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Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational Study of Veterans With Prostate Cancer
Abstract
Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer.
We conducted an observational study of 37,443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration from January 1, 2001, through December 31, 2004, with follow-up through December 31, 2005. Cox proportional hazards models were used to assess whether androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists, oral antiandrogens, the combination of the two (ie, combined androgen blockade), or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke, after adjustment for patient and tumor characteristics. All statistical tests were two-sided.
Overall, 14,597 (39%) of the 37,443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen monotherapy was not associated with any outcome studied.
Androgen deprivation therapy with GnRH agonists was associated with an increased risk of diabetes and cardiovascular disease.
... Many studies have reported up to a 60% increased incidence of new T2DM in PC patients not living with T2DM on ADT [57,58]. The indirect effect of ADT includes elevated levels of low-density lipoprotein (LDL) and triglycerides, which promotes adipose tissue accumulation while reducing lean body mass, which induces insulin resistance, impairs glucose tolerance, and induces metabolic syndrome. ...
... Men with pre-existing CVD, including a history of congestive heart failure or myocardial infarction, are at the highest risk of cardiovascular events with ADT exposure, especially during the first 6 months of ADT initiation [62]. The initial identification of the relationship between ADT and CVD risk emerged from an observational study conducted by Keating et al. in 2006, utilizing data from the national SEER-Medicare database [58]. The study found that the utilization of gonadotropin-releasing hormone (GnRH) agonists in PC patients was linked to a notable rise in T2DM, myocardial infarction, and sudden cardiac death by 44%, 11%, and 16%, respectively [58]. ...
... Men with pre-existing CVD, including a history of congestive heart failure or myocardial infarction, are at the highest risk of cardiovascular events with ADT exposure, especially during the first 6 months of ADT initiation [62]. The initial identification of the relationship between ADT and CVD risk emerged from an observational study conducted by Keating et al. in 2006, utilizing data from the national SEER-Medicare database [58]. The study found that the utilization of gonadotropin-releasing hormone (GnRH) agonists in PC patients was linked to a notable rise in T2DM, myocardial infarction, and sudden cardiac death by 44%, 11%, and 16%, respectively [58]. ...
Purpose of review
The primary objective of this review article is to dissect the intricate relationship between disparities, aging, diabetes, and their collective influence on cardiovascular disease (CVD) risk in prostate cancer (PC) patients. We sought to answer how these determinants interact with each other and contribute to the varying CVD outcomes observed in different subsets of PC patients.
Recent findings
It has become evident that social determinants of health (SDOH) significantly impact PC outcomes. Particularly, cardiovascular outcomes in non-Hispanic Black (NHB) patients, those from lower socioeconomic backgrounds, and residing in rural areas are notably worse. Diabetes, a growing concern worldwide, has been linked to increased PC-specific and all-cause mortality. Interestingly, recent studies highlight the potential of metformin therapy in enhancing survival rates, especially pivotal for those undergoing androgen deprivation therapy (ADT). Furthermore, the implications of age on PC are profound. The age-driven alterations in factors like allostatic load, responses to ADT, and vascular health play a crucial role in influencing CVD outcomes.
Summary
Our article highlights the multifaceted factors influencing cardiovascular risk in PC patients. Social disparities, aging, and diabetes mellitus significantly shape CVD outcomes. A holistic approach that targets both systemic and individual concerns, focusing on bridging healthcare access gaps and devising effective diabetes management strategies, is imperative. Metformin therapy emerges as a beacon of hope, especially for those patients on ADT. To improve cardiovascular outcomes in PC patients, there is an urgent need to target modifiable risk factors, emphasizing special attention to vulnerable populations. Further research is still needed to develop targeted interventions to mitigate the risk of disparities while improving cardiovascular outcomes, especially in vulnerable populations.
... Another study using SEER/Medicare data similarly noted a higher likelihood of incident diabetes with GnRH agonist use as early as the first month (HR 1.44 [1.34-1.55]) (14). In patients with pre-existing diabetes, there is evidence of worsening glycemic control with ADT initiation after the first year (mean hemoglobin A1C 7.24 (0.04) to 7.38 (0.05)) and higher need for adding diabetic medications (HR 1.20 [1.09-1.32]) ...
... With these limitations in mind, Table 1 provides an overview of the major observational studies and meta-analyses of large populations evaluating the association between ADT and CVD outcomes in patients with prostate cancer. Several observational studies and a majority of meta-analyses conclude that there is an association between ADT exposure and the development of CVD events (14,(26)(27)(28)(29)(30)(31)(32). Conversely, two observational studies and one meta-analysis found no association between CVD outcomes and ADT (13,33,34). ...
... Several studies identified a stronger association between ADT exposure and CVD events among patients with preexisting CVD (26)(27)(28). However, most studies (including the meta-analyses) did not formally assess the presence of prior CVD and its potential effect on CVD events during ADT treatment (13,14,(29)(30)(31)(32)(33)(34). ...
Purpose of Review
Cardiovascular disease (CVD) is the leading cause of non-cancer mortality in men with prostate cancer. This review summarizes the existing and emerging literature examining the cardiometabolic effects of androgen deprivation therapy (ADT) in prostate cancer.
Recent Findings
The evidence behind the metabolic effects of ADT is derived from older studies and has not been validated in modern cohorts. Most of the newer studies focus on the risk of cardiovascular disease (CVD) with ADT. Recently published studies like the HERO and PRONOUNCE trials have once again sparked debate about the effects of different types and durations of ADT on cardiovascular outcomes.
Summary
The link between ADT and CVD is inherently complex with a majority of the evidence collected from population-based or non-randomized trials without enriching for high-risk populations. Ongoing clinical trials may provide more informative data to guide the cardiovascular care of prostate cancer survivors.
... However, growing clinical trials and observations found that ADT with orchiectomy and GnRH agonists may increase the risk of dying from cardiovascular diseases (CVDs). 5,6 The mortality rate caused by adverse cardiovascular events, such as coronary artery disease, myocardial infarction, [7][8][9] sudden cardiac death, 10 and stroke, 7,8,11 is as high as 30%, even the same as the specific fatality rate of PCa. 12,13 Therefore, it is urgent and essential to explore the mechanisms for ADT-induced cardiac issues. ...
... However, growing clinical trials and observations found that ADT with orchiectomy and GnRH agonists may increase the risk of dying from cardiovascular diseases (CVDs). 5,6 The mortality rate caused by adverse cardiovascular events, such as coronary artery disease, myocardial infarction, [7][8][9] sudden cardiac death, 10 and stroke, 7,8,11 is as high as 30%, even the same as the specific fatality rate of PCa. 12,13 Therefore, it is urgent and essential to explore the mechanisms for ADT-induced cardiac issues. ...
... A, The experimental design in which 8-week-old ApoE −/− mice were fed a Western diet and subcutaneously injected with saline, leuprolide (Leu), or degarelix (Deg) every month (8,12, and 16 wk). One group of Leu-injected mice was also fed bicalutamide (Bica). ...
BACKGROUND
Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases.
METHODS
We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE −/− mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms.
RESULTS
Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist–treated mice, blocking of short FSH surge by anti-FSHβ antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist–treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA/CREB/c-Jun and PI3K/AKT/GSK-3β (glycogen synthase kinase 3 beta)/GATA-6 pathways. In monocytes, FSH upregulated CD29 expression via the PI3K/AKT/GSK-3β/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist–induced endothelial inflammation and atherosclerosis in mice.
CONCLUSIONS
FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.
... Prior epidemiological studies exploring the effect of ADT on cardiovascular events have shown increased incidence of major adverse cardiac events (MACE) such as cardiovascular death in 4.5%, non-fatal myocardial infarction (MI) in 4.5% [4]. These findings were more pronounced in patients who had pre-existing CAD which increased all-cause mortality [5]. ...
... In addition, ADT also results in the reduction of steroid synthesis and ketogenesis which leads to deranged glucose homeostasis [30]. ADT was associated with new-onset DM, worsening HbA1c levels, and increasing FBS levels in large population studies [2,4,31]. But among Asian men, the literature regarding the effect of ADT on glycemic status is contradictory. ...
