Months Of Androgen Deprivation Therapy Research Articles

Kinetics of Serum Androgen Normalization and Factors Associated With Testosterone Reserve After Limited Androgen Deprivation Therapy for Nonmetastatic Prostate Cancer

Groups have investigated time to testosterone recovery in patients who have undergone androgen deprivation therapy, usually by measuring androgen every 3 months, with varying results. To our knowledge this represents the largest study using monthly testosterone and dihydroxytestosterone measurement to evaluate the kinetics of androgen recovery following limited androgen deprivation therapy. Monthly serum androgen levels were analyzed following 2, 6-month cycles of gonadotropin-releasing hormone agonist therapy as part of a randomized, placebo controlled study of the role of thalidomide in delaying time to prostate specific androgen progression. By the Kaplan-Meier method the median time to testosterone normalization in cycles 1 vs 2 was 15.4 vs 18.3 weeks with similar dihydroxytestosterone recovery times. Neither on-study prostate specific antigen, Gleason score nor thalidomide treatment had a significant impact on time to testosterone normalization. However, in cycle 1 men with low baseline dihydroxytestosterone and those who were more than 67 years old had significantly longer time to T normalization on Cox model analysis. Additionally, in cycle 2 patients with prior local radiation therapy had longer time to testosterone normalization, although this was no longer significant on Cox model analysis. Cox model analysis in cycle 2 showed that low baseline dihydroxytestosterone and testosterone, low testosterone nadir and white race were associated with longer time to testosterone normalization. Findings of delayed testosterone recovery may be useful for designing and analyzing clinical trials of limited androgen deprivation therapy and for estimating the duration of treatment associated side effects in patients undergoing limited androgen deprivation therapy.

Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer.

Men with prostate-specific antigen (PSA)-only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT. Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of 9 months of complete androgen blockade (CAB) achieved with combined leuprolide and flutamide followed by an 'off treatment' period. Cognitive function tests and mood measures were administered at baseline, after 3 and 9 months of ADT and after 3 months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals. ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared with baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self-rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared with baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group. These findings, suggest that 9 months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT.

Prostate Specific Antigen Working Group Guidelines on Prostate Specific Antigen Doubling Time

Prostate specific antigen is a glycoprotein found almost exclusively in normal and neoplastic prostate cells. Prostate specific antigen doubling time, or the change in prostate specific antigen over time, has emerged as a useful predictive marker for assessing disease outcome in patients with prostate cancer. It is important to agree on definitions and values for the calculation of prostate specific antigen doubling time, and to develop a common approach to outcome analysis and reporting. In September 2006 a conference was held at the National Cancer Institute in Bethesda, Maryland to define these parameters and develop guidelines for their use. The Prostate Specific Antigen Working Group defined criteria regarding prostate specific antigen doubling time including the calculation of prostate specific antigen doubling time, evidence to support prostate specific antigen doubling time as a predictive factor in the setting of biochemical recurrence and the use of prostate specific antigen doubling time as a stratification factor in clinical trials. We propose that investigators calculate prostate specific antigen doubling time before enrolling patients in clinical studies and calculate it as an additional measurement of therapeutic activity. We believe we have developed practical guidelines for the calculation of prostate specific antigen doubling time and its use as a measurement of prognosis and outcome. Furthermore, the use of common standards for prostate specific antigen doubling time in clinical trials is important as we determine which treatments should progress to randomized trials in which "hard" end points such as survival will be used.

