Receipt Of Androgen Deprivation Therapy Research Articles

Metformin Use is Associated with Improved Survival for Patients with Advanced Prostate Cancer on Androgen Deprivation Therapy

Metformin is commonly prescribed for patients with type 2 diabetes mellitus. We hypothesized that metformin plus androgen deprivation therapy may be beneficial in combination. Our objective was to assess this combination in a retrospective cohort of patients with advanced prostate cancer. Using national Veterans Affairs databases we identified all men diagnosed with prostate cancer between 2000 and 2008 who were treated with androgen deprivation therapy with followup through May 2016. Study exclusions included treatment with androgen deprivation therapy for 6 months or longer, or receipt of androgen deprivation therapy concurrently with localized radiation. Three patient cohorts were developed, including no diabetes mellitus, diabetes mellitus with no metformin and diabetes mellitus with metformin. Cox proportional HRs were calculated for overall survival, skeletal related events and cancer specific survival. After exclusions the cohort consisted of 87,344 patients, including 61% with no diabetes mellitus, 22% with diabetes mellitus and no metformin, and 17% with diabetes mellitus on metformin. Cox proportional hazard analysis of overall survival showed improved survival in men with diabetes mellitus on metformin (HR 0.82, 95% CI 0.78-0.86) compared to those with diabetes mellitus who were not on metformin (HR 1.03, 95% CI 0.99-1.08). The reference group was men with no diabetes mellitus. Cox proportional hazard analysis of predictors of skeletal related events revealed a HR of 0.82 (95% CI 0.72-0.93) in men with diabetes mellitus on metformin. Cox proportional hazard analysis of cancer specific survival showed improved survival in men with diabetes mellitus on metformin (HR 0.70, 95% CI 0.64-0.77) vs those with diabetes mellitus without metformin (HR 0.93, 95% CI 0.85- 1.00). The reference group was men with no diabetes mellitus. Metformin use in veterans with prostate cancer who receive androgen deprivation therapy is associated with improved oncologic outcomes. This association should be evaluated in a prospective clinical trial.

Association Between Androgen Deprivation Therapy and Patient-reported Depression in Men With Recurrent Prostate Cancer.

Previous studies have reported conflicting results on the relationship between androgen deprivation therapy (ADT) and the risk of depression. We assessed whether ADT is associated with depression in a unique data set of men with recurrent prostate cancer. We studied a cohort of 656 men in the prospective COMPARE (Comprehensive, Multicenter, Prostate Adenocarcinoma) registry who experienced biochemical recurrence after radiation therapy (RT) only, radical prostatectomy (RP) with or without RT, or ADT with RP or RT. Multivariable logistic regression was used to determine the relationship between the modality of treatment and patient-reported depression. Of 656 men, 44 (6.7%) experienced depression. The prevalence of depression stratified by treatment was 3.2% for RT only, 5.9% for RP with or without RT, and 9.1% for ADT plus RP or RT. Compared with RT-only, ADT plus RP or RT was associated with a significantly increased rate of depression (P= .031) and RP with or without RT was not (P= .195). On multivariate analysis adjusting for age and baseline comorbidities, the receipt of ADT was associated with an increased risk of depression (odds ratio, 3.29; 95% confidence interval, 1.11-9.76; P=.032) compared with RT only. No statistically significant difference was found in the risk of depression for men who received RP with or without RT versus RT only (odds ratio, 2.12; 95% confidence interval, 0.68-6.65; P=.19). Men with recurrent prostate cancer who underwent ADT were 3 times more likely to report experiencing depression. Treating physicians should discuss depression as a possible side effect when considering the use of ADT and should screen for depression in men who have received ADT.

Prognostic factors in men receiving androgen deprivation therapy (ADT) for recurrent prostate cancer: Using absolute PSA and PSA doubling time (DT) to guide timing of ADT initiation.