Androgen deprivation therapy (ADT) is the mainstay in the management of metastatic prostate cancer (PCa). There is a concern regarding the cardiovascular effects of ADT. Despite a reported incidence of major adverse cardiac event (MACE) in up to 6%, some Asian studies show no significant change. We aimed to find the cardiovascular effects of ADT in Indian men with PCa. In this prospective cohort study, men who underwent treatment for PCa from January 2022 to January 2023 were included. The ADT arm comprised patients with locally advanced and metastatic PCa who received ADT. The control arm included localized PCa patients who underwent radical prostatectomy without any ADT treatment. The primary outcomes were the incidence of MACE, changes in the Framingham risk score (FRS), ECG, and echocardiography at 1 year. Secondary outcomes were changes in the body mass index (BMI), waist-hip ratio, lipid profile, glycaemic parameters, and ankle brachial pressure index at 1 year. Forty cases and 23 controls were analyzed. There were three (7.5%) MACE in the ADT group at 1 year with no events in the control group. The ADT group had a significant increase in the mean FRS (2.54 ± 4.45 vs 0.67 ± 2.13; p = 0.021), weight (2.83 ± 2.97 vs. 0.94 ± 1.8 kg; p = 0.004), BMI (0.9 ± 1.08 vs. 0.32 ± 0.66 kg/m 2 ; p = 0.016), and HbA1c (0.54 ± 1.64 vs. 0.18 ± 1.08%; p = 0.023) compared to controls. A total of 7.5% of patients who received ADT developed MACE at 1 year. FRS, BMI, and HbA1c increased with ADT. Rigorous follow-up for cardiovascular and metabolic effects is essential in patients who receive ADT.
... Hormone therapy (HT), which is the backbone of prostate cancer therapy, has also been associated with cardiotoxicity through alterations in body composition, lipid abnormalities, and impaired glucose control [5]. Even though the association of prostate cancer and HT with development of T2DM and cardiovascular disease is known for decades, a recent study reported that a significant portion of prostate cancer patients have undiagnosed or poorly controlled T2DM [6,7]. This suggests that there is an unmet need for early diagnosis and appropriate treatment of T2DM tailored towards the prevention of cardiovascular disease. ...
... HT is the backbone of prostate cancer therapy, and it is used for as many as 50% of patients with prostate cancer at some point in their disease course. In 2006, Keating et al. were one of the first to report an association between GnRH agonists and increased incidence of DM, coronary heart disease, MI, and sudden cardiac death [6]. Since then, several studies and clinical trials have confirmed that GnRH agonists, abiraterone, androgen receptor antagonists, and less so GnRH antagonists are associated with increased incidence of adverse cardiovascular events. ...
Purpose
Studies have reported associations between prostate cancer, type II diabetes mellitus (T2DM), and cardiovascular disease in the context of treatment with hormone therapy (HT). This study aimed to assess the role of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) in preventing adverse cardiovascular and renal outcomes in diabetics with prostate cancer.
Methods
Patients ≥ 18 years of age with T2DM and prostate cancer who received HT between August 1, 2013, and August 31, 2021, were identified using the TriNetX research network. Patients were divided into two cohorts based on treatment with SGLT2i or alternative antidiabetic therapies. The primary outcome was the composite of all-cause mortality, new-onset heart failure (HF), acute myocardial infarction (MI), and peripheral artery disease over 2 years from HT initiation.
Results
After propensity score matching, 2155 patients remained in each cohort. The primary composite outcome occurred in 218 patients (16.1%) in the SGLT2i cohort versus 355 patients (26.3%) in the non-SGLT2i cohort (OR 0.539, 95% CI 0.446–0.651; p < 0.001). Furthermore, SGLT2i were associated with significantly lower odds of HF, HF exacerbation, peripheral artery disease, atrial fibrillation/flutter, cardiac arrest, need for renal replacement therapy, overall emergency room visits/hospitalizations, and all-cause mortality.
Conclusions
Use of SGLT2i for the treatment of T2DM among patients with prostate cancer on HT is associated with favorable cardiovascular, renal, and all-cause mortality outcomes. This observation supports the hypothesis that a therapeutically relevant link exists between HT and cardiovascular disease in the context of prostate cancer.
... This burden is compounded by the heightened risk of cardiovascular disease (CVD) amongst patients with PCa [3][4][5]. The prospective RADICAL PC cohort study revealed that 69% of population [11,12] and even compared with patients not receiving treatment [13]. A 2010 meta-analysis showed that GnRH agonists led to higher risks of diabetes and CVD than those of men who did not receive GnRH agonists [13]. ...
... The prospective RADICAL PC cohort study revealed that 69% of population [11,12] and even compared with patients not receiving treatment [13]. A 2010 meta-analysis showed that GnRH agonists led to higher risks of diabetes and CVD than those of men who did not receive GnRH agonists [13]. Manufacturers of GnRH agonists subsequently updated safety labels to communicate these risks [14]. ...
Purpose
Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD).
Methods
The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape.
Results
The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists’ practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk.
Conclusion
In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.
... It may elevate the risk of fatal and nonfatal cardiovascular events especially when Luteinizing hormone-releasing hormone (LHRH) analogues are used. Surgical castration and antiandrogen monotherapy seemed to have a lower impact on cardiac function [39][40][41]. ADT can also lead to an increased risk of developing diabetes due to reducing the insulin receptor sensitivity, especially when administered for a longer time [40,42,43]. Another well-known side efect of ADT is the bone mineral density reduction [44], which may lead to osteoporosis and eventually to elevated risk of fractures [45,46]. ...
... Surgical castration and antiandrogen monotherapy seemed to have a lower impact on cardiac function [39][40][41]. ADT can also lead to an increased risk of developing diabetes due to reducing the insulin receptor sensitivity, especially when administered for a longer time [40,42,43]. Another well-known side efect of ADT is the bone mineral density reduction [44], which may lead to osteoporosis and eventually to elevated risk of fractures [45,46]. ...
The aim of the study was to compare the side effects of high-dose-rate brachytherapy (HDRBT) and low-dose-rate brachytherapy (LDRBT), with a particular focus on the effects on sexual functions and sexual well-being (PROMOBRA study, NCT02258087). Localized low-risk and low-intermediate-risk prostate cancer patients were treated with mono LDR (N = 123, 145 Gy dose) or mono HDR brachytherapy (N = 117, 19/21 Gy). Prior to the treatment and during follow-up (at 3, 6, 9, 12, 18, and 24 months after treatment, and then annually after two years), patients completed patient-reported outcome measurement (PROM) questionnaires EORTC QLQ-PR-25, International Index of Erectile Function (IIEF), and IIEF-5 (SHIM). We compared the patients in different group breakdowns (HDR vs. LDR, hormone naïve and hormone-receiving HDR vs. LDR, hormone naïve and hormone-receiving patients in general, and 19 Gy HDR vs. 21 Gy HDR). In the hormone-naive LDR group, erectile function, orgasm function, sexual desire, satisfaction with intercourse, and overall satisfaction functions significantly decreased compared to baseline throughout the whole follow-up period. However, there were significant decreases in function at a maximum of three time points after HDR therapy without hormone therapy. In hormone-receiving patients, the orgasm function was significantly better in the HDR group at multiple time points compared to the baseline, and sexual desire improved at four time points. According to our results, both LDRBT and HDRBT can be safely administered to patients with localized prostate cancer. In hormone-naive patients, the HDR group showed only recovering decreases in sexual functions, while the LDR group showed a lasting decline in multiple areas. Thus, HDR appears to be more advantageous to hormone-naive patients.
... Furthermore, those undergoing ADT were at higher risk of myocardial infarction (adjusted hazard ratio (HR) 1.09; 95% confidence interval (CI) 1.02-1. 16 [7]. In a retrospective study of 354 patients with prostate cancer, incidental coronary calcification on PET/ CT was associated with a significant incidence of MACE (21%) [8]. ...
Over 1 million cases of prostate cancer are reported every year, and it is the second most common cancer in men. Androgen deprivation therapy (ADT) is a hallmark treatment for prostate cancer but is associated with the development or exacerbation of cardiovascular disease. The most common cause of non-cancer death in patients with prostate cancer is cardiovascular disease. Thus, a better understanding of the prevalence of cardiovascular toxicity across all therapies, management of potential cardiovascular complications, and prevention of cardiovascu-lar events is essential as treatments continue to evolve. In this article, the first in a 2-part series, we provide a review of the current landscape of ADT therapy and its association with cardiovascular disease, summarize recent clinical trial data evaluating cardiovascular outcomes, and provide insights on the management of cardiovascular risk factors and adverse events for clinicians managing this high-risk population of men undergoing potentially cardiotoxic treatment for prostate cancer.