Physical Function Changes in Prostate Cancer Patients on Androgen Deprivation Therapy: A 2-Year Prospective Study

To investigate the influence of androgen deprivation therapy (ADT) in men with nonmetastatic prostate cancer. We conducted a 2-year controlled, prospective study. Twenty-three men on 6 months or longer of ADT (chronic), 12 men on less than 6 months of ADT (acute), and 13 men not on ADT (healthy controls or prostate cancer patients not on ADT) were studied. We used validated, objective tests for physical and visual-motor function and dual X-ray absorptiometry for body composition at baseline and at 24 months. We found the baseline percentage of body fat increased and baseline percentage of lean mass decreased with duration of ADT (P <0.002 across groups for both). After 24 months, men on chronic ADT had significant declines in lean body mass percentage (P = 0.058) and increases in body fat percentage (P = 0.029). Men on acute ADT had smaller but still significant differences in body composition at baseline and similar trends at 24 months. At baseline, men on chronic ADT had longer chair rise times than men on no ADT (P = 0.073) or acute ADT (P = 0.035). Four-meter walk velocities at 24 months were slower in men on acute (P = 0.006) and chronic ADT (P <0.001). Declines in lean body mass and increases in body fat percentage over 2 years are observed in men on ADT. Lower body physical function performance is reduced in men on chronic ADT. Changes in body composition and physical function should be considered in men on long-term ADT.

Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610

Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.

Competing Risks for Patients With Localized Prostate Cancer

In health care, as in the rest of life, decisions have consequences. A chosen treatment for prostate cancer can yield benefits, but it can also cause harm. In localized prostate cancer, as in most diseases, baseline characteristics influence the natural history of the disease and thus a treatment’s potential for benefit. The most relevant estimates for an individual come from studies involving patients who are similar to the individual selecting treatment. The recently updated guideline from the American Urological Association lists the following primary treatments for localized prostate cancer: watchful waiting, active surveillance, interstitial brachytherapy, external beam radiotherapy, radical prostatectomy, primary hormonal therapy, and others (e.g., cryotherapy) ( 1 ). To choose from this menu, patients must fi rst weigh their individualized risk of death from prostate cancer in the absence of treatment and then each treatment’s likely effect on that risk, along with associated specifi c types and risks of complications. These guidelines caution patients that there are important limitations to the available studies because follow-up is often insuffi cient for most treatment options, researchers use inconsistent defi nitions for the most commonly reported complications, and authors often fail to adequately detail baseline patient characteristics. Finally, because most evidence is derived from case series and small randomized trials that frequently pool data from patients with various levels of disease burden, the evidence base is subject to selection and other biases. Selecting a primary therapy is not the only choice facing patients with localized prostate cancer. Some patients are offered androgen deprivation therapy (ADT) after prostatectomy or radiation therapy (adjuvant ADT) that can continue for years. Others are offered several months of ADT (neoadjuvant ADT) before defi nitive primary therapy. Many trials on adjuvant or neoadjuvant ADT for localized or locally advanced prostate cancer fail to report the key outcome of interest, and most do not report outcomes stratifi ed by risk groups. Some reviews address side effects of ADT ( 2 , 3 ) but focus primarily on morbidity and quality of life. A recently published Cochrane systematic review ( 4 ) reported estimates for outcomes of treatment effi cacy by primary therapy (prostatectomy or radiation therapy) and by type of hormonal deprivation (adjuvant or neoadjuvant). ADT use for patients with localized prostate cancer has increased substantially over time ( 5 ), and recent evidence suggests that ADT may be associated with increased risk for diabetes and cardiovascular disease ( 6 ). In this issue of the Journal, Tsai et al. ( 7 ) use registry data from the Cancer of the Prostate

Comparative study of the protective effect of different intravenous bisphosphonates on the decrease in bone mineral density in patients submitted to radical prostatectomy undergoing androgen deprivation therapy. A prospective open‐label controlled study

