in a cohort of 705 patients with clinically localized prostate cancer, who were treated conservatively. Patients were selected through UK Cancer Registries. End‐points included prostate cancer death and overall death rates. Standard biological variables, including diagnostic serum PSA, contemporary Gleason scoring, clinical staging and cancer extent were available. p53 expression was measured semi‐quantitatively on microscopic examination and compared with current clinical biomarkers.

RESULTS

p53 over expression was a significant predictor of cause‐specific survival (hazard ratio [HR] 2.95, 95% CI 2.05–4.25, P < 0.001) and overall survival (HR 2.37, 95% CI 1.84–3.05, P < 0.001). In multivariate analysis including competing biological variables p53 expression was still significantly linked to prostate cancer survival (HR 1.51, 95% CI 1.04–2.19, P = 0.03) and overall survival (HR 1.57, 95% CI 1.21–2.05, P = 0.001).

CONCLUSIONS

We conclude that p53 may have a role in the future assessment of newly diagnosed prostate cancer, as it significantly adds to the current prognostic model.     

Increasing prostate specific antigen following radical prostatectomy and adjuvant hormonal therapy: doubling time predicts survival

PURPOSE: Adjuvant hormonal therapy may be beneficial in patients who are treated with RRP and found to have adverse pathological findings. We assessed the natural history of detectable PSA in such patients with particular emphasis on the prognostic usefulness of PSADT. MATERIALS AND METHODS: We identified 903 patients treated with RRP and adjuvant hormonal therapy (started less than 90 days postoperatively) for prostate cancer at our institution between 1990 and 1999. PSADT was calculated by log linear regression in men with 2 or more PSA measurements available at least 90 days apart. CSS and sRFS were estimated by the Kaplan-Meier method and analyzed using Cox proportional hazard models. RESULTS: At a median followup of 9.1 years PSA had become detectable in 369 of 771 patients (47.9%) who achieved an undetectable nadir. PSADT evaluable in 463 patients was less than 12 months in 68 (14.6%) and more than 10 years in 283 (61.1%). N stage and Gleason score were significantly associated with sRFS and CSS. PSADT was a significant predictor of sRFS and CSS in N+ and N0 cases with a cancer death HR of 0.55 (95% CI 0.43 to 0.71) and 0.50 (95% CI 0.31 to 0.79), respectively. The association between PSADT and survival persisted after multivariate adjustment for preoperative PSA, specimen Gleason score and seminal vesicle invasion. CONCLUSIONS: This study demonstrates that many patients have slow progression despite increasing PSA following RRP and adjuvant hormonal therapy. Nodal status, cancer grade and PSADT are predictive of sRFS and CSS, and may be a useful means of selecting patients for future adjuvant therapy trials.     

Lymphovascular invasion is an independent prognostic factor in prostatic adenocarcinoma

PURPOSE: Gleason grade and tumor stage are well established prognostic factors in prostate cancer. Histological demonstration of tumor in lymphovascular spaces has been associated with poor prognosis in many tumor types but it is not included in current prostate cancer grading and staging schemes. Whether lymphovascular invasion is an independent prognostic factor for disease progression in prostate cancer is uncertain. We retrospectively investigated lymphovascular invasion as a predictive factor for biochemical failure and cancer specific survival following radical prostatectomy. MATERIALS AND METHODS: The records of 504 patients with prostatic adenocarcinoma undergoing radical prostatectomy were reviewed for lymphovascular invasion. Clinical followup data were available on 459 cases. Mean followup was 44 months (range 1.5 to 144). Multivariate analysis was performed using the Cox model. RESULTS: Lymphovascular invasion was identified in 106 cases (21%). Univariate analysis showed a significant association between lymphovascular invasion and higher preoperative serum prostate specific antigen (PSA), advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, lymph node metastasis and perineural invasion (each p <0.001). No association was observed between lymphovascular invasion and patient age at surgery, prostate weight or high grade prostatic intraepithelial neoplasia. Lymphovascular invasion was an independent predictor of PSA recurrence (HR 1.6, 95% CI 1.12 to 2.38, p = 0.01) and cancer specific survival (HR 2.75, 95% CI 1.04 to 2.28, p = 0.041) after controlling for tumor stage, surgical margins and Gleason grade on multivariate analysis. Five-year cancer specific survival was 90% in men with lymphovascular invasion compared to 98% in those without lymphovascular invasion (p <0.001). CONCLUSIONS: Lymphovascular invasion can be identified in approximately 20% of prostate cancer cases. Lymphovascular invasion is an independent risk factor for PSA recurrence and cancer death in patients with prostate cancer.     