129 Background: ADT is the first-line treatment for men experiencing recurrence after undergoing radical therapy for prostate cancer. However, timing of ADT initiation is controversial and there are limited data on prognostic factors in patients starting ADT. Methods: We identified consecutive men who underwent radical prostatectomy (RP) for localized prostate cancer at our institution between 1987 and 2007 and who subsequently received salvage ADT. Early progression on ADT was defined as development of metastatic disease within 2yrs of initiation. The primary outcomes of interest were cancer-specific (CSS) and overall survival (OS). Results: A total of 2418 men were included. Median age at RP was 64yrs and median follow-up was 13.9yrs. 48% and 20% of men had pathologic Gleason scores of 7 and 8-10 respectively. The median PSA was 2.6ng/ml, while 385 men (16%) had metastatic disease at receipt of ADT. Overall, 1060 men (44%) developed clinical metastases, with 625 (59%) of these doing so within 2yrs of starting ADT. On multivariable analysis, longer PSA DT before ADT was associated with lower odds of early progression on ADT (DT 3-9mths, OR = 0.19; DT ≥9mths, OR = 0.10, both p < 0.001). 10- and 20-year CSS were 89% and 70%, and 10- and 20-year OS were 82% and 40% respectively. Independent predictors of lower CSS included metastatic disease at time of ADT (HR = 2.60), PSA at ADT of 5-50ng/ml (HR = 2.68) and > 50ng/ml (HR = 4.33, all p < 0.001), while longer PSA DT was associated with higher CSS (DT 3-9mths, HR = 0.54; DT ≥9mths, HR = 0.45, both p < 0.001). PSA at ADT of 5-50ng/ml (HR = 3.10) and > 50ng/ml (HR = 5.20, both p < 0.001) were independent predictors of OS. Conclusions: PSA DT < 3mths and absolute PSA at ADT initiation of ≥ 5ng/ml are adverse prognostic indicators in men receiving salvage ADT for relapse after RP. For patients with these features, their risk of early progression and death should be part of a discussion about the timing of ADT and consideration given to more aggressive treatment strategies. Conversely, men with biochemical relapse who have longer DT and PSA < 5ng/ml are at lower risk and could make an informed decision to defer ADT initiation.

Androgen‐deprivation therapy, dementia, and cognitive dysfunction in men with prostate cancer: How much smoke and how much fire?

Androgen-deprivation therapy (ADT) remains the cornerstone of management for patients with metastatic prostate cancer. Although the toxicities of ADT are well established, there is increasing controversy surrounding the association between cognitive dysfunction and the receipt of ADT, with some evidence suggesting an increased risk of dementia. The authors conducted a literature search to identify pertinent clinical studies in this field. This general review outlines the key findings and discusses the relative strengths and weaknesses when drawing conclusions about the risk of cognitive dysfunction or dementia with ADT use. Cancer 2018;124:1326-34. © 2018 American Cancer Society.

Stereotactic Body Radiotherapy for High-Risk Prostate Cancer: Preliminary Toxicity Results of a Phase 2 Trial

Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Herein we present the preliminary toxicity results of a phase II trial evaluating a five fraction SBRT regimen for high-risk CaP that allows for the integration pelvic nodal radiation (RT) and androgen deprivation therapy (ADT). Men with high-risk CaP, as defined by Gleason score >= 8, clinical stage T3-T4, or initial PSA >= 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate. Radiation to the pelvic nodes with 25 Gy in a simultaneous integrated boost plan (5 Gy per fraction) and/or a nine months neoadjuvant and concurrent androgen deprivation therapy (ADT) could be integrated with prostate SBRT at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). SBRT was delivered with a linear accelerator using volumetric modulated arc therapy or with a CyberKnife system. A total of 73 patients have been treated on this protocol, with a median follow-up of 13.8 months. Forty-six (63%) received ADT and 23 (32%) received nodal RT. The median initial PSA was 8.8 ng/mL and 11% of patients had clinical T3-T4 disease; 48% and 33% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher genitourinary (GU) or gastrointestinal (GI) toxicities were seen. For patients receiving nodal radiation, rates of acute grade 1 and 2 GU toxicities were 18.2% and 4.5%; for those not receiving nodal RT, they were 23.5% and 17.6%. Rates of acute grade 1 and 2 GI toxicities were 9.1% and 9.1% with and 11.8% and 3.9% without nodal RT. Late grade 1 and 2 GU toxicities rates with nodal RT were 27.3% and 4.5%; without nodal RT, the rates were 18.6% and 7.0%. Late grade 1 and 2 GI rates were 13.6% and 13.6% with nodal radiation and 11.6% and 4.7% without it. Mean changes in EPIC urinary and bowel domain scores at 4 months were +0.13 and -4.17 with nodal RT, and +0.79 and -2.97 without it. Mean changes in EPIC urinary and bowel domain scores at 12 months were -1.52 and -5.12 with nodal RT and -1.71 and -5.67 without it. Overall, the receipt of nodal RT had no significant association with either physician- or patient-reported toxicity profiles (p > 0.1, Fisher’s exact test). Similarly, the receipt of ADT had no significant association with any toxicity parameter. Two patients (2.7%) experienced biochemical failure; in both cases, the PSA never decreased after SBRT. SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP, with or without the integration of nodal RT and/or short-course ADT. Despite the short followup, the low rate of biochemical failure is encouraging.