To establish whether androgen deprivation therapy (ADT) promotes osteoporosis and osteopenia Ninety-four prostatectomized men with rising prostrate-specific antigen (PSA) were enrolled into the placebo group (31), monthly i.v. clodronate (39) or monthly i.v. zoledronic acid (24) groups for 36 months. Dual-energy X-ray absorptiometry measured the bone density in the lumbar (L2-L4) area. chi(2) and anova tests were used to analyze data.. After 6 months of androgen deprivation, 17 of the 31 control cases developed osteopenia in the lumbar area. At 12 months, nine control cases had osteoporosis with 13 additional cases of osteopenia. At the end of the 36-month study period, the untreated group showed an average bone mineral density (BMD) loss of -1.82 (+/-0.94) with 13 cases of osteopenia and 18 cases of osteoporosis. The clodronate group had two cases of osteoporosis out of 39 subjects after 6 months of ADT with 28 developing osteopenia and seven cases of osteoporosis after 36 months of follow up. Mean BMD loss in this group was -0.72 (+/-0.34). The zoledronic acid studied arm had seven cases of osteopenia after 6 months of ADT while 20 and five cases developed osteopenia and osteoporosis, respectively, after 36 months of follow up. The former group had a mean bone loss of -0.88 (+/-0.32). There was statistical difference for BMD loss in the treated groups starting at 6 months in comparison to the control group. Six months of ADT promoted impressive bone loss in the lumbar area of the non-treated patients. This tendency is progressive and may be delayed by i.v. bisphosphonates.

Functional heterogeneity of prostatic intraepithelial neoplasia: the duration of hormonal therapy influences the response

To use a clinical model of androgen-deprivation therapy (ADT) followed by radical prostatectomy (RP) to test the hypothesis that prostatic intraepithelial neoplasia (PIN, a premalignant lesion of the prostate causally linked to prostate cancer) is heterogeneous for hormone responsiveness, which might explain aspects of the heterogeneity of the natural history of prostate cancer, for although ADT has been used to reduce prostate cancer, there are controversial data on the effect of ADT on PIN. We assessed retrospectively patients with biopsy-confirmed prostate cancer who had RP; some patients had received >or=3 months of ADT at the discretion of their surgeons, and patients from the same cohort who did not have ADT were used as controls. Patients were sequentially selected from the database and their pathology slides were reviewed by a pathologist unaware of the initial presence of PIN (assessed by an independent observer). Fisher's exact test was used to compare the proportions of patients who had residual PIN in the study and control groups. Exact logistic regression was used to evaluate the duration of ADT on PIN regression. Eighteen patients initially diagnosed with PIN who had no ADT were identified, and 28 with PIN who had ADT were also assessed. All patients who had had no ADT had residual PIN, whereas seven of 28 receiving ADT had no residual PIN (P=0.043). The evaluation of ADT between responders and nonresponders showed a statistically significant association between PIN regression and the duration of ADT (P<0.001). However, the response of PIN to ADT was not uniform, as 16% of patients on ADT for >6 months had residual PIN, suggesting variable sensitivity of PIN to ADT. These results show that ADT causes PIN to regress, and that there is heterogeneity in this effect with the duration of ADT. We propose future prospective, multicentre, randomized trials in which the effect of ADT on PIN is characterized further.

Androgen Deprivation in Veterans with Prostate Cancer: Implications for Skeletal Health

Common risk factors for osteoporosis in older men include smoking, heavy use of alcohol, propensity to falls, and use of bone-toxic medications such as prednisone. There is also increasing appreciation of the skeletal risk faced by men receiving androgen deprivation therapy (ADT) for prostate cancer. Measures to prevent bone loss in such patients are available. To test the following hypotheses in a population of veterans receiving ADT for prostate cancer: (1) fracture risk factors in addition to androgen deprivation would be found in most patients, (2) bone mass measurements would be assessed in a minority of patients, and (3) a minority of the subjects would receive bisphosphonate therapy or have contraindications for such treatment. We conducted a retrospective chart review of male veterans receiving ADT from 1993 through 2001, at the Veterans Affairs Medical Center, Madison, WI. One hundred and seventy-four subjects met study criteria, with a mean age of 76 years and median duration of 21 months of ADT. Eighty-one percent had risk factors in addition to ADT. Only 13% underwent bone density measurement by dual energy X-ray absorptiometry (DXA) and, of those measured, more than half had osteoporosis. Only 19% of the men received both calcium and vitamin D supplements. Antiresorptive therapy was provided to 11% of men, although more than two-thirds had no contraindications to therapy. A total of 24 men sustained a fracture after starting ADT. For men who did undergo bone density measurement, 77% received antiresorptive therapy. Of those who exhibited osteoporosis by DXA scan, 85% received antiresorptive therapy. Male veterans receiving ADT for prostate cancer received inadequate evaluation and treatment for osteoporosis. Based on our data, a simple and practical strategy to prompt further evaluation and improved care may be to undertake bone density measurements in men prior to or soon after commencing ADT.

