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.     

Population based study of hormonal therapy and survival in men with metastatic prostate cancer

PURPOSE: Although the palliative benefits of hormonal therapy for metastatic prostate cancer are widely recognized, little information is available regarding the effect of hormonal therapy on cancer specific and overall survival, and the types of patients who might benefit the most or least from hormonal therapy. MATERIALS AND METHODS: Prostate cancer specific and overall survival according to hormonal therapy use was determined by the Kaplan-Meier method in 6,098 men 65 years or older diagnosed with metastatic prostate cancer in 1991 to 1999 who were identified through the population based Surveillance, Epidemiology, and End Results, and Medicare linked database. Cox proportional hazards and propensity score methods were used to adjust for potential confounders, such as disease status and patient comorbidity. RESULTS: Propensity score adjusted median overall survival was 26 months in men who received hormonal therapy compared with 13 months in those who did not (HR 0.66, 95% CI 0.17-0.70, p <0.0001). The benefit of hormonal therapy was observed across all comorbidity strata and races. Effects were most evident in patients with poorly differentiated cancer (cancer specific mortality in favor of treatment HR 0.60, 95% CI 0.53-0.69, p <0.001). Benefit was not found in patients with well differentiated cancer (cancer specific mortality in favor of no treatment HR 1.92, 95% CI 0.90-4.10, p = 0.09). CONCLUSIONS: Hormonal therapy is associated with improved prostate cancer specific and overall survival in men with poorly differentiated cancer. Improved survival does not appear evident in men with well differentiated disease.     

Osteoporosis in men treated with androgen deprivation therapy for prostate cancer

PURPOSE: We surveyed the growing literature on osteoporosis secondary to androgen deprivation therapy and provide suggestions regarding its identification and treatment. MATERIALS AND METHODS: We reviewed pertinent studies of male osteoporosis, osteoporotic fracture incidence or bone mineral density loss as a possible side effect of prostate cancer treatment and potential therapies for this side effect. RESULTS: Hypogonadism is a well-known cause of secondary osteoporosis in men. There is evidence of decreased bone mineral density with all types of androgen deprivation therapy, presumably due to its anti-testosterone effect. Bone mineral density loss is 3% to 5% yearly in the first few years of androgen deprivation therapy with an increase in osteoporotic fracture incidence. There are little data on potential treatments, although bisphosphonates and intermittent androgen deprivation therapy may have salutary effects. CONCLUSIONS: Osteoporosis is an important and debilitating side effect of androgen deprivation therapy, although precise estimates of its incidence, degree and cost are not completely elucidated. Until more data are available, it is prudent for all men beginning androgen deprivation therapy to receive calcium and vitamin D, and maintain a moderate exercise regimen. Baseline and at least 1 followup bone density measurement seem appropriate with bisphosphonate treatment a possibility in those in whom osteoporosis develops. More research is needed to explore the effect of bisphosphonates, calcium and vitamin D supplementation, exercise, calcitonin, selective estrogen re-uptake inhibitors, estrogens and intermittent androgen deprivation therapy on the course of androgen deprivation therapy induced osteoporosis. The osteoporotic fracture incidence and bone mineral density should be regularly incorporated into studies involving the hormonal treatment of prostate cancer.     

Management of decreased bone mineral density in men starting androgen‐deprivation therapy for prostate cancer

OBJECTIVE

To determine whether clinicians discuss bone‐specific side‐effects with patients on androgen‐deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side‐effect of ADT, leading to increased risk of fracture.

PATIENTS AND METHODS

Sixty‐six men (mean age 70.6 years) with non‐metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual X‐ray absorptiometry (DXA) at baseline. Patients were interviewed to obtain their medical histories, and charts were reviewed to determine whether clinicians documented potential bone side‐effects in clinic notes, and made lifestyle and/or medication recommendations. Both were done at the start of ADT, and 3 and 6 months later. Patients were classified based on DXA T‐score as having normal BMD, as osteopenic, or osteoporotic.

RESULTS

At baseline, 53% of patients had osteopenia and 5% had osteoporosis. Within 6 months of starting ADT, general side‐effects and bone‐specific side‐effects of ADT were documented as being discussed with 26% and 15%, respectively. Clinicians recommended lifestyle interventions to 11% of patients. Pharmacological interventions (calcium, vitamin D, and/or bisphosphonates) were recommended to 18% of all patients within 6 months of starting ADT, and to 26% and 67% of osteopenic and osteoporotic patients, respectively.