... Furthermore, those undergoing ADT were at higher risk of myocardial infarction (adjusted hazard ratio (HR) 1.09; 95% confidence interval (CI) 1.02-1. 16 [7]. In a retrospective study of 354 patients with prostate cancer, incidental coronary calcification on PET/ CT was associated with a significant incidence of MACE (21%) [8]. ...
... PCa and MetS research has advanced significantly in the last two decades. Table 4 lists the top 10 high-cited references (27)(28)(29)(30)(31)(32)(33)(34)(35). All references are from high-quality JCR Q1 journals. ...
Background
According to recent studies, prostate cancer (PCa) is strongly associated with metabolic syndrome (MetS). However, there has not been any bibliometric visual analysis of relevant papers. In order to acquire knowledge about research settings and possible future paths, a thorough bibliometric study of MetS-related PCa research was carried out.
Methods
From January 1, 2004 to December 31, 2023, original and review publications about MetS and PCa were retrieved from the Web of Science Core Collection (WOSCC) database. Analysis of co-authorship and co-occurrence was done using VOSviewer. To find the top terms with the greatest citation burst, CiteSpace was used.
Results
There were 1,296 publications on PCa and MetS in all. The analysis showed that the number of yearly scientific papers in the sector was on the rise. The three most productive nations were China, Italy, and the USA. Most papers were published in the PLoS One, while most citations were obtained by the European Urology. The most influential author in terms of citations was Professor Smith MR, whereas the most prolific author was Professor Freedland SJ. Keyword analysis revealed that, apart from PCa and MetS, “obesity” was the most often used phrase, with “risk”, “meta-analysis”, and “inflammation” appearing as study subjects. Furthermore, “components” and “sex hormones” gained more and more attention.
Conclusions
The findings provide a thorough understanding of the larger context of this field of study. Future studies need to investigate PCa’s metabolic processes and inflammatory mechanism. Furthermore, switching from observational research to meta-analysis offers the possibility of illness prediction and tailored therapies. These results may help researchers navigate the most recent advancements and influence the field’s future paths.
... Recent studies have suggested a complex relationship between cancer and cardiovascular events, underscoring the shared risk factors and pathophysiological mechanisms [5][6][7]. In particular, the fact that chronic diseases such as diabetes and the use of medications such as metformin affect both cancer and cardiovascular disease development also contributes to the complex relationship between cancer and cardiovascular events [8,9]. However, there remains a gap in understanding how frequently OHCA events occur in patients with cancer, and this gap hinders proactive, informed decision-making regarding appropriate care when OHCA occurs in patients with cancer. ...
Background
The importance of assessing out-of-hospital cardiac arrest (OHCA) risk in cancer patients is increasing as cancer incidence rises in aging populations.
Objective
This study aimed to investigate the association between newly diagnosed cancer and OHCA risk using a metropolitan cohort from South Korea.
Methods
A population-based retrospective cohort study was conducted, linking the nationwide OHCA registry with the National Health Information Database. The study included adults aged 40 years or older, residing in Seoul between 2015 and 2018, with no history of cancer or OHCA. The main exposure was cancer development. The primary outcome was the occurrence of OHCA with medical cause. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated using a cause-specific hazard model considering death as a competing risk. Analyses stratified by age group and cancer type were also conducted.
Results
During a follow-up period of up to 4 years for 5,450,438 individuals, 174,785 participants developed cancer. The incidence rates of OHCA per 100,000 person-years were 54.0 in non-cancer and 145.0 in cancer groups, respectively. The aHR (95% CI) for OHCA associated with cancer development was 3.18 (2.97–3.41). The aHR (95% CI) for OHCA was highest in the 40–49 years of age group (7.52 [5.52–10.25]), followed by 50–59 years old (6.66 [5.56–7.97]) compared to older age groups. By cancer type, pancreatic, lung, biliary tract, and liver cancer were associated with a significantly increased risk of OHCA.
Conclusion
We found an association between newly diagnosed cancer and the occurrence of OHCA. Our findings underscore the importance of tailored risk assessments and proactive care planning for patients with cancer.
... The National Comprehensive Cancer Network (NCCN) defines high-risk disease as a clinical stage of T3 or T4 or Gleason score over 7 or PSA over 20 ng/ml. ADT leads to significant adverse effects such as increased adipose tissue, loss of lean muscle and bone mineral density, insulin resistance, dyslipidemia, systemic inflammation, type 2 diabetes (T2D) [2,3] and cardiovascular disease (CVD) [4][5][6][7]. Many men with PC also have multiple cardiovascular risk factors [8]. ...
Background
Androgen deprivation therapy (ADT) is the cornerstone treatment strategy for men diagnosed with high-risk prostate cancer (PC) but may increase risk for major adverse cardiovascular events (MACE). We examined whether men treated with ADT and radiation therapy (ADT + RT) developed MACE at a higher rate than men receiving RT alone. Secondly, we sought to determine if Black men receiving RT + ADT developed MACE at a higher rate than White men.
Methods
This retrospective cohort study examined time to diagnosis of MACE among Veterans with PC. We used a 1:1 propensity score matching process to determine whether treatment type (ADT + RT vs. RT alone), race (Black vs. White men) or having a previous diagnosis of a cardiometabolic disease (CMD) were associated with differences in the rate at which men develop MACE.
Results
Veterans with PC were White (68%) and Black (32%). At PC diagnosis, the mean age was 65.9 years. The majority had stage 2 disease (83.0%) classified as intermediate risk (43.1%). Treatment-matched models showed men receiving ADT + RT were less likely to develop MACE when they no pre-existing CMD. Men treated with ADT + RT or RT alone had significantly increased risks of MACE is they had pre-existing CMD. Black men had the same risk of MACE as non-Hispanic Whites.
Conclusions
Preexisting CMD and multimorbidity are significant risks for MACE among men treated for PC within the VA healthcare system whether treated with ADT + RT or with RT alone, highlighting the importance pretreatment optimization of comorbidities.
... Numerous observational studies and meta-analyses of observational studies reported increased CV morbidity including coronary heart disease, myocardial infarction, and stroke, as well as increased CV mortality in association with ADT [2,5,[17][18][19][20]. In meta-analyses of randomized controlled trials, no significant increase in CV mortality was found in men undergoing ADT [21][22][23]. ...
Androgen deprivation therapy (ADT), a key element of prostate cancer treatment, is associated with increased risk for cardiovascular morbidity and mortality. The underlying mechanisms include adverse metabolic alterations, but further mechanisms are likely. Animal studies suggest increased progression of atherosclerosis in androgen deprived conditions. Based on in vitro studies, lack of androgens may modulate immune cells including monocytes, macrophages, and T-cells towards a pro-inflammatory phenotype and pro-atherogenic function. As a novel aspect, this review summarizes existing data on the effect of androgens and androgen deprivation on platelet activity, which play a major role in inflammation and in the initiation and progression of atherosclerotic lesions. Testosterone modulates platelet aggregation responses which are affected by dose level, source of androgen, and age. Data on the effects of ADT on platelet activity and aggregation are limited and conflicting, as both increased and decreased aggregation responses during ADT have been reported. Gaps in knowledge about the mechanisms leading to increased cardiovascular risk during ADT remain and further research is warranted. Improved understanding of pathogenic pathways linking ADT to cardiovascular risk may help identify clinically useful diagnostic and prognostic biomarkers, and accelerate finding novel therapeutic targets, and thus optimize prostate cancer treatment outcomes.
... The association between ADTs and cardiovascular (CV) disorders is still controversial and unclear, but the possibility of CV events induced by GnRH agonists and antagonists are a growing concern due to prevalence of cardiovascular disease (CVD) in cancer patients [43]. Utilization of GnRH agonists is in conjunction with a higher risk for diabetes, MI, and CSD among PCa patients [46]. Another study has shown an increase in CV mortality risk in patients treated with antiandrogens and GnRH agonists [47]. ...