Cardiovascular and Skeletal-related Events Following Localized Prostate Cancer Treatment: Role of Surgery, Radiotherapy, and Androgen Deprivation

To examine the impact of androgen deprivation therapy (ADT) and primary treatment modality on cardiovascular and skeletal-related events and to investigate potential effect modification in a contemporary cohort of patients treated for clinically localized prostate cancer. We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare linked databases for men aged 65-79 years who underwent radical prostatectomy or radiotherapy for cT1 or cT2 prostate cancer from 2000 to 2008. We categorized treatment according to primary therapy and receipt of ADT. We described the cumulative incidence of cardiovascular and skeletal-related events. Among 60,156 men, 14,403 underwent surgery and 45,753 underwent radiotherapy. Median follow-up was 6.0 years. After adjusting for baseline differences, treatments with radiotherapy (adjusted hazard ratios [aHR] 1.16-1.28, P <.0001-.04) and ADT (aHR 1.18-1.32, P <.0001-.008) were each independently associated with increased risk of coronary heart disease, sudden cardiac death, fracture, and fracture requiring hospitalization. Radiotherapy was associated with an increased risk of myocardial infarction (aHR 1.20, P = .02), whereas ADT was not (P = .5). We did not identify a significant statistical interaction between primary and hormonal treatment. Care for cardiovascular and skeletal-related events is an important part of the survivorship phase for a significant proportion of patients with localized prostate cancer. Increasing use of ADT for patients with localized disease undergoing radiotherapy and the observed higher prevalence of these events in these patients should be considered when discussing the risks and benefits of treatment for localized prostate cancer and when formulating a survivorship plan.

Evaluation of the effectiveness of adding androgen deprivation to modern dose-escalated radiotherapy for men with favorable intermediate-risk prostate cancer.

Randomized trials have shown that androgen-deprivation therapy (ADT) improves survival for men with intermediate-risk prostate cancer treated with radiotherapy (RT). The benefit of ADT to patients with favorable intermediate-risk prostate cancer treated with modern dose-escalated RT is unknown. This study evaluated the effectiveness of ADT on survival of men with favorable intermediate-risk prostate cancer treated with dose-escalated RT. This study was a retrospective cohort analysis of men with favorable intermediate-risk prostate cancer from 2004 to 2007 in the National Cancer Data Base. Favorable intermediate-risk disease was defined as 1 adverse risk factor (prostate-specific antigen level of 10-20 ng/mL or Gleason score of 7) and clinical T1/T2 prostate cancer. All patients were treated with primary dose-escalated RT (≥75.6 Gy or RT with a brachytherapy boost). Overall survival was analyzed with propensity score adjustment and Cox multivariate modeling. The study included 18,598 patients. The use of ADT decreased from 43.5% in 2004 to 39.5% in 2007. The propensity score-adjusted survival analysis demonstrated similar 8-year overall survival for men treated with dose-escalated RT and ADT and men treated with RT alone (77.7% vs 78.4%). ADT was not associated with improved survival in any age or comorbidity subgroup. In a sensitivity analysis using Cox multivariate modeling, the receipt of ADT was not associated with overall survival (hazard ratio, 0.99; 95% confidence interval, 0.91-1.07; P = .768). Adding ADT to modern dose-escalated RT was not associated with improved survival for patients with favorable intermediate-risk prostate cancer. The applicability of the survival benefit seen in older trials to modern patients is unclear. Because of the morbidity associated with ADT, dose-escalated RT alone for patients with favorable intermediate-risk prostate cancer may be a reasonable option. Cancer 2016;122:2341-2349. © 2016 American Cancer Society.

Survival outcomes of dose-escalated external beam radiotherapy (DE-EBRT) versus combined brachytherapy for intermediate- and high-risk prostate cancer using the National Cancer Data Base.