CONCLUSIONS

A minority of patients is being informed of bone‐specific side‐effects of ADT. Lifestyle and drug interventions to prevent declines in BMD were recommended uncommonly. Practices around bone health for men starting ADT are suboptimal.     

Bone health in men receiving androgen deprivation therapy for prostate cancer

PURPOSE: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. MATERIALS AND METHODS: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. RESULTS: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. CONCLUSIONS: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential.     

The effect of androgen deprivation therapy on periodontal disease in men with prostate cancer

PURPOSE: We tested the hypothesis that men undergoing androgen deprivation therapy as treatment for prostate cancer are at greater risk for periodontitis and tooth loss. MATERIALS AND METHODS: A total of 81 men with a mean age of 68.5 years who had prostate cancer were consecutively recruited among 325 enrolled in an academic osteoporosis study. Of these men 68 were eligible to participate in the research. The prevalence of periodontal disease in 41 men with prostate cancer undergoing androgen deprivation for a mean of 1.5 years was compared to that in 27 with prostate cancer not undergoing androgen deprivation, who served as controls. The prevalence of periodontal disease was examined in relation to bone mineral density in men with prostate cancer with and without androgen deprivation therapy. A periodontist (PF) blinded to androgen deprivation status recorded probing depth, clinical attachment level, bleeding, plaque scores, gingival recession, missing teeth and calculus. Logistic regression models were used to test the association between androgen deprivation therapy and periodontal disease. Linear regression models were used to assess the association between periodontal disease and bone mineral density in the 2 groups with prostate cancer (treated/untreated). We adjusted for variables known to influence periodontal disease, including patient age, race, smoking and periodontal disease history. RESULTS: The prevalence of periodontal disease was 80.5% in men on androgen deprivation therapy compared with 3.7% in those not on androgen deprivation therapy (OR 3.33, 95% CI 1.07-10.35). Men on androgen deprivation therapy had significantly greater probing depth and higher plaque scores (p<0.001 and <0.09, respectively). A total of 81 men (76.9%) completed bone mineral density examinations. There was no relationship between bone mineral density and periodontal disease. CONCLUSIONS: Men with prostate cancer undergoing androgen deprivation therapy were more likely to have periodontal disease than men not on androgen deprivation therapy. If confirmed in larger studies, this observation could have important public health implications, given the increasing use of androgen deprivation therapy to treat prostate cancer.     

An analysis of men with clinically localized prostate cancer who deferred definitive therapy

PURPOSE: We evaluated expectant management of prostate cancer with definitive treatment deferred until evidence of cancer progression in men with low risk, localized cancers. MATERIALS AND METHODS: We retrospectively reviewed prospectively entered data base records. Patients with low risk cancer who were eligible for definitive therapy but chose deferred management between 1984 and 2001 composed the cohort. Followup included regular evaluations to detect progression by prostate specific antigen (PSA), digital rectal examination, transrectal ultrasound and prostate biopsy. Objective progression was defined by a point scale of changes in prognostic factors. Definitive treatment was recommended in patients with objective progression. RESULTS: The cohort comprised 88 patients with clinical stages T1-2, NX0, M0 prostate cancer, a mean age of 65.3 years and a mean initial PSA of 5.9 ng/ml. Systematic biopsy, which was repeated after the initial diagnostic biopsy, showed no cancer in 61% of cases. During a median followup of 44 months 22 patients had progression. Factors that predicted progression were repeat biopsy showing cancer (p = 0.004) and initial PSA (p = 0.014). Actuarial 5 and 10-year progression-free probabilities were 67% and 55%, respectively. Of the 31 patients treated 17 underwent radical prostatectomy, 13 received radiation therapy and 1 received androgen ablation. Seven men who did not show objective progression were treated because of anxiety. Only 1 patient, who was treated with radiation therapy, had biochemical recurrence. CONCLUSIONS: Deferred therapy may be a feasible alternative to curative treatment in select patients with favorable, localized prostate cancer. About half of these patients remain free of progression at 10 years and definitive treatment appeared effective in those with progression. Absent cancer on repeat needle biopsy identified cases highly unlikely to progress.     