Bladder cancer incidence and risk factors in men with prostate cancer: results from Cancer of the Prostate Strategic Urologic Research Endeavor

PURPOSE: We evaluated a large disease registry to determine the incidence of bladder cancer in patients with prostate cancer and investigate whether the type of treatment for prostate cancer increased the risk of bladder cancer. MATERIALS AND METHODS: We analyzed the CaPSURE disease registry for men diagnosed with prostate cancer plus bladder cancer between 1989 and 2003. Demographics, comorbidities and prostate cancer treatment modalities were compared in patients with and without bladder cancer. A backward stepwise Cox proportional hazards regression model was used to predict bladder cancer onset after treatment for prostate cancer in patients who had bladder cancer 30 days or greater after prostate cancer treatment. RESULTS: Of 9,780 patients from CaPSURE 143 (1.46%) also had bladder cancer. Patients with bladder cancer and prostate cancer were older (p<0.01) and more likely to be white (p=0.03), and they had lower levels of income (p<0.01) and education (p=0.04) than patients with prostate cancer only. Comorbidities did not differ between patients with and without bladder cancer. Patients treated with radical prostatectomy were approximately half as likely to have posttreatment bladder cancer as patients who underwent radiation therapy (HR 0.51, 95% CI 0.29-0.89). Patients who smoked had an independent increase in the risk of bladder cancer (HR 2.08, 95% CI 1.09-3.97), while smokers treated with radiation therapy were at almost 4-fold risk for bladder cancer (HR 3.65, 95% CI 1.45-9.16). CONCLUSIONS: The incidence of bladder cancer in patients with prostate cancer was 1.5%. Radiation therapy and smoking increased the risk of bladder cancer.     

Metastatic small cell carcinoma of the prostate: Population-based analysis of patient characteristics and treatment paradigms

IntroductionSmall cell carcinoma of the prostate is a rare malignancy comprising<1% of prostate cancers. Little is known about population-based treatment patterns for metastatic small cell carcinoma of the prostate. We evaluated clinical characteristics, treatment patterns, and survival outcomes.MethodsUsing the National Cancer Database, we identified patients between 1998 and 2011 diagnosed with pure small cell carcinoma of the prostate as their only malignancy who presented with nodal involvement or distant metastasis.ResultsTreatment information was available for 379 patients. Of them, 122 (32.5%) underwent chemotherapy (CT) alone, 25 (6.7%) received hormonal therapy (androgen-deprivation therapy) alone, 10 (2.7%) underwent radiation therapy alone, 3 (1%) underwent radical prostatectomy, and 167 (44.4%) underwent combination therapy. The 1- and 3-year survival rates were 35.3% and 4.4%, respectively. Those receiving any CT as part of their treatment had a median survival of 9.3 vs. 3.2 months for those not receiving it (P<0.001). Those receiving CT, androgen-deprivation therapy, and radiation had a median survival of 15.1 vs. 7 months for those receiving CT alone (P<0.001). On multivariable analysis (controlling for age, Charlson comorbidity index, extent of metastasis, prostate-specific antigen level, and type of treatment), older age (hazard ratio [HR] = 3.87; 95% CI: 1.41–9.34; P = 0.007) and distant metastatic disease (HR = 7.17; 95% CI: 1.62–31.8; P = 0.010) increased risk of death, whereas receipt of CT (HR = 0.15; 95% CI: 0.05–0.44; P = 0.001) decreased risk of death.ConclusionMen presenting with metastatic small cell carcinoma of the prostate have poor overall survival. Older patients and those presenting with distant metastases have an increased risk of death. It appears that patients receiving CT experience a modest survival benefit. The role of hormonal therapy in this population remains unclear.     