7 Background: The purpose was to evaluate survival outcomes between dose-escalated external beam radiotherapy (DE-EBRT) versus EBRT plus brachytherapy for intermediate- and high-risk prostate cancer, using the National Cancer Data Base (NCDB). Methods: Patients with cN0M0 prostate cancer treated from 2004-2006, with available data for radiation therapy dose were included. Radiation treatment comparison groups were the following: EBRT alone (75.6-81 Gy) and EBRT (40-50.4 Gy) plus brachytherapy, with EBRT delivered in 1.8-2.0 Gy per fraction. Eligible patients had known T-stage, prostate-specific antigen, Gleason score, and receipt of androgen deprivation therapy. Results: A total of 20,279 patients with intermediate (n = 12,617) and high-risk (n = 7,662) prostate cancer were included; 71.3% (n=14,452) received EBRT alone, 28.7% (n = 5,827) received EBRT plus brachytherapy. Median follow up was 82 months (range, 3-120 months) and median age was 70 years (36-90 years). By multivariate analysis, EBRT plus brachytherapy had a significantly improved survival benefit (hazard ratio [HR], 0.75; p &lt; 0.001) compared to EBRT alone (75.6-81 Gy); this significance remained consistent for both intermediate-risk (HR, 0.73; p &lt; 0.001) and high-risk (HR, 0.76; p &lt; 0.001) when analyzed separately. On subset analysis however, EBRT plus brachytherapy did not have a significant survival improvement (HR, 0.91; p = 0.083) when compared to very high dose EBRT alone (79.2-81 Gy) for all patients combined; this persisted for intermediate-risk (HR, 0.73; p = 0.062) and high-risk (HR, 0.93; p = 0.400) patients when analyzed separately. Conclusions: Patients receiving EBRT plus brachytherapy had improved survival compared to DE-EBRT alone (75.6-81 Gy) for intermediate- and high-risk prostate cancer. When comparing EBRT plus brachytherapy versus very high dose EBRT alone (79.2-81 Gy), this survival advantage disappeared. Given these findings, intermediate- and high-risk prostate cancer patients may benefit from EBRT plus brachytherapy compared with DE-EBRT alone; however, very high doses of EBRT may also be an equivalent option.

Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer.

Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72). Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.

The impact of pathologic staging on the long‐term oncologic outcomes of patients with clinically high‐risk prostate cancer

In the prostate-specific antigen (PSA) screening era, approximately 15% of US men still present with clinically high-risk prostate cancer (PC). However, high-risk PC may be downgraded/downstaged at radical prostatectomy (RP), making additional therapy unnecessary. The authors tested the oncologic outcomes in men with clinically high-risk disease stratified on RP pathology. A total of 611 men with high-risk PC (PSA level > 20 ng/mL, biopsy Gleason sum [bGS] ≥ 8, or clinical classification of ≥ T3) underwent RP and pelvic lymphadenectomy between 1998 and 2011. Outcomes included biochemical disease recurrence (BCR), receipt of androgen deprivation therapy (ADT), metastases, and PC-specific and overall survival. RP pathology was classified as unfavorable (pathologic Gleason sum ≥ 8, pathologic classification of ≥ T3, or lymph node-positive disease), or favorable (no unfavorable features). Multivariable analyses tested oncologic outcomes stratified by pathologic classification. Overall, 527 men had complete pathologic data and were included in the current analysis. Of the cohort, 206 of 527 men (39%) had favorable pathology. This finding was more common in men with only 1 clinical high-risk feature, and a lower body mass index, PSA level, bGS, and percentage positive biopsy cores. Favorable pathology was associated with decreased BCR (hazards ratio [HR], 0.34), metastases (HR, 0.17), and PC death (HR, 0.17). After a median follow-up of 82 months (range, 49 months-131 months), 193 of the 527 men (37%) received ADT, including only 35 of the 206 men with favorable pathology (17%). Unfavorable pathology was associated with early (≤ 5 years) but not late treatment with ADT. In a large cohort of men with high-risk PC who were managed with RP, 39% had favorable pathology and superior oncologic outcomes.

Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

What's known on the subject? and What does the study add? Receipt of androgen deprivation therapy (ADT) has been associated with an increased risk of skeletal-associated complications, such as a decrease in bone mineral density and an increase in fracture risk. Many men with pre-existing health conditions receive ADT as their primary treatment because they are considered to be inappropriate candidates for attempted curative treatments. However, several chronic health conditions, such as diabetes, rheumatoid disease and chronic liver disease, are strong predictors for osteoporosis and fractures. We undertook the present study aiming to quantify the impact of treating men with ADT who carry known risk factors for skeletal complications. Among these high-risk men, more than 58% develop at least one fracture after ADT within the 12 years of follow-up. Men who sustained a fracture within 48 months experienced an almost 40% higher risk of mortality than those who did not. Our findings suggest that treating men with a high fracture risk at baseline with long-term ADT may have serious adverse consequences. Objective To quantify the impact of androgen deprivation therapy (ADT) in men with a high baseline risk of skeletal complications and evaluate the risk of mortality after a fracture. Patients and Methods We studied 75 994 men, aged ≥66 years, with localized prostate cancer from the Surveillance, Epidemiology and End Results–Medicare linked data. Cox proportional hazard models were employed to evaluate the risk. Results Men with a high baseline risk of skeletal complications have a higher probability of receiving ADT than those with a low risk (52.1% vs 38.2%, P < 0.001). During the 12-year follow-up, more than 58% of men with a high risk and 38% of men with a low risk developed at least one fracture after ADT. The dose effect of ADT is stronger among men who received ADT only compared to those who received ADT with other treatments. In the high-risk group, the fracture rate increased by 19.9 per 1000 person-years (from 52.9 to 73.0 person-years) for men who did not receive ADT compared to those who received 18 or more doses of gonadotropin-releasing hormone agonist among men who received ADT only, and by 14.2 per 1000 person-years (from 45.2 to 59.4 person-years) among men who received ADT and other treatments. Men experiencing a fracture had a 1.38-fold higher overall mortality risk than those who did not (95% CI, 1.34–1.43). Conclusions Men with a high baseline risk of skeletal complications developed more fractures after ADT. The mortality risk is 40% higher after experiencing a fracture. Consideration of patient risk before prescribing ADT for long-term use may reduce both fracture risk and fracture-associated mortality.

Incidence of skeletal-related events (SREs) among prostate cancer patients.

e16035 Background: Skeletal related events (SREs) occur in men with prostate cancer and may result from both bone metastases and exposure to androgen deprivation therapy (ADT). The objective of this study was to quantify the incidence of SREs in patients with prostate cancer treated with ADT or orchiectomy in clinical practice. Methods: Prostate cancer patients served by Henry Ford Health System (HFHS) were identified via the HFHS tumor registry. Eligible patients were newly diagnosed with prostate cancer between 2004 and 2010 and treated with ADT or orchiectomy. Comprehensive population-based data were compiled using tumor registry with linkages to pharmacy, laboratory results, and healthcare encounter databases. SREs included spinal cord compression, surgery to bone, pathologic fracture and radiation to bone. Disease progression and metastases were identified by medical record review. Results: We identified 702 patients with prostate cancer and receipt of ADT or orchiectomy; 57.6% were &gt;70 years of age and 43.7% were African American. 56.3% of patients were initially diagnosed at AJCC stage II, 9.8% at stage III, 22.1% at stage IV, and 11.8% had missing or unknown stage. A total of 93 patients (13.2%) had one or more SREs: radiation to bone (8.5%) and spinal cord compression (3.1%) were the most common SREs. We then limited the cohort to patients initially diagnosed with or progressing to AJCC stage IV prostate cancer (N=207). Among this group, 47.8% were &gt;70 years of age. The mean time from stage IV diagnosis to end of follow-up was 35.6 months. In this subgroup, 16.4% of patients were initially diagnosed at AJCC stage II, 8.2% at stage III, 69.6% at stage IV, and 5.8% had missing or unknown stage. 57 patients (27.5%) had one or more SREs. Conclusions: Some clinical trials have found 36-41% of high-risk metastatic prostate cancer patients developed SREs during 3 years of follow-up. In this population-based cohort of patients with prostate cancer receiving ADT or orchiectomy and treated in real-world clinical practice, we found the incidence of SREs to be lower than what has been reported in clinical trials. Additional analyses exploring the incidence of SREs in patients diagnosed with metastatic castrate resistant prostate cancer will be presented.

Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Receipt of androgen deprivation therapy (ADT) has been associated with an increased risk of skeletal-associated complications, such as a decrease in bone mineral density and an increase in fracture risk. Many men with pre-existing health conditions receive ADT as their primary treatment because they are considered to be inappropriate candidates for attempted curative treatments. However, several chronic health conditions, such as diabetes, rheumatoid disease and chronic liver disease, are strong predictors for osteoporosis and fractures. We undertook the present study aiming to quantify the impact of treating men with ADT who carry known risk factors for skeletal complications. Among these high-risk men, more than 58% develop at least one fracture after ADT within the 12 years of follow-up. Men who sustained a fracture within 48 months experienced an almost 40% higher risk of mortality than those who did not. Our findings suggest that treating men with a high fracture risk at baseline with long-term ADT may have serious adverse consequences. To quantify the impact of androgen deprivation therapy (ADT) in men with a high baseline risk of skeletal complications and evaluate the risk of mortality after a fracture. We studied 75994 men, aged ≥ 66 years, with localized prostate cancer from the Surveillance, Epidemiology and End Results-Medicare linked data. Cox proportional hazard models were employed to evaluate the risk. Men with a high baseline risk of skeletal complications have a higher probability of receiving ADT than those with a low risk (52.1% vs 38.2%, P < 0.001). During the 12-year follow-up, more than 58% of men with a high risk and 38% of men with a low risk developed at least one fracture after ADT. The dose effect of ADT is stronger among men who received ADT only compared to those who received ADT with other treatments. In the high-risk group, the fracture rate increased by 19.9 per 1000 person-years (from 52.9 to 73.0 person-years) for men who did not receive ADT compared to those who received 18 or more doses of gonadotropin-releasing hormone agonist among men who received ADT only, and by 14.2 per 1000 person-years (from 45.2 to 59.4 person-years) among men who received ADT and other treatments. Men experiencing a fracture had a 1.38-fold higher overall mortality risk than those who did not (95% CI, 1.34-1.43). Men with a high baseline risk of skeletal complications developed more fractures after ADT. The mortality risk is 40% higher after experiencing a fracture. Consideration of patient risk before prescribing ADT for long-term use may reduce both fracture risk and fracture-associated mortality.

Validation and comparison of the two Kattan nomograms in patients with prostate cancer treated with 125iodine brachytherapy

Study Type - Prognostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Nomograms are based on large patient population. Their applicability should be externally validated. Among 747 brachytherapy patients we evaluated two Kattan nonograms and conclude that they have limited value to predict PSA-free survival. To validate and compare the preoperative and postoperative Kattan prediction nonograms for prostate cancer recurrence after brachytherapy. Patients (n= 747) treated with (125) I-brachytherapy were evaluated. Both nomograms were used to calculate the prediction of 5-year biochemical-freedom from failure (BFFF) based on clinical stage, Gleason score, prostate-specific antigen (PSA) level, receipt of androgen deprivation therapy and the post-implant dosimetry variable D90 (values of the minimal dose received by 90% of the prostate volume). The predicted values using the Kattan nomograms and the observed values were compared. Predictive accuracy was determined using the concordance index. The 5-year BFFF probability was 94% (95% confidence interval [CI], 92-96%) for the modified American Society for Radiation Oncology (ASTRO) definition and 97% (95% CI, 95-98%) for the Phoenix definition using Kaplan-Meier analysis. The predicted values of BFFF using both Kattan nomograms were lower than the observed rates in our cohort. The concordance index values were 0.51 and 0.52 for preoperative and postoperative nomograms, respectively. Concordance correlation coefficient between the two nomograms was 0.15. In our population, the 5-year BFFF outcomes rates were superior to nomogram predictions. Neither nomogram predicted outcomes after (125) I-brachytherapy in this non-US cohort. The postoperative nomogram was also a poor predictor, although it included D90 dosimetry values, as a variable of treatment quality. Strict inclusion criteria, perhaps more favourable than the ones on which the Kattan nomograms were based, could be the explanation for these discrepancies.