2302: Greater Than 6 Months of Androgen Deprivation Therapy Does Not Improve Overall Survival for High-Risk Prostate Cancer Patients Treated With Radiotherapy or Prostatectomy

To analyze the effect of the duration of androgen deprivation (AD) in the definitive treatment of high-risk prostate cancer. A total of 579 patients with high-risk prostate cancer were treated definitively at the Cleveland Clinic from 1998 to 2003 with either external beam radiation (RT, n=390), radical prostatectomy (RP, n=165), or permanent prostate implant (PI, n=24). High-risk disease was defined as: initial PSA (iPSA)> 20, Gleason score (GS) 8–10, clinical stage T3, or iPSA 10–20 and GS 7. The study endpoints were: biochemical failure [(bF), using the ASTRO consensus definition for RT and PI patients and two consecutive PSA’s ≥0.2ng/ml for RP patients], clinical failure [(cF), defined as the detection of biopsy proven local recurrence, or evidence of definite metastases to bone, lymph nodes, or elsewhere] and overall survival (OS). Cox proportional hazards regression was used to determine what factors, including iPSA, GS, stage, AD, age, race, income, BMI, and smoking history correlated with bF, cF, and OS. Median follow up was 60 months (range: 24–114). Median age for all patients was 67 years (range: 41–85). AD was given to 426 (73.6%) patients, with 82.6% of those patients receiving 1–6 months (median 6 months) and 17.4% receiving >6 months (median 15 months) of AD. Univariate analysis revealed that > 6 months of AD had no statistically significant impact on bF or cF, but did result in a statistically significant worse OS, (p=0.0003). Other factors found to result in worse OS on univariate analysis included GS ≥ 8 (p=0.0424), active tobacco use (p=0.0467), and increasing number of pack-years smoked (p=0.0139). Kaplan-Meier estimates of OS for patients receiving no AD vs. 1–6 months of AD vs. > 6 months of AD were 92%, 92%, and 76% at 5-years and 78%, 84%, and 67% at 7-years, respectively (p=0.0007). The use of >6 months of AD remained an independent predictor of death on multivariate analysis (RR 2.158, p=0.0329), as did Gleason score and increasing number of pack-years smoked. While smoking and use of >6 months of AD both had a detrimental effect on OS, no synergistic effect between the two factors was detected. In high-risk patients treated with radiotherapy or prostatectomy, longer duration of androgen deprivation (> 6 months) does not improve biochemical or clinical failure rates, and appears to result in worse overall survival. The cause of this lower overall survival is unknown and warrants further investigation.

The prognostic value of hemoglobin change after initiating androgen‐deprivation therapy for newly diagnosed metastatic prostate cancer

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

Functional heterogeneity of prostatic intra-epithelial neoplasia: Length of hormonal therapy influences response