Effectiveness of androgen deprivation therapy in prolonging survival of older men treated for locoregional prostate cancer

Epidemiologic and experimental evidence suggests the effectiveness of androgen deprivation therapy (ADT) in prostate cancer (CaP) management. Although ADT has been increasingly used as mono-therapy in CaP, the survival benefit of ADT remains unclear. We examined the effectiveness of ADT in prolonging survival in a community-based cohort of 64 475 older men diagnosed with locoregional CaP, in 1992-1999 with last follow-up through December 2002, in 11 Surveillance Epidemiology and End Results (SEER) registries. The effect of ADT on survival was assessed using Kaplan-Meier's method, log-rank test and Cox proportional hazards. After adjustment for propensity to receive ADT, the ADT and non-ADT groups were significantly different in the distribution of covariates except for comorbidity score and SEER registries. The crude overall mortality was significantly higher in cases with ADT compared with cases that received no ADT, hazard ratio (HR=1.54; 95% CI=1.50-1.58). However, mortality was substantially reduced (1.04, 1.00-1.08) after adjusting for standard care, socio-demographics, tumor characteristics, prognostic factors and chemotherapy. Therefore, ADT was not associated with significantly increased survival benefit for older men with locoregional CaP. Further studies may be needed to explore whether ADT is associated with other health benefits and the cost-effectiveness of these benefits.     

Comparison of the clinical outcome after hormonal therapy for prostate cancer between Japanese and Caucasian men

OBJECTIVE: To investigate the impact of race on the effectiveness of hormonal therapy in patients with prostate cancer, by comparing the outcomes of Caucasian men (CM) and Japanese-American men (JAM) treated with hormonal therapy at one institution. PATIENTS AND METHODS: Fifty-nine CM and 105 JAM with prostate cancer were treated with hormonal therapy at The Queen's Medical Center in Honolulu. Age, stage, Gleason score, race, and pretreatment PSA levels were abstracted. The Kaplan-Meier method was used to construct overall and cause-specific survival curves, which were compared using log-rank statistics. These factors were assessed as to their interdependence and correlation with the clinical course using a Cox proportional hazards regression model. RESULTS: Although there were no statistical differences in patient background, JAM who had received hormonal treatment had a better outcome than CM for overall and cause-specific survival rate (P = 0.001 and 0.036, respectively). Race was one of the significant prognostic factors in the multivariate analysis (P = 0.03). The findings suggest a difference in the effectiveness of hormonal therapy for prostate cancer in JAM living in Hawaii compared to CM. CONCLUSIONS: There were marked racial differences in clinical outcome after hormonal therapy between JAM and CM. A prospective study with more patients might be necessary to elucidate the differential effectiveness of hormonal therapy for prostate cancer in different races, especially between Japanese and Caucasians.     

Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials

BackgroundThe importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown.ObjectiveTo evaluate the clinical implications of LF after definitive RT.Design, setting, and participantsIndividual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials.Outcome measurements and statistical analysisMultivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints.Results and limitationsMedian follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37–2.10]), PCSS (3.10 [95% CI 2.33–4.12]), and DMFS (HR 1.92 [95% CI 1.54–2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04–0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22–4.93], p = 0.01) than those who did not.ConclusionsLF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined.Patient summaryMen who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.     