Influence of prostate volume and percent free prostate specific antigen on prostate cancer detection in men with a total prostate specific antigen of 2.6 to 10.0 ng/ml

PURPOSE: Percent free prostate specific antigen and prostate specific antigen density have been independently shown to increase the specificity of prostate cancer screening in men with prostate specific antigen levels between 4.1 and 10.0 ng/ml. Recent data suggest the total prostate specific antigen cutoff for performing a biopsy should be 2.6 ng/ml. We assessed the influence of percent free prostate specific antigen and prostate volume on cancer detection in men with a prostate specific antigen between 2.6 and 10.0 ng/ml. MATERIALS AND METHODS: From 1991 to 2005 all transrectal ultrasound guided prostate biopsies (5,587) for abnormal digital rectal examination and/or increased age specific prostate specific antigen were evaluated. A total of 1,072 patients with a prostate specific antigen between 2.6 and 10.0 ng/ml and any percent free prostate specific antigen were included in study. The cancer detection rate was calculated for each percent free prostate specific antigen/volume stratum. RESULTS: Prostate cancer was detected in 296 patients (27.6%). The mean age and prostate specific antigen of the patients with benign pathology and prostate cancer were similar. Mean percent free prostate specific antigen was 17.5% and 14.1% (p>0.05), and the mean volume was 62.0 and 46.0 cc (p=0.001), respectively. The strongest risk factors for a positive biopsy were percent free prostate specific antigen (odds ratio 0.004, p<0.001), volume (OR 0.977, p<0.001) and digital rectal examination (OR 1.765, p=0.007), but not total prostate specific antigen (p=0.303). When stratified by volume and percent free prostate specific antigen, distinct risk groups were identified. The probability of detecting cancer inversely correlated with prostate volume and percent free prostate specific antigen. CONCLUSIONS: In men with prostate specific antigen levels between 2.6 and 10.0 ng/ml, the probability of detecting cancer was inversely proportional to prostate volume and percent free prostate specific antigen. This table may assist in predicting patient risk for harboring prostate cancer.     

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.     

Continuing controversy over monitoring men with localized prostate cancer: a systematic review of programs in the prostate specific antigen era

PURPOSE: There is continuing controversy over the most appropriate treatment for screen detected and clinically localized prostate cancer, and increasing interest in monitoring such men initially with radical treatment targeted at cancers showing signs of progressive potential but while they are still curable. Current evidence on monitoring protocols and biomarkers used to predict disease progression was systematically reviewed. MATERIALS AND METHODS: The MEDLINE and Excerpta Medica (EMBASE) bibliographic databases were searched from 1988 to October 2004, supplemented by manual searches of reference lists, focusing on studies reporting monitoring of men with localized prostate cancer. RESULTS: A total of 48 potentially eligible articles were found but only 5 studies, in which there was a total of 451 participants, restricted entry criteria to men with clinically localized (T1-T2) prostate cancer. Monitoring protocols varied with little consensus, although the majority used prostate specific antigen and digital rectal examination, while some added re-biopsy to assess progression. Actuarial probabilities of freedom from disease progression at 4 to 5 years of followup were 67% to 72%. However, up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to increasing prostate specific antigen rather than objective evidence of disease progression. There was no robust evidence to support prostate specific antigen doubling times or velocity to identify men in whom disease may progress. Studies were characterized by small sample size, short-term followup, observer bias and uncertain validity around variable definitions of progression. CONCLUSIONS: Current evidence suggests that some form of monitoring would be a suitable treatment option in men with localized prostate cancer but there is little consensus over what markers should be used in such a program or how progression should be properly defined. The search for a method that safely identifies men with prostate cancer who could avoid radical intervention must continue.     

Prevalence of prostate specific antigen testing for prostate cancer in elderly men

PURPOSE: We investigated the prevalence and outcome of PSA testing for prostate cancer screening or diagnosis in elderly men 75 years or older at our academic medical center. MATERIALS AND METHODS: A cross-sectional study design was used to identify all men 75 years or older who underwent a PSA test through the family medicine or internal medicine service at our institution between January 1, 1998 and June 30, 2004. All patients with a suspected (PSA less than 0.1 ng/ml) or confirmed prior diagnosis of prostate cancer were excluded. The prevalence of PSA testing was then compared to that in younger age groups (45 to 54, 55 to 64 and 65 to 74 years). We then examined the frequency and nature of further evaluation and treatment performed in men following the PSA test. RESULTS: The 8,787 male patients who were 75 years or older generated a total of 82,672 visits in the 5.5-year period. Of these patients 505 (5.7%) underwent at least 1 PSA test. The prevalence of PSA testing in the younger age groups was 10.3% (1,769 of 17,175) in patients 45 to 54 years old, 14.9% (2,052 of 13,772) in those 55 to 64 years old and 11.8% (1,258 of 10,661) in those 65 to 74 years old (chi-square test p <0.001). Of these patients 98 of 343 (28.6%) with PSA between 0.1 and 4 ng/ml were referred to a urologist at our institution and 3 underwent biopsy. None had a prostate cancer diagnosis. Of the 162 patients with PSA more than 4 ng/ml 84 (51.9%) were referred to a urologist. Only 10 of the 84 patients (11.9%) who were referred to a urologist underwent prostate biopsy. Six of the 10 men (60%) were diagnosed with prostate cancer, including 1 with a Gleason 6 tumor, 1 with a Gleason 7 tumor and 4 who were found to have tumors with a Gleason score of 8 or greater. All patients received androgen deprivation therapy, except 1 who received local external beam radiation therapy. An additional patient was diagnosed by biopsy of a vertebral lesion and he received hormone therapy. At a median followup of 51 months (range 28 to 72) 4 of 7 men (57%) were alive with disease. CONCLUSIONS: PSA testing for prostate cancer screening and diagnosis appear to decrease with advancing age. A small but significant proportion of men who are 75 years or older continue to undergo PSA testing. Abnormal PSA results do not always result in further evaluation and therapy for prostate cancer in elderly men. The establishment of firm guideline recommendations regarding PSA testing and further evaluation for prostate cancer in elderly men, perhaps based on individualized geriatric assessment, may be helpful.     