Cardiovascular Toxicity of Androgen Deprivation Therapy: A New Door Opens

Cardiovascular Toxicity of Androgen Deprivation Therapy: A New Door Opens

721 CAUSES OF MORTALITY FOLLOWING TREATMENT FOR PROSTATE CANCER: WHAT IS THE IMPACT OF ANDROGEN DEPRIVATION?

INTRODUCTION AND OBJECTIVES: Androgen deprivation therapy (ADT) is commonly used for prostate cancer as primary, neoadjuvant/adjuvant, and secondary. Several recent reports have drawn attention to important skeletal, metabolic, cardiovascular, and cognitive side effects of ADT. The association between ADT use and cardiovascular mortality (CVM), in particular, remains controversial. We analyzed mortality outcomes in a large national registry to elucidate the impact of treatment selection on mortality. METHODS: 8,095 men in the CaPSURE registry diagnosed between 1998 and 2005 were analyzed. Treatment was categorized as local alone, primary ADT (PADT), local treatment with adjuvant / neoadjuvant therapy (local ADT), and watchful waiting/active surveillance (WW). A competing hazards survival analysis was performed, including events defined as prostate cancer-specific mortality (CSM), CVM, and other. The model was adjusted for age, cardiovascular disease, other comorbidities, prostate cancer risk characteristics, and duration of ADT. A propensity score analysis was undertaken to adjust further for imbalances in covariate among men receiving various treatments. RESULTS: 4889 men (63.7%) received local treatment, 1044 (13.6%) PADT, 1248 (16.3%) local ADT, and 497 (6.5%) WW. 1104 (14.6%) received secondary therapy, which was ADT in 837 cases and local treatment in 267 cases. Overall, 2553 (32.2%) of men in the dataset received ADT at some point during treatment. 1068 (13.2%) men died of any cause: 132 (1.6%) with CSM, 251 (3.1%) with CVM, 593 (7.4%) of other causes, and 86 (1.1%) of unknown causes. On riskand comorbidity-adjusted survival analysis, the hazard ratios (HRs) for CSM relative to local treatment was 4.4 (2.7–7.4) for PADT, 2.8 (1.7–4.7) for local ADT, and 2.5 (1.6–3.9) for WW. For CVM, the HRs relative to local treatment were 2.1 (1.4–3.0) for PADT, 1.8 (1.0–3.2) for local ADT, and 2.5 (1.6–3.9) for WW. For overall mortality, the HRs relative to local treatment were 1.6 (1.3–2.0) for PADT, 1.3 (1.0–1.5) for local ADT, and 1.7 (1.3–2.1) for WW. In the propensity-matched analysis, receipt of ADT was associated with overall mortality, but not CVM. CONCLUSIONS: Men treated with ADT have higher likelihood of CSM, CVM, and overall mortality than those treated with local therapy onlyebut so do those managed with WW. With respect to CVM, therefore, despite adjustment for disease risk and major comorbidities, unmeasured variablesewhich influence treatment decision-making but are not recorded databaseselikely confound analyses of the impact of ADT on cardiac endpoints.

Patterns of use of docetaxel in stage IV prostate cancer (PCa) patients in SEER-Medicare.

4658 Background: To date, docetaxel (D) is the only chemotherapy agent that has provided a survival benefit to metastatic castration resistant PCa patients (pts). The objective of this study was to determine usage patterns of D in a large observational dataset, with stratification by demographics, treatment regimen, and time. Methods: We analyzed pts aged 66 or older from the linked Surveillance, Epidemiology, and End Results and Medicare (SEER-Medicare) database who received any type of chemotherapy. Pts were diagnosed with PCa between 2000 and 2005 and were followed until death or the end of the study period (December 31, 2007). We restricted the cohort to those with incident Stage IV disease (according to the AJCC-TNM classification). Using weekly and monthly data we calculated summary statistics and chi-square tests on D usage patterns by race groups, by age groups, and over time. Results: Application of the inclusion/exclusion criteria resulted in 1,248 Stage IV PCa pts on chemotherapy with 788 on D, of which 97% (N=761) also report receipt of androgen deprivation therapy (ADT). Docetaxel use increased from 55% in 2000 to 71% in 2005 (p-value <0.001). Among D pts, similar increases over time were noted for the proportion with M1 disease (73% to 91%; p- value <0.001), while the proportion using ADT remained high (97%) and stable over time. The distribution of D pts according to race (White; African American; Other) and age (66-74; 75-84; 85+) were [85%; 11%; 4%] and [59%; 38%; 3%], respectively. Among D pts, the vast majority (97%) received only D. A histogram of the average time between D claims followed a right-skewed, bimodal distribution with peaks at 1 week (34%) and 3 weeks (27%). The peaks were more defined by conditioning on ADT receipt, in the 66-74 year old (v. 75+) and 2003-2005 (v. 2000-2002) patient subgroups. Conclusions: The SEER-Medicare data set allows a rich characterization of docetaxel usage patterns. We find that the use of docetaxel varies over time and patient subgroups. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis

Impact of androgen deprivation therapy on racial/ethnic disparities in the survival of older men treated for locoregional prostate cancer.