Androgen-deprivation Therapy in Treatment of Prostate Cancer and Risk of Myocardial Infarction and Stroke: A Nationwide Danish Population-based Cohort Study

BackgroundAndrogen-deprivation therapy (ADT) has been suggested to increase the risk for cardiovascular diseases, including myocardial infarction (MI) and stroke, but data are inconsistent.ObjectivesTo investigate the association between ADT and risk for MI and stroke in Danish men with prostate cancer.Design, setting, and participantsA national cohort study of all patients with incident prostate cancer registered in the Danish Cancer Registry from January 1, 2002, through 2010 was conducted.Outcome measurements and statistical analysisWe used Cox regression analysis to estimate hazard ratios (HR) of MI and stroke for ADT users versus nonusers, adjusting for age, prostate cancer stage, comorbidity, and calendar period. Additionally, we stratified the analysis on preexisting MI/stroke status.Results and limitationsOf 31 571 prostate cancer patients, 9204 (29%) received medical endocrine therapy and 2060 (7%) were orchidectomized. Patients treated with medical endocrine therapy had an increased risk for MI and stroke with adjusted HRs of 1.31 (95% confidence interval [CI], 1.16–1.49) and 1.19 (95% CI, 1.06–1.35), respectively, compared with nonusers of ADT. We found no increased risk for MI (HR: 0.90; 95% CI, 0.83–1.29) or stroke (HR: 1.11; 95% CI, 0.90–1.36) after orchiectomy. One limitation of the study is that information on prognostic lifestyle factors was not included and might have further informed our estimates.ConclusionsIn this nationwide cohort study of >30 000 prostate cancer patients, we found that endocrine hormonal therapy was associated with increased risk for MI and stroke. In contrast, we did not find this association after orchiectomy.     

Race and cause specific survival with prostate cancer: influence of clinical stage, Gleason score, age and treatment

PURPOSE: We assess the influence of race on stage stratified cause specific survival of men with prostate cancer, and Gleason score, age at diagnosis and treatment on potential racial differences in survival. MATERIALS AND METHODS: A total of 524 black and 396 white men were diagnosed with prostate cancer at a Veterans Affairs Medical Center between January 1982 and December 1992. Clinical stage was determined by retrospective review of the medical records and Gleason score of biopsy material as assigned by a single uropathologist. Of 611 patients who died the cause of death was determined by retrospective or prospective review of hospital records in 493 and by review of the death certificates in 102. In 16 cases the cause of death was indeterminate. Median potential followup was 112 months (range 60 to 182) and median period of observation was 61 months (range 1 to 182). RESULTS: Cause specific survival with stage T1b-2 cancer was lower in 231 black than in 264 white men of all ages (p = 0.02) and lower in 110 black than in 170 white men younger than in 70 years at diagnosis (p = 0.04). Gleason 7 to 10 cancer, which was associated with a less favorable cause specific survival compared to Gleason 2 to 6 cancer (p <0.0001), was more common in black than in white men with stage T1b-2 cancer of all ages (p = 0.01) and younger than 70 years at diagnosis (p = 0.04). No or unknown treatment status, which was associated with a less favorable cause specific survival compared to treatment (p = 0.05), was more common in black than in white men with stage T1b-2 cancer of all ages (p = 0.0005) but not significantly different when stratified by age. In men of all ages racial differences in cause specific survival were not significant when adjusted for age and Gleason score (p = 0.14) or age, Gleason score and treatment status (p = 0.17). In men younger than 70 years racial differences in cause specific survival were not significant when adjusted for age and Gleason score (p = 0.22). There were no significant racial differences in overall or age stratified all cause survival of men with stage T1b-2 cancer. There were no significant differences in overall or age stratified cause specific or all cause survival of 112 black and 58 white men with stage T3-4 cancer, or 181 and 74, respectively, with metastatic cancer. CONCLUSIONS: Our data indicate that local stage prostate cancer is more lethal in black than in white men and the difference is most pronounced in men younger than 70 years. The survival disadvantage of black men with local stage cancer is due in part to a propensity for development of less differentiated and more aggressive malignancies.