Survival outcomes in men receiving androgen‐deprivation therapy as primary or salvage treatment for localized or advanced prostate cancer: 20‐year single‐centre experience

OBJECTIVES

To evaluate the overall survival (OS) and disease‐specific survival (DSS) in men receiving primary androgen‐deprivation therapy (PADT) or salvage medical ADT (SADT) for prostate cancer.

PATIENTS AND METHODS

After Institutional Review Board approval, we retrospectively reviewed patients receiving ADT for prostate cancer between July 1987 and June 2007. Variables included age at diagnosis and ADT induction, race, PSA level before ADT, ADT schedule (continuous/intermittent), clinical/pathological stage, hormone‐refractory prostate cancer (HRCP) status, PADT or SADT, and deaths.

RESULTS

In all, 548 men were analysed. The mean age at diagnosis and ADT induction were 70.1 and 72.3 years, respectively, and 321 (58.6%) were African‐American. The median PSA level before ADT was 16.3 ng/mL. ADT was administered continuously in 497 (90.7%) patients; 342 (62.4%) received PADT while 206 (37.6%) received SADT. At mean (range) follow‐up of 81.8 (2.1–445) months, 98 (17.9%) deaths occurred; 31 (31.6%) were cancer‐specific. The OS and DSS in the PADT and SADT groups were not significantly different (P = 0.36 and P = 0.81, respectively). Mortality rates/distributions were similar between groups (P = 0.68). Multivariate predictors of OS and DSS included age at diagnosis (P = 0.03) and ADT induction (P = 0.009), tumour stage (P < 0.001), and PSA level at ADT induction (P = 0.01). Progression to HRPC worsened OS and DSS (both P < 0.001).

CONCLUSION

PADT and SADT prolong survival in men with prostate cancer. HRPC portends a poor DSS. Age at diagnosis and ADT induction, PSA level before ADT, and disease stage predict both OS and DSS in this population. However, most men died from causes unrelated to prostate cancer, thus questioning the true value of ADT in prolonging patient survival.     

Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails

PURPOSE: We investigate the prostate specific antigen (PSA) response rate with nilutamide as a second line hormonal agent in patients with advanced prostate cancer in whom androgen ablation failed. MATERIALS AND METHODS: From 1998 to 2001, 28 patients with hormone resistant prostate cancer were treated with nilutamide as second line hormonal therapy. Average patient age +/- SD was 72.9 +/- 9.1 years. Median time from diagnosis of cancer to hormone failure was 48 months (range 2 to 120). Median followup from initiation of nilutamide therapy was 26 months (range 15 to 44). All patients had previously received at least 1 antiandrogen (flutamide or bicalutamide) in addition to medical or surgical castration, which failed. RESULTS: Upon initiation of nilutamide therapy 18 of the 28 patients (64%) had an initial reduction in PSA and 8 (29%) sustained a PSA response (greater than 50% decrease) beyond 3 months (range 3 to 21). PSA response to nilutamide in patients with a previous antiandrogen withdrawal response versus nonresponse was 100% and 18%, respectively. In 10 of the 28 patients, (36%) PSA continued to increase. Interstitial pneumonitis developed, in 1 patient and 5 had nonspecific complaints (headaches, nausea, dizziness). During followup 6 of the 28 patients died 1 of whom was a nilutamide responder. No patient died while on nilutamide. CONCLUSIONS: Nilutamide can achieve a significant sustained PSA response with a favorable toxicity profile. Patients with a previous antiandrogen withdrawal response have a significantly greater chance of responding to nilutamide.