Chemotherapy is one of the routine treatment for preventing rapid growth of the tumor cells. However, chemotherapeutic agents, especially doxorubicin cause damages to the normal cells especially cardiomyocytes. Cardiotoxicity induced by chemotherapeutic drugs lead to the myocardial cell injury and finally causes left ventricular dysfunction. It seems that there were some differences in the severity of cardiovascular side effects of drugs used in the treatment of cancers. Sex hormones in male and female play crucial roles in cardiovascular development and physiological function of the heart and blood vessels. Gender differences and sex-specific hormones influence various aspects of cardiovascular health, including ventricular function, mitochondrial autophagy, and the development of abdominal aortic aneurysms. The most important gender related hormones are LH, FSH, testosterone, estrogen, progesterone, prolactin and oxytocin. They exert very important cardiovascular effects via different signaling mechanisms. Sex related hormones are also important in the cardiovascular side effects of chemotherapeutic agents, so that chronic cardiotoxicity induced by anthracyclines is more common in women. During different stages of life (before, during, and after sexual life), the levels of these hormones will be changed. This alterations can affect cardiovascular function during physiological conditions and pathological process. Because of the importance of the sex related hormones in the cardiac function, in this review we tried to comprehensively elucidate the role of these physiological hormones in cardiotoxicity induced by chemotherapeutic agents with emphasizing their signaling mechanisms.
Graphical Abstract
... По данным нескольких крупных исследований, у пациентов, получающих АДТ, повышается риск развития как фатальных (в 2-5 раз), так и несмертельных сердечно-сосудистых осложнений (ССО) [4][5][6][7]. Кроме этого, у мужчин, страдающих РПЖ, с наличием сердечно-сосудистых факторов риска или предшествующими сердечно-сосудистыми событиями риск возникновения ССО особенно высок [6,7]. Основной причиной смертности являются сердечно-сосудистые заболевания (ССЗ), к ним относят ишемическую болезнь сердца (ИБС), инсульт, сердечную недостаточность (СН), заболевания периферических артерий и ряд других [8]. ...
Prostate cancer (PCa) is the most common oncological disease in men in Russia. For a long time, long-term androgen deprivation therapy (ADT) decreasing native testosterone level has been the basis of PCa drug therapy. At the time of PCa diagnosis, 2/3 of men have various risk factors for cardiovascular diseases (CVDs) or established CVDs (one fourth of the patients have CVDs associated with atherosclerosis; 45 % have a diagnosis of arterial hypertension). ADT is associated with increased risk of CVD and cardiovascular complications (CVC) development. Patients with PCa die of 2 main causes: directly due to cancer or due to CVD. Previously, luteinizing hormone-releasing hormone (LHRH) antagonists were considered to have a better safety profile compared to LHRH agonists. Comparison of all LHRH agonists (leuprorelin, triptorelin, goserelin, buserelin) with LHRH antagonists in meta-analyses showed that the risk of serious CVCs during LHRH antagonist therapy was 43 % lower than during agonist therapy. However, comparison of leuprorelin with antagonists did not show a significant difference in CVC rate. Leuprorelin is a drug with the most favorable profile of cardiological safety among the ADT drugs and the most frequently used LHRH agonist in the world. Considering high risk of CVDs and CVCs in patients with PCa, along with treatment of the main disease, careful control and reduction of risks of CVD development from the moment of PCa diagnosis should be implemented, the patients must be informed on the necessity of healthy lifestyle, established CVDs should be treated with rational regimens of antihypertensive, hypolipidemic, and hypoglycemic drugs. Risk control and reduction, as well as CVD treatment, should be performed for the whole duration of ADT. The article proposes an algorithm of cardiometabolic risk stratification prior to ADT initiation and during ADT.
... Population-based studies showed that ADT can elevate the risk of cardiovascular issues, especially in men with existing heart conditions [19,20]. Contrarily, another research indicated that ADT does not elevate the likelihood of cardiac-related death in patients with clinically localised PCa [21]. ...
Background
This study assessed the biochemical disease-free survival (bDFS), prostate cancer-specific survival (PCSS), overall survival (OS), and side effects in patients aged < 70 and ≥ 70 years following definitive radiotherapy (RT). It also analysed the correlation between age at diagnosis and clinicopathological characteristics of prostate cancer (PCa).
Methods
The prognostic factors for bDFS, PCSS, and OS were determined through univariable and multivariable analyses. Two age groups were also compared in terms of acute and late grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicities, the predictors of which were determined through logistic regression analysis.
Results
Of the 1,328 patients, 715 (53.8%) and 613 (46.2%) were aged < 70 and ≥ 70 years, respectively. Median follow-up time was 84.5 months. No significant differences in the 7-year bDFS (86.3% vs. 86.8%) and PCSS rates (92.9% vs. 93.3%) were found between the ≥ 70 and < 70 age groups. The multivariable analysis showed that advanced clinical T stage, high International Society of Urological Pathology (ISUP) grade, and high-risk disease independently predicted poor bDFS and PCSS. Metastatic lymph nodes were another bDFS prognostic factor. The multivariable analysis identified age ≥ 70 years, cardiac events at diagnosis, advanced stage, higher ISUP grade, and non-use of simultaneous integrated boost technique as negative factors for OS. Additionally, diabetes and transurethral resection of the prostate (TUR-P) independently predict late-grade ≥ 2 GU toxicity.
Interpretation
Definitive RT is a safe and effective treatment for patients with localised PCa no matter their age. Although patients over 70 years have higher risk factors and comorbidities, their bDFS, PCSS, and toxicities were comparable to those of patients aged < 70 years.
... Cardiovascular risk assessment and monitoring Cardiovascular events are a significant cause of morbidity and mortality among patients with advanced PC [235]. Numerous factors, including age, male phenotype, obesity, familial cardiovascular disease, tobacco use, diabetes, and sedentary lifestyle, among others, contribute to greater susceptibility to cardiovascular events in this population [236][237][238][239][240]. In addition, ADT is associated with increases in lowdensity lipoprotein cholesterol and triglyceride levels and visceral fat, a decrease in lean body mass, an increase in insulin resistance, and a decrease in glucose tolerance [241,242]. These changes can predispose patients to metabolic syndrome and accelerate atherosclerosis, resulting in higher risk of coronary artery disease [243][244][245][246][247]. ADT is associated with both arterial and venous thromboembolic events, and can ultimately increase rates of acute myocardial infarction and heart failure, and cardiovascular morbidity and mortality rates overall [241,244,[248][249][250]. ...
... 76 Data from studies of men with prostate cancer receiving androgen deprivation therapy (ADT) can also provide insight into the effects of hypogonadism on cardiovascular health as this provides a group of men who develop severe, new-onset hypogonadism. ADT for prostate cancer was associated with increased insulin resistance 77 and newonset diabetes 78 in men without diabetes and poor diabetes control in men with diabetes, 79 suggesting a causal effect of male hypogonadism on insulin resistance and diabetes. This could be related to increased visceral and subcutaneous fat mass observed with ADT. ...
This review assesses the evidence of the physiological effects of testosterone on cardiovascular health, the association between male hypogonadism and cardiovascular health, and the effects of testosterone therapy on cardiovascular health in male hypogonadism. Preclinical studies suggest complex effects of testosterone on cardiovascular risk by acting on skeletal muscle, cardiomyocytes, vasculature, adipocytes, insulin action, and erythropoiesis. Furthermore, low testosterone has a bi‐directional association with cardiometabolic risk. Observational studies have reported worse metabolic profiles in men with organic hypogonadism. However, a consistent association between major cardiovascular events and male hypogonadism has not been established. Hematocrit increases with testosterone therapy; however, most studies do not report an increase in venous thromboembolism risk. Although some observational studies and a small randomized controlled study reported an increased risk of cardiovascular disease, recent data confirm the medium‐term cardiovascular safety of testosterone therapy in middle‐aged and older men with low testosterone.
... T prevents T2D in males. Androgen deprivation therapy (ADT), the standard of treatment of prostate cancer, produces severe T deficiency and is a severe risk factor for developing T2D in males (97,98). Moderate T deficiency also predisposes to T2D, while T replacement therapy (TRT) prevents or reverses T2D in T-deficient men (99). ...
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T’s conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
... The problem related to the use of ADT is the alteration in quality of life due to associated adverse effects, including depression, fatigue, hot flashes, and sexual dysfunction [79]. In addition, there is a higher risk of cardiovascular disease, diabetes mellitus, and osteoporosis [80][81][82]. The TOAD study evaluated OS with the use of immediate vs. delayed ADT in 293 men [83]. ...
Simple Summary
Patients undergoing definitive prostate cancer therapy experience recurrence despite standard-of-care interventions. Biochemical recurrence is detected initially via prostate-specific antigen (PSA) monitoring and is defined as biochemical recurrence. The clinical importance of the early detection of biochemical recurrence is underscored in this study. This review seeks to further elucidate modalities used for earlier identification of biochemical recurrence. Specifically, we highlight in this review the clinical utility of both tissue biomarkers and prostate-specific membrane antigen-positron emission tomography (PSMA PET) in monitoring patients for recurrence. The summarization provided in this article can help guide clinicians in understanding the recent developments in this field.