4648 Background: Prostatic intraepithelial neoplasia (PIN) is a premalignant lesion of the prostate etiologically linked to prostate cancer. While androgen deprivation therapy (ADT) has been used to reduce prostate cancer, there are controversial data regarding the effect of ADT on PIN. We hypothesized that PIN is a heterogeneous entity with respect to hormone responsiveness, that this may explain aspects of the heterogeneity in the natural history of this disease, and have used the clinical model of ADT followed by radical prostatectomy as a test of this hypothesis. Methods: We performed a retrospective study on a cohort of patients who underwent prostatectomy with biopsy proven prostate cancer. Study patients were those who must have received at least 3 months of ADT at the discretion of their surgeons. Patients from the same cohort who did not undergo ADT were used as controls. Patients were randomly selected from the database and their pathology slides were reviewed by a blinded pathologist looking for presence of PIN with an independent observer. Fisher’s exact test was used to compare the proportions of subjects who had residual PIN in the study group and the control group. Exact logistic regression was used to evaluate the duration of ADT in PIN regression. Results: Eighteen patients initially diagnosed with PIN who did not receive hormonal therapy were identified; 28 patients with PIN who underwent hormonal therapy were also studied. All patients who did not receive hormonal therapy had residual PIN whereas 7 of 28 patients undergoing ADT had no residual PIN (p = 0.043). Evaluation of hormonal therapy between responders and non-responders showed statistically significant association between PIN regression and hormone therapy duration (p &lt; 0.001). However PIN response to ADT was not uniform as 16% of patients with ADT longer than 6 months had residual PIN, suggesting variable sensitivity of PIN to ADT. Conclusions: Our results demonstrate that ADT does cause PIN regression, and that there is heterogeneity in this effect with respect to hormonal duration. We propose for future prospective, multi-centered, randomized trials in which ADT impact on PIN is characterized further. No significant financial relationships to disclose.

Is physical function affected by androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer?

4615 Background: Although prolonged use ofADT is hypothesized to adversely affect physical function, only a few small studies have examined this relationship and it remains unclear if self-reported weakness represents a decline in actual physical performance or is related to fatigue. Loss of physical function may be particularly important to older men who already have limited functional reserves. Methods: Men age 50 or older with non-metastatic prostate cancer who were starting continuous ADT were enrolled in this prospective longitudinal study. Physical function was tested using a Jamar dynamometer (grip strength), the Timed Up and Go (TUG) test, and the six-minute walk test (6MWT), representing upper extremity strength, lower extremity strength, and endurance, respectively. Assessments were done at baseline (prior to ADT), 3 months, 6 months, and 12 months. Results: 42 patients on ADT have been enrolled to date (mean age 74.8 y). There was a gradual but steady decline in grip strength from baseline (39.2 kg) to 3 months (38.1 kg), 6 months (37.9 kg), and 12 months (35.3 kg) (p &lt; 0.05 for all comparisons). On average, patients took 7.3 seconds to complete the TUG and walked 1507 feet during the 6MWT at baseline. TUG and 6MWT scores did not worsen over time (p &gt; 0.05). Conclusions: Preliminary data suggest that 3–12 months of ADT is associated with worsening upper extremity strength but lower extremity strength and endurance are relatively unaffected. A larger sample size is needed to determine if all aspects of physical function or only upper extremity strength deteriorate with ADT use. Additionally, most patients in our study reported excellent health and functional status at baseline and our results may not adequately reflect the impact of ADT in more frail older men. No significant financial relationships to disclose.

The Increasing Responsibility of the Urologist in Maintaining Bone Health in Prostate Cancer Patients

Objectives Many men with prostate cancer are osteoporotic or osteopenic before the initiation of androgen deprivation therapy (ADT). Furthermore, they may develop decreased bone mineral density (BMD) and associated increased risks of skeletal complications during therapy. This review provides urologists with information to address bone health issues in men with prostate cancer. Methods Guidelines and therapies were identified and researched through PubMed. Results Studies report clinically significant changes in BMD after 12 months of ADT, and after 5 to 7 years there is a substantially increased risk of fracture. An algorithm for the assessment of BMD, treatment of osteoporosis, and prevention of fractures in patients with prostate cancer has been developed. BMD assessments before ADT is initiated and annually thereafter are recommended. Bisphosphonates effectively preserve BMD in this setting. Zoledronic acid not only prevented bone loss, but produced an increase from baseline BMD at one year in the lumbar spine, femoral neck, trochanter, and hip. Conclusions Maintaining bone health in men with prostate cancer may be an important part of overall disease management. Indeed, proactive intervention with an intravenous bisphosphonate such as pamidronate or zoledronic acid may prevent bone loss and improve BMD in these patients.

Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime

High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of < or =6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered. Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an alpha /beta of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen > or =10, Gleason score > or =7, or clinical stage > or =T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used. Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G0. Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of < or =6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation.

The effect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer

Objective. To evaluate body composition changes, specifically skeletal muscle mass, in men receiving androgen deprivation with luteinizing-hormone releasing hormone-agonist (LHRH-A) for prostate cancer (PCa) in comparison with healthy controls.Design. Retrospective analysis of body composition changes in men with prostate cancer receiving LHRH-A therapy from 2 clinical trials compared to men without prostate cancer serving as a placebo-control in another clinical trial.Setting. Clinical Research Center in Connecticut.Participants. Thirty men (> 60 years) receiving 6 months of LHRH-A therapy for PCa were compared to a healthy group of 25 men without PCa.Measurements. Appendicular skeletal muscle/height2 (ASM/ht2), lean and fat mass were assessed by dual energy x-ray absorptiometry. Total testosterone levels were assessed by enzyme immunoassay.Results. At baseline, 12/30 (40%) of the treatment group and 7/25 (28%) of the control group (p = 0.11) met criteria for sarcopenia. There were no differences between control groups in ASM/ht2 or lean mass. The LHRH-A group had a higher percent body fat than the control group, 29.8 ± 6.3 versus 26.3 ± 4.6 (p = 0.02). ASM/ht2 and lean mass decreased in the LHRH-A group from 7.5 ± 0.9 kg to 7.3 ± 0.9 kg (−2.3% ± 0.03; p ⩽ 0.001) and 53.5 ± 5.4 kg to 52.3 ± 5.3 kg (−2.1% ± 0.03; p ⩽ 0.001), respectively. There was no muscle loss in the control group. At 6 months, the LHRH-A group had increased percent body fat from 29.8 ± 6.4 to 32.2 ± 5.8 (9.5% ± 0.13; p ⩽ 0.001), whereas the control group had decreased in percent body fat from 26.6 ± 4.6 to 25.3 ± 5.0 (−3.8% ± 0.08; p = 0.02).Conclusions. Men undergoing LHRH-A treatment for PCa decreased appendicular skeletal muscle and lean tissue and increased body fat within 6 months of initiation of therapy. Lifestyle changes or medical interventions to minimize the effects of androgen deprivation therapy for PCa deserve investigation.

P1-094 Rapid-progressors, who decline cognitively over six months, show subtle spatial working memory defects at baseline

Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown.To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT.A total of 680 men who received adjuvant radiation therapy (n = 105) or salvage radiation therapy (n = 575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo.RT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen.Biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis.Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p = 0.003) and DM (HR: 2.48; p = 0.03) compared with patients receiving ≥12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for ≥12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p = 0.0004), DM (HR: 0.88; p = 0.0004), and PCSM (HR: 0.90; p = 0.037). These findings are limited by the retrospective nature of our analysis.For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT ≥12 mo may be preferable. Validation of our findings is needed.We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes.

The impact of prostate volume and neoadjuvant androgen-deprivation therapy on urinary function following prostate brachytherapy.