Racial disparities persist in prostate cancer (CaP) treatment and survival, but disparities in androgen deprivation therapy (ADT) and the degree to which it affects racial differences in survival remains to be fully assessed. Using the Surveillance, Epidemiology and End Results-Medicare linked data, we examined a large cohort of men (N = 64,475) diagnosed with locoregional CaP during 1992 to 1999 and followed through 2003. The effects of ADT and race on survival were analyzed using a Cox proportional hazards model. The receipt of ADT was significantly lower in African Americans (24%) relative to Caucasians (27%), Asians (34%), and Hispanics (28.7%) (P < .05). Compared with Caucasian race, African American race was associated with a statistically significant increased mortality (HR = 1.26, 95% CI = 1.21-1.32), which remained significant after adjusting for ADT but was substantially decreased after controlling for primary therapies such as radical prostatectomy, radiation, and watchful waiting (HR = 1.06, 95% CI = 1.01-1.10) and was no longer statistically significant after controlling for comorbidities (HR = 0.98, 95% CI = 0.94-1.03). There were marked racial variations in the receipt of ADT, primary therapies (namely surgery and surgery combined with radiation), and comorbidities. However, racial disparities in survival were not affected by racial variations in ADT but were explained by racial variations in primary therapies and by racial differences in comorbidities.

Use of androgen deprivation therapy for metastatic prostate cancer in older men.

To assess factors associated with early or delayed androgen deprivation therapy (ADT) among men diagnosed with metastatic prostate cancer, and to assess the relationship between ADT and overall survival, as there is uncertainty about the ideal timing for initiating ADT in men with metastatic prostate cancer. We studied a population-based cohort of American men aged >or=66 years diagnosed with metastatic prostate cancer during 1992-2002 and followed to 2003. We assessed the receipt of ADT early (<or=4 months from diagnosis), delayed (>4 months), or not at all, using multinomial logistic regression to identify factors associated with treatment, and Cox proportional-hazard models to assess whether treatment was associated with survival. Overall, 69.5% of men received early ADT and 7.3% delayed. Adjusted rates of early ADT were lower for black than white men (58.3% vs 71.0%), and of delayed ADT were higher for black than white men (12.7% vs 6.2%). Receipt of ADT was associated with improved survival (adjusted hazard ratio 0.69, 95% confidence interval 0.66-0.73). The benefit of early treatment did not differ from delayed treatment (P = 0.58). A large minority of men with metastatic prostate cancer, particularly black men, receive delayed or no ADT. Early or delayed ADT was associated with similarly prolonged survival. After controlling for patient and tumour characteristics, survival did not differ by race, and receipt of ADT did not contribute to racial differences in survival.

Association Between Androgen-Deprivation Therapy and Incidence of Diabetes Among Males with Prostate Cancer

Previous research has documented an increase in metabolic syndrome among patients who use androgen-deprivation therapy (ADT). Given that metabolic syndrome is related to diabetes, this research examined whether use of ADT was associated with an increase in the incidence of diabetes. A retrospective, claims database was used to compare men diagnosed with prostate cancer who received ADT (N = 1231) with men diagnosed with prostate cancer who did not receive ADT (N = 7250). Unjustified comparisons among the cohorts were examined using chi-square statistics for categorical variables and t-statistics for continuous variables. A multivariate logistic regression was estimated to examine the association between receipt of ADT and the incidence of diabetes, while controlling for a wide range of factors that also potentially affect the probability of being newly diagnosed with diabetes. Descriptive statistics revealed that the patients who initiated ADT were significantly older (P <0.01), in poorer health (P <0.01), and more likely to have a prior diagnosis of hypertension (P = 0.04). Results from the multivariate regression indicate that for men diagnosed with prostate cancer, demographic characteristics, comorbid conditions, prior statin use, and receipt of ADT all affect the probability of incident diabetes. While controlling for other factors, the estimated relative risk of incident diabetes associated with the receipt of ADT was 1.36 (P = 0.01). Results from this study suggest that among prostate cancer patients, those initiating ADT are more likely to develop incident diabetes within 1 year. This finding supports previous research that established the relationship between ADT and metabolic syndrome.