Abstract
Despite curative-intent local therapy, approximately 27% to 53% of prostate cancer (PCa) patients experience prostate-specific antigen (PSA) recurrence, known as biochemical recurrence (BCR). BCR significantly raises the risk of PCa-related morbidity and mortality, yet there is no consensus on optimal management. Prostate-specific membrane antigen-positron emission tomography (PSMA PET) has emerged as highly sensitive imaging, distinguishing local recurrences from distant metastases, crucially influencing treatment decisions. Genomic biomarkers such as Decipher, Prolaris, and Oncotype DX contribute to refining recurrence risk profiles, guiding decisions on intensifying adjuvant therapies, like radiotherapy and androgen deprivation therapy (ADT). This review assesses PSMA PET and biomarker utility in post-radical prostatectomy BCR scenarios, highlighting their impact on clinical decision-making. Despite their promising roles, the routine integration of biomarkers is limited by availability and cost, requiring further evidence. PSMA PET remains indispensable for restaging and treatment evaluation in these patients. Integrating biomarkers and PSMA PET promises to optimize personalized management strategies for BCR, though more comprehensive consensus-building studies are needed to define their standardized utility in clinical practice.
... However, increased androgen levels are not found to be correlated with heart failure. In contrast, observations in prostate cancer patients receiving androgen deprivation therapy (ADT) revealed an increased risk of heart failure in these patients [103,104]. Furthermore, studies in male patients with chronic heart failure showed a decrease in serum dehydroepiandrostenedione sulfate (DHEAS) and E2 as well as an increase in the sex hormonebinding globulin (SHBG) levels [84,105,106]. Some studies found that the derangement levels of these hormones and proteins were in proportion to the severity of chronic heart failure [107,108]. ...
Cardiovascular kidney metabolic (CKM) syndrome represents a complex interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic comorbidities, posing a significant public health challenge. Gender exerts a critical influence on CKM syndrome, affecting the disease severity and onset through intricate interactions involving sex hormones and key physiological pathways such as the renin–angiotensin system, oxidative stress, inflammation, vascular disease and insulin resistance. It is widely known that beyond the contribution of traditional risk factors, men and women exhibit significant differences in CKM syndrome and its components, with distinct patterns observed in premenopausal women and postmenopausal women compared to men. Despite women generally experiencing a lower incidence of CVD, their outcomes following cardiovascular events are often worse compared to men. The disparities also extend to the treatment approaches for kidney failure, with a higher prevalence of dialysis among men despite women exhibiting higher rates of CKD. The impact of endogenous sex hormones, the correlations between CKM and its components, as well as the long-term effects of treatment modalities using sex hormones, including hormone replacement therapies and gender-affirming therapies, have drawn attention to this topic. Current research on CKM syndrome is hindered by the scarcity of large-scale studies and insufficient integration of gender-specific considerations into treatment strategies. The underlying mechanisms driving the gender disparities in the pathogenesis of CKM syndrome, including the roles of estrogen, progesterone and testosterone derivatives, remain poorly understood, thus limiting their application in personalized therapeutic interventions. This review synthesizes existing knowledge to clarify the intricate relationship between sex hormones, gender disparities, and the progression of CVD within CKM syndrome. By addressing these knowledge gaps, this study aims to guide future research efforts and promote tailored approaches for effectively managing CKD syndrome.
... The problem related to the use of ADT is the alteration in quality of life due to associated adverse effects, including depression, fatigue, hot flashes, and sexual dysfunction [77]. In addition, there is a higher risk of cardiovascular disease, diabetes mellitus, and osteoporosis [78][79][80]. The TOAD study evaluated OS with the use of immediate vs. delayed ADT in 293 men [81]. ...
Despite curative-intent local therapy, approximately 27% to 53% of prostate cancer (PCa) patients experience prostate-specific antigen (PSA) recurrence, known as biochemical recurrence (BCR). BCR significantly raises the risk of PCa-related morbidity and mortality, yet there is not consensus on optimal management. Prostate-specific membrane antigen-positron emission tomography (PSMA PET) has emerged as highly sensitive imaging, distinguishing local recurrences from distant metastases, crucially influencing treatment decisions. Genomic biomarkers such as Decipher, Prolaris, and Oncotype DX contribute to refining recurrence risk profiles, guiding decisions on intensifying adjuvant therapies like radiotherapy and androgen deprivation therapy (ADT). This review assesses PSMA PET and biomarkers utility in post-radical prostatectomy BCR scenarios, highlighting their impact on clinical decision-making. Despite their promising roles, routine integration of biomarkers is limited by availability and cost, requiring further evidence. PSMA PET remains indispensable for restaging and treatment evaluation in these patients. Integrating biomarkers and PSMA PET promises to optimize personalized management strategies for BCR, though more comprehensive consensus-building studies are needed to define their standardized utility in clinical practice.
... Interestingly, in Supplementary Table S2, compared with FAERS, leuprolide (JADER) had stronger signals in metabolism disorders such as increased blood glucose (aROR 2.59 vs. no-significant), increased blood triglycerides (aROR 3.48 vs. no-significant), diabetes mellitus (aROR 11.43 vs. 1.26), and marasmus (aROR 45.03 vs. 14.58). An observational study of 37,443 population-based men showed that androgen deprivation therapy with GnRHa was associated with an increased risk of diabetes (Keating et al., 2010). In a mechanistic study of fat accumulation, Dr Hefeng Huang found that FSH downregulated aquaporin 7 (AQP7) expression and glycerol efflux function in mature adipocytes of post-menopausal women and ovariectomized (OVX) mice (Chen et al., 2020). ...
Background
Gonadotrophin-releasing hormone analogs (GnRHas) play a significant role in addressing gynecological diseases, central precocious puberty, and cancer. However, ensuring the safety of GnRHas in real-world applications requires continuous vigilance. In light of this, we undertook a disproportionality analysis focused on adverse events (AEs) associated with GnRHas using data from both the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). We evaluated GnRHas-associated AEs and characterized the clinical priority of unlisted AEs caused by each GnRHa from the different databases.
Methods
In the disproportionality analysis, we applied two adjusted algorithms to identify signals related to GnRHas in the FAERS and JADER databases from 2004 to 2023. Additionally, we utilized the Statistical Analysis System (SAS, 9.4) to examine potential and high-aROR (adjusted reporting odds ratio) signals associated with GnRHas. We performed clinical priority assessment for suspicious PTs and an analysis of serious/non-serious outcomes. We also gathered information on the onset times of AEs linked with GnRHas from both databases.
Results
From January 2004 to September 2023, FAERS and JADER recorded a total of 50,360,413 and 1,440,200 AEs, respectively. Employing two algorithms, the suspicious preferred terms (PTs) related to leuprolide (Leu) were 562 potential PTs (44 unlisted in specifications), followed by goserelin (Gos) with 189 PTs (28 unlisted), triptorelin (Tri) with 172 PTs (28 unlisted), and Leu-JADER with 85 PTs (10 unlisted). At the same PT level, the differences in GnRHas between the two databases were observed, such as cardiac failure, diabetes mellitus, liver disorder, dementia, suicidal ideation, interstitial lung disease, urinary disorders, and hypertensive crisis. In an analysis of serious vs. non-serious outcomes, a total of 43 AEs of Leu were more likely to be reported as serious AEs with p < 0.05 (such as asthenia, urinary retention, diabetes mellitus, interstitial lung disease, gait disturbance, and so on), following by Tri (6 AEs), and Gos (4 AEs). Based on the clinical priority score, 41 PTs of Leu, 26 PTs of Tri, 24 PTs of Gos, and 8 PTs of Leu-JADER were graded as weak. There were 3 PTs of Leu, 2 PTs of Tri, 4 PTs of Gos, and 2 PTs of Leu-JADER that were graded as moderate. Notably, in the assessment of the relevant evidence, 2 PTs (loss of libido and urinary tract toxicity caused by Leu), 1 PT (electrolyte imbalance caused by Tri), and 2 PTs (anorexia and suicidal ideation caused by Gos) showed a strong level of evidence with “++.” The differences in the signal strength of the same PTs from two databases were also worth noting. Moreover, the median onset time for GnRHas (Leu, Tri, and Gos) was 23 days (0, 298), 22 days (0, 181), and 217 days (29, 706), respectively, as median (Q1, Q3).