The purpose of this article is to evaluate the impact of prostate size and the magnitude of cytoreduction after neoadjuvant androgen-deprivation therapy (ADT) on catheter dependency, urinary symptomatology, and need for postbrachytherapy surgical intervention. From February 1998 to August 2002, 186 consecutive patients under went monotherapeutic brachytherapy (no supplemental external-beam radiotherapy or ADT), and 101 consecutive patients received < or = 6 months of ADT (a luteinizing hormone-releasing hormone agonist and an anti-androgen) in conjunction with brachytherapy without supplemental external-beam radiotherapy for clinical Tlc-T2b (2002 American Joint Committee on Cancer) prostate cancer. ADT was initiated approximately 3 months before brachytherapy. The median follow-up was 38.6 months. An alpha-blocker was initiated before implantation and continued at least until the International Prostate Symptom Score (IPSS) returned to baseline levels. Evaluated parameters included patient age, pretreatment prostate-specific antigen, Gleason score, clinical T stage, preimplantation IPSS, ultrasound volume, hormonal status, isotope, D(90), V(100/150/200), and urethral dose (average and maximum). Patients receiving neoadjuvant ADT were statistically older, presented with higher preimplantation IPSS scores, and larger prostate volumes. Patients receiving ADT were likelier to require a urinary catheter for the first 3 days after implantation; however, by day 4, no statistical difference in catheter dependency could be discerned between the two cohorts. Hormonal status did not predict for postbrachytherapy surgical intervention. IPSS returned to baseline at a mean of 1.8 and 1.7 months in hormone-naive and ADT patients, respectively. In multivariate Cox regression analysis, the preimplantation IPSS and the maximum postimplantation IPSS predicted for IPSS normalization overall and in both cohorts. Ultrasound prostate volume did not predict for IPSS normalization, catheter dependency, or need for postimplantation surgical intervention. Although patients receiving ADT were likelier to require a urinary catheter for the first three days after implantation, hormonal manipulation did not affect IPSS normalization, prolonged catheter dependency, or need for postbrachytherapy surgical intervention in these patients treated with brachytherapy without supplemental external-beam radiotherapy.

The role of androgen deprivation therapy combined with prostate brachytherapy

Several prospective randomized clinical trials have demonstrated improved outcomes in men receiving androgen deprivation therapy (ADT) in combination with definitive local therapy (external-beam radiotherapy or surgery). ADT is commonly combined with prostate brachytherapy (PB) to “downsize” the prostate gland. As PB is increasingly used, more men are being treated with a combination of ADT and PB. The purpose of this article is to review the effects of ADT in men treated with PB. A structured literature review was performed. The effects of ADT on 3 separate outcomes were examined: (1) volume of the prostate gland, (2) treatment-related morbidity, and (3) disease-free survival. No prospective randomized trials addressing the effects of ADT combined with PB were discovered. There is evidence that prostate volume is reduced by 25% to 40% after 3 months of ADT. There is some evidence that ADT may be associated with increased acute urinary morbidity and decreased erectile function after PB. There is little evidence that disease-free survival in men treated with PB is improved with the addition of ADT. Neoadjuvant ADT before PB reduces prostate volume. ADT may lead to increased acute urinary morbidity and decreased erectile function after PB. No substantial effects of ADT on disease-free survival are apparent. Prospective randomized trials of PB and ADT are required.

Androgen deprivation therapy for prostate cancer results in significant loss of bone density

Objectives. Advanced prostate cancer is a frequently diagnosed condition in the aging male population, and many men will ultimately be treated with androgen deprivation therapy (ADT). Long-term consequences of ADT on bone mineral density (BMD) have not been systematically studied. We performed a pilot study to test the hypothesis that ADT in patients with prostate cancer results in the measurable loss of BMD. Methods. A cross-sectional study of 32 men with prostate cancer who were about to begin ADT or who had been receiving ADT for more than 1 year was conducted. BMD was measured by single and dual energy x-ray absorptiometry in the lumbar spine, hip, and forearm. Linear regression analysis was used to estimate the time necessary to develop significant BMD loss in the spine, hip, and forearm regions. Results. Five (63%) of 8 men who had not received ADT and 21 (88%) of 24 men who had received ADT for more than 1 year fulfilled the BMD criteria for osteopenia or osteoporosis at one or more sites. When BMD was compared at each site, men who received ADT for more than 1 year had significantly lower BMD in the lumbar spine than men who had not started treatment ( P <0.05). On the basis of regression analysis, an estimated 48 months of ADT would be necessary to develop BMD criteria for osteopenia in the lumbar spine for a man with average BMD at the initiation of therapy. Conclusions. Pre-existing osteopenia and osteoporosis were common in men with prostate cancer before initiating ADT. Both ADT and the duration of ADT were significantly associated with the loss of BMD in men with prostate cancer.