Conclusion
An examination of two databases revealed suspicious AEs associated with GnRHas. Our study found potential new AE signals of GnRHas and supported continuous clinical monitoring, pharmacovigilance, regional differences, and further studies of GnRHas.
... The reports on EBRT with LDR-BT for prostate cancer showed that adding HT did not improve bFFF, CSS, or OS [8,9]. Furthermore, HT has several adverse effects and may not be routinely added depending on the patient's general condition and willingness to receive the treatment [10]. Therefore, identifying a subgroup of patients in the high-risk prostate cancer group who receive HDR-BT and require less HT would be beneficial; however, there is a lack of sufficient evidence regarding this distinction. ...
Purpose
Until March 2018, patients with high-risk localized prostate cancer had been administered high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT) without additional hormone therapy (HT) at our institution. In this study, we aimed to evaluate long-term outcomes of this treatment.
Materials and methods
Patients with prostate cancer who received HDR-BT and EBRT between April 1997 and March 2021 and who were followed up for at least 6 months were included in the study. High-risk groups were classified into five levels according to the National Comprehensive Cancer Network guidelines. The EBRT and HDR-BT doses were 39–45 Gy/13–25 fractions. and 16.5–22 Gy/2–4 fractions, respectively. None of the patients received HT during initial treatment. The Kaplan–Meier method was used to estimate biochemical freedom from failure (bFFF), cause-specific survival (CSS), and overall survival (OS) rates. Biochemical failure was also determined.
Results
Seventy-two patients were enrolled in the study, with a median follow-up of 91.9 months. The median age and initial prostate-specific antigen (iPSA) level were 71 years and 10.95 ng/mL, respectively. The median biologically effective dose for HDR-BT plus EBRT was 270.3 Gy. The 5- and 7-year bFFF, CSS, and OS rates were 85.2 and 74.2%, 100 and 100%, and 95.7 and 91.9%, respectively. Only the iPSA ≤ 20 group was associated with the higher bFFF rate. The 7-year bFFF rates in the groups with iPSA ≤ 20 and iPSA > 20 were 86.6 and 48.6%, respectively.
Conclusion
HDR-BT plus EBRT without HT might be an alternative treatment option for patients with high-risk localized prostate cancer and iPSA levels ≤ 20. Further studies are required to validate the efficacy of this treatment strategy.
... [10][11][12][13] Observational studies indicate that ADT exposure increases the risk of adverse CV events, including myocardial infarction, stroke, heart failure, and CV death, particularly in patients with preexisting CVD or multiple CV risk factors. [14][15][16][17][18][19] Thus, we sought to answer the following questions: What are the differences in major adverse cardiovascular events (MACE) in men with prostate cancer receiving ADT as a function of race ( The cause-specific hazards method was used for the primary analysis of time-to-event outcomes given the etiologic nature of our study questions. 39 Unadjusted rates of incident CV outcomes were estimated and compared using the Kaplan-Meier estimator and the log-rank test. ...
Abstract
Background: Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in men with prostate cancer; however, data on racial disparities in CVD outcomes are limited.
Objectives: We quantified the disparities in CVD according to self-identified race and the role of the structural social determinants of health in mediating disparities in prostate cancer patients.
Methods: A retrospective cohort study of 3,543 prostate cancer patients treated with systemic androgen deprivation therapy (ADT) between 2008 and 2021 at a quaternary, multisite health care system was performed. The multivariable adjusted association between self-reported race (Black vs White) and incident major adverse cardiovascular events (MACE) after ADT initiation was evaluated using cause-specific proportional hazards. Mediation analysis determined the role of theme-specific and overall social vulnerability index (SVI) in explaining the racial disparities in CVD outcomes.
Results: Black race was associated with an increased hazard of MACE (HR: 1.38; 95% CI: 1.16-1.65; P < 0.001). The association with Black race was strongest for incident heart failure (HR: 1.79; 95% CI: 1.32-2.43), cerebrovascular disease (HR: 1.98; 95% CI: 1.37-2.87), and peripheral artery disease (HR: 1.76; 95% CI: 1.26-2.45) (P < 0.001). SVI, specifically the socioeconomic status theme, mediated 98% of the disparity in MACE risk between Black and White patients.
Conclusions: Black patients are significantly more likely to experience adverse CVD outcomes after systemic ADT compared with their White counterparts. These disparities are mediated by socioeconomic status and other structural determinants of health as captured by census tract SVI. Our findings motivate multilevel interventions focused on addressing socioeconomic vulnerability.
... 31 abiraterone are associated with an increased risk of cardiovascular disease, hepatotoxicity, diabetes mellitus and myocardial infarction, but not overall cardiovascular mortality. 59 Treating clinicians and general practitioners (GPs) should highlight red flag symptoms to high-risk patients being treated with ARPIs, and patients should have routine blood tests for monitoring (Figure 3). 6 Given the risk of metabolic diseases, patients should have yearly haemoglobin A1C (HbA1c) and triglyceride studies to monitor for diabetes and hypercholesterolaemia ( Figure 3). ...
Background:
Prostate cancer (PCa) is the most common malignancy after skin cancer in men in Australia. Its management varies according to tumour stage. Due to the significant dependence on androgen receptor signalling, agents that interfere with this pathway (most commonly medical castration in the form of androgen deprivation therapy [ADT]) are the mainstay treatment of advanced disease.
Objective:
This review provides a contemporary update on ADT, with further discussion of emerging novel therapies for primary care.
Discussion:
ADT is currently indicated for the treatment of metastatic prostate cancer, disease recurrence following attempted local curative therapy, as well as combined use with radiotherapy for intermediate/high-risk disease. There has been rapid development of new pharmaceuticals targeting the androgen receptor. These are reviewed historically with an emphasis placed on emerging therapies, their common side effects, and how to manage them in the general practice setting.
... For example, 12 weeks of ADT have been shown to increase body fat by 5% and reduce lean body mass, predisposing men towards sarcopenia [9]. Furthermore, abdominal obesity, hyperglycaemia, and an increased risk of cardiovascular disease have been observed in men receiving ADT [10][11][12][13]. Subsequently, the impact of ADT adverse events on quality of life (QoL) [14] and healthcare/treatment costs [15] is increasingly recognised. ...
Background
UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS.
Methods
Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a ‘safety to exercise’ check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences.
Discussion
The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services.
Trial registration
ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022.
... Más allá de los efectos en la calidad de vida, la supresión de producción de testosterona ha sido asociada con varios y severos efectos adversos, tales como el síndrome de derivación androgénica 5 , con manifestaciones como pérdida del libido, disfunción eréctil, fatiga, osteoporosis, bochornos, resistencia a la insulina, eventos cerebrovasculares, dislipidemia y síndrome metabólico [6][7][8][9][10][11][12] . ...
... The incidence is most common among those aged 50 years and older and is higher among African Americans. 1 Androgen-deprivation therapy (ADT) is the cornerstone of systemic therapy for men with high-risk, localized, recurrent, and metastatic disease because of the fundamental reliance of the disease on oncogenic androgen signaling. Modern ADT relies on testosterone suppression through blockade of the hypothalamus-pituitary-gonadal axis using gonadotropin-releasing hormone (GnRH) agonists or antagonists (Table 1) including MI, stroke, and even CV death, compared with patients who did not receive ADT. [15][16][17][18][19][20][21][22][23] However, data from randomized controlled trials (RCTs) on the association between GnRH agonists and CV death have been contradictory. A notable meta-analysis of pooled results from eight RCTs involving men with unfavorable-risk prostate cancer failed to find an association between ADT and CV death. ...
Prostate cancer is the most common malignancy among men worldwide, and androgen‐deprivation therapy (ADT) is a mainstay of treatment. There are observational data demonstrating an increased risk of cardiovascular events in patients who receive ADT, particularly those who have an elevated baseline cardiovascular risk. Because, for most patients with prostate cancer, death is predominantly from noncancer‐related causes, cardiovascular disease and its risk factors should be optimized during cancer treatment. This review provides an overview of the landscape of ADT treatment and serves as a guide for appropriate cardiovascular screening and risk‐mitigation strategies. The authors emphasize the importance of shared communication between the multidisciplinary cancer team and primary care to improve baseline cardiovascular screening and treatment of modifiable risk factors within this higher risk population.
... Individuals diagnosed with prostate cancer (PCa) and treated with androgen deprivation therapy (ADT) have an increased cardiovascular disease (CVD) risk because of metabolic complications associated with this treatment (1). Endothelial dysfunction, an established predictor of future cardiovascular events (2), has been reported in men on long-term ADT (3). ...
... | 1 in men with PCa, ADT has been linked with multiple adverse effects, including cardiovascular, psychological, and neurocognitive complications. 2,3 According to recent studies, ADT has been linked with an increased risk of depression, [4][5][6][7][8] however, few studies have contradicted this correlation. [9][10][11][12][13] There are several pathophysiological mechanisms suggested, out of which the most implicated one, is that testosterone has a direct effect on serotonin levels in the brain. ...
Background
Androgen deprivation therapy (ADT) is an effective treatment for advanced prostate cancer (PCa). Multiple studies have highlighted serious consequences this therapy poses to mental health, particularly depression. We aimed to review the incidence and association between ADT in men with PCa and the risk of depression.
Methods
We systematically searched multiple databases, including MEDLINE, Scopus till August 2023 for studies that compared ADT versus control for treating PCa reporting depression as outcome. Meta-analysis was performed using random-effects models and results presented as odds ratios (ORs) with 95% confidence interval (CI). Quality assessment of the included studies was conducted using Joanna Briggs Institute critical appraisal checklists.
Results
A total of 38 studies (17 retrospective studies, 16 prospective studies, two cross-sectional studies and two randomized trials) with 360,650 subjects met the inclusion criteria and were included in this meta-analysis. The estimated pooled incidence of depression among ADT patients is 209.5 (95% CI = 122.3; 312.2) per 1000 patients. There is statistically significant relationship between ADT treatment and depression (OR = 1.46, 95% CI = 1.28, 1.67; p = 0, I2 = 86.4%). The results remained consistent across various subgroups. No risk of publication bias was detected by funnel plot and Eggers's test (p > 0.05).
Conclusion
There is a higher risk of depression for men receiving ADT. Further studies evaluating optimal treatments for depression in men on ADT are warranted
... ADT has been reported to have modest survival benefits, especially for those at lower risk of clinical progression. However, long-term use of ADT is associated with several side effects, such as fatigue, impaired sexual and hormonal quality of life, anemia, osteoporosis, diabetes mellitus, and cardiovascular morbidity [61][62][63][64][65]. ...
Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.
... Conversely, ADT seems to be associated with a higher cardiovascular (CV) toxicity and, more importantly, CV mortality [3][4][5]. However, this detrimental effect has been showed on large observational studies but not in RCTs maybe because these events occur in previously comorbid patients who were not included in RCTs. ...
The utilization of Androgen Deprivation Therapy (ADT) in conjunction with Stereotactic Body Radiotherapy (SBRT) and Brachytherapy (BT) boost in prostate cancer treatment is a subject of ongoing debate and evolving clinical practice. While contemporary trends lean towards underutilizing ADT with these modalities, existing evidence suggests that its omission may lead to potentially inferior oncologic outcomes. Recommendations for ADT use should be patient-centric, considering individual risk profiles and comorbidities, with a focus on achieving optimal oncologic outcomes while minimizing potential side effects.
Ongoing clinical trials, such as PACE-C, SPA, SHIP 0804, and SHIP 36B, are anticipated to provide valuable insights into the optimal use and duration of ADT in both SBRT and BT settings. Until new evidence emerges, it is recommended to initiate ADT for unfavorable intermediate-risk and high-risk prostate cancer patients undergoing radiotherapy, with a minimum duration of 6 months for unfavorable intermediate-risk patients and at least 12 months for those with high-risk characteristics. The decision to incorporate ADT into these radiation therapy modalities should be individualized, acknowledging the unique needs of each patient and emphasizing a tailored approach to achieve the best possible oncologic outcomes.
... However the recent meta-analysis has declared the benefit and effects of exercise therapy on the cancer-specific quality of life and fatigue in patients with prostate cancer. 8 In patients with prostate cancer treated by ADT, multiple studies proved resistance training as an effective way of exercise to increase strength, physical function, lean mass, and quality of life in males with prostate cancer treated by ADT 9 . Also resistance training exercise might be a good and beneficial way of exercise as it helps in losing fats, controlling body weight, and improving the quality of life. ...
Background and Purpose:The purpose of this study is to evaluate the response of muscles to resistance training exercise program during androgen deprivation treatment in prostate cancer patients. Materials and Methods:Thirty patients suffering from prostate cancer during androgen deprivation therapy participated in this study their ages ranged from 50 to 70 years. They were selected from oncological outpatient clinic of Al-Hussien University Hospital and were divided equally into 2 groups. Group A (Control group): received medical treatment (ADT) and advised not to start strength training and maintain their daily activities.Group B (Study group): received medical treatment (ADT) and resistance training exercise for lower limbs. Assessment of response of muscles and functional performance was done by using Manual muscle test (MMT) and 5X Sit-to-Stand Test (5XSST). Results: At the end of the treatment course, percentage of improvement in MMT and 5XSST was significantly high in the study group compared to the control group which means that resistance training exercise has beneficial effects in muscle response and function in patients with prostate cancer disease during the treatment with androgen deprivation therapy. Conclusion:Resistance training exercise program has beneficial effects in increase muscle function and performance in patients suffering from prostate cancer during androgen deprivation therapy.
... This may be particularly important if targeting prostate cancer patients receiving androgen deprivation therapy (ADT) and radiation therapy as it has been reported that men opting for this treatment option tend to be older, have poorer performance status and unfavourable disease characteristics [30]. ADT has also been reported to increase the risk of coronary heart disease, sudden death and myocardial infarction [31]. Future trials may want to consider, as suggested by some interviewees, incorporating an introductory period to allow the exercise participants to build their confidence, mobility and exercise skillset before attempting to employ desired intensities and volumes. ...
Background
Exercise intervention research has shown promising results in preventing and reversing the side effects caused by prostate cancer and its’ treatment. However, there are still unanswered questions and the need for additional research. As the field of exercise oncology in the context of prostate cancer presents unique challenges and complexities, seeking the advice of experienced exercise oncology researchers before initiating a similar trial could help to design more effective and efficient studies and help avoid pitfalls.
Methods
A qualitative descriptive study design and a nonprobability, purposive sampling method was employed. An interview guide was developed and included topics such as recruitment, retention, programme goals, research design, health considerations, treatment considerations, adverse events, exercise prescription and outcome tools. Individual semi-structured interviews were conducted and interviews were transcribed and analysed using thematic analysis.
Results
Eight individuals with extensive experience working with prostate cancer patients in exercise oncology research settings were interviewed. Four main themes and seven subthemes were generated and supported by the data. Theme 1 highlighted the critical role of recruitment, with associated subthemes on recruitment barriers and recruitment methods. Theme 2 explored the positives and negatives of home-based programmes. Theme 3 focused on specific health characteristics, exercise prescription and outcome measure factors that must be considered when working with prostate cancer cohorts. Finally, theme 4 centered around the emotional dimensions present in exercise oncology trials, relating to both researchers and study participants.
Conclusion
Exercise oncology remains a challenging area in which to conduct research. Learning from experienced personnel in the field offers valuable information and guidance that could impact the success of future trials.
Objectives
To evaluate the effects of supervised recreational football‐based exercise intervention on physical functioning, cardiovascular and metabolic health, bone strength and quality of life in men with PCa receiving ADT.
Materials and Methods
Men with locally advanced or metastatic PCa undergoing ADT were allocated to a supervised recreational football‐based exercise programme. Patients were invited to participate in 2–3 one‐hour weekly sessions for 8 months and encouraged to participate in at least 2 session/week. Outcomes were physical functioning (postural balance, agility, muscle strength and aerobic capacity), blood pressure, lipid profile (LDL‐cholesterol, HDL‐cholesterol, total‐cholesterol and triglycerides), glucose, glycated haemoglobin (HbA1C) and high sensitivity C‐reactive protein (CRP), proximal femoral and lumbar spine (L2‐L4) bone mineral density (BMD) and quality of life (EORTC QLQ‐C30 and QLQ‐PR25). Descriptive and inferential statistical analysis was performed using the IBM® SPSS® Statistics version 29 software.
Results
From September to October 2022, 23 interested patients were screened and 12 were included and completed the supervised recreational football‐based exercise programme. A significant improvement in aerobic capacity was recorded, with the patients improving the distances walked over 6 minutes (580.0 vs. 537.5, p = 0.005). There was a significant reduction in systolic blood pressure from a median of 134 to 123 and a non‐statistically significant decrease in diastolic blood pressure from a mean of 80 to 73 mmHg. There were no significant differences for lumbar and femoral BMD. A tendency for higher general health status post‐intervention (80.6 vs. 70.8, p = 0.094) and a significant difference in the cognitive domain (83.0 vs. 100.0, p = 0.020) were recorded.
Conclusions
Men with PCa undergoing ADT experience side effects that, when combined with the physical inactivity and poor fitness often seen in these patients, may heighten their risk of cardiovascular and metabolic complications. A recreational football‐based exercise programme can be implemented to improve physical fitness, aerobic capacity, systolic blood pressure and quality of life.
Background: Prostate cancer therapy with surgical or chemical castration with GnRH agonists has been linked to elevated FSH levels, which may contribute to secondary health disorders, including atherosclerosis and diabetes. Although recent findings suggest a role for FSH beyond the reproductive system, its metabolic impact remains unclear and difficult to disentangle from that of androgens. In this study, we examined the metabolic changes induced by FSH and distinguished them from those caused by testosterone.
Methods: Plasma samples from temporarily medically castrated young men (n=33) treated with FSH and/or testosterone were characterized by proteomics and metabolomics approaches. All subjects received GnRH antagonists. Sixteen men were randomized to recombinant FSH (rFSH, 300 IU 3 times/week) for 5 weeks, while seventeen men served as controls. After 3 weeks, all men received 1000 mg testosterone undecanoate intramuscular. Blood samples were collected at the start, after 3 weeks, and after 5 weeks. The proteome and metabolome signatures were characterized in all samples.
Results: FSH significantly upregulates key proteins involved in the modulation of inflammatory response and innate immune system (p≤0.03) and dysregulates lipid metabolism, evidenced by downregulation of multiple apolipoproteins (p≤0.04) and increased levels of cholesterol and glycerophospholipids (p≤0.03). Additionally, low FSH levels were correlated with a reduction in the active form of vitamin D (p<0.02). These results highlight the short-term metabolic impacts of FSH in males.
Conclusions and Clinical Implications: Our findings underlined the FSH effect on extra-gonadal systems and its connection to metabolic disorders often seen as secondary effects of prostate cancer treatment.
The landscape for advanced prostate cancer has significantly evolved over the past decade. However, there remains a notable lack of robust evidence across various facets of clinical practice. The Taiwan Urological Association organized the 2022 Taiwan Advanced Prostate Cancer Consensus Conference (TAPCCC) to address specific topics designed to augment existing guidelines. The TAPCCC 2022 questionnaire was designed based on the Advanced Prostate Cancer Consensus Conference 2022 held by the Advanced Prostate Cancer Society and tailored to regional characteristics and medical practice in Taiwan. The questionnaire involved 7 areas of advanced prostate cancer: high-risk and locally advanced prostate cancer, biochemical recurrence, management of metastatic hormone-sensitive prostate cancer, management of nonmetastatic castration-resistant prostate cancer, importance of lifestyle and prevention of complications in advanced prostate cancer, management of metastatic castration-resistant prostate cancer, and oligometastatic and oligoprogressive prostate cancer. The panel experts voted anonymously on 93 predefined questions before and after the conference following a modified Delphi process. A consensus was defined as ≥75% agreement of answer options and strong consensus was defined as ≥90% agreement of answer options. A total of 61 Taiwanese panel experts were involved. Of the 93 questions asked, 40 (43.0%) achieved consensus and 14 (15.1%) reached a strong consensus. In addition, 18 questions (19.4%) demonstrated a ≥75% agreement while combining answer options. The voting results were presented alongside the most recent guidelines and evidence found in the literature, a detailed report of which is included in Supplementary Materials, http://links.lww.com/URSC/A51. In conclusion, the TAPCCC 2022 successfully identified salient issues, and the consensus answer options arising from the conference merit thorough evaluation for integration into clinical practice. The voting results offer guidance for clinicians navigating the management of advanced prostate cancer, particularly in situations where there is a paucity of robust evidence.
Background
Androgen‐deprivation therapy (ADT) remains a cornerstone in treatment for patients with advanced prostate cancer. ADT is associated with several adverse effects, including osteoporosis, metabolic syndrome, and cardiovascular events, leading to guidelines recommending routine testing to monitor for these toxicities. There is a lack of data assessing adherence to these recommendations.
Methods
The authors conducted a retrospective cohort study using administrative data from Ontario, Canada between 2008 and 2021. They identified all older men (aged 65 years and older) who received ADT for prostate cancer using comprehensive provincial health databases. The primary outcomes were the use of testing for lipids, dysglycemia (glucose), bone health serum, and bone density between 6 weeks before and 1 year after the initiation of ADT.
Results
In total, 29,097 patients were examined, of whom 52.8% were prescribed ADT by urologists, 37.9% were prescribed ADT by radiation oncologists, 2.8% were prescribed ADT by medical oncologists, and 2.4% were prescribed ADT by other physicians. Adherence to guidelines was low: only 21.3% of patients received a bone density scan, 41.2% underwent bone health–related serum tests, 51.3% completed a lipid profile, and 65.9% underwent dysglycemia testing within 1 year of diagnosis. Overall, only 11.9% of patients received all of the recommended investigations. Adherence to testing did not appear to improve over time (2008–2021) or with guideline publication. Patient (age) and physician (specialty) factors had important associations with adherence to testing.
Conclusions
Most patients receiving ADT for prostate cancer do not receive recommended testing to monitor for treatment‐related toxicity. Further study is required to address barriers to therapeutic monitoring of men on ADT and to reduce treatment‐associated adverse events.
In an age characterized by an influx of information, access to comprehensive volumes on uro-oncology is becoming increasingly practical. This publication endeavors to present contemporary insights into the management of metastatic prostate cancer. The integration of new imaging methodolo-gies and therapeutic interventions signifies a transformative phase in prostate cancer management. Authored with contributions from esteemed professionals possessing both national and international expertise, this text offers a com-prehensive discourse on the holistic management of meta-static prostate cancer. By facilitating interdisciplinary collab-oration among fields such as urology, radiology, pathology, nuclear medicine and oncology, it serves as a guiding beacon amidst the complexities of contemporary clinical practice and scholarly pursuits.
Background
Studies have reported associations between prostate cancer, type II diabetes mellitus (T2DM) and cardiovascular disease in the context of treatment with hormone therapy (HT). This study aimed to assess the role of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) in preventing adverse cardiovascular and renal outcomes in diabetics with prostate cancer.
Methods
Patients ≥ 18 years of age with T2DM and prostate cancer who received HT between August 1, 2013, and August 31, 2021, were identified using the TriNetX research network. Patients were divided into two cohorts based on treatment with SGLT2i or alternative antidiabetic therapies. The primary outcome was the composite of all-cause mortality, new onset heart failure (HF), acute myocardial infarction (MI), and peripheral artery disease over two years from HT initiation.
Results
After propensity score matching, 2,155 patients remained in each cohort. The primary composite outcome occurred in 218 patients (16.1%) in the SGLT2i cohort versus 355 patients (26.3%) in the non-SGLT2i cohort (HR 0.689, 95% CI 0.582–0.816; p < 0.001). Furthermore, SGLT2i were associated with significantly lower odds of HF, HF exacerbation, peripheral artery disease, atrial fibrillation/flutter, cardiac arrest, need for renal replacement therapy, overall emergency room visits/hospitalizations and all-cause mortality.
Conclusions
Use of SGLT2i for the treatment of T2DM among patients with prostate cancer on HT is associated with favorable cardiovascular, renal and all-cause mortality outcomes. This observation supports the hypothesis that a therapeutically relevant link exists between HT and cardiovascular disease in the context of prostate cancer.
Background
The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited.
Methods
A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event.
Results
There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26).
Conclusions
Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.
Background
Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear.
Methods
The ADT & Metabolism Study was a single‐center, 24‐week, prospective observational study that enrolled ADT‐naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non‐ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks.
Results
At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], −2.10 to 4.43; p = .47) or skeletal muscle (−3.2; 95% CI, −7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non‐ADT group. Men undergoing ADT gained 3.7 kg of fat mass.
Conclusions
In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short‐term ADT.
Background
Androgen deprivation therapy (ADT) increases the risk of frailty, falls, and, poor physical functioning in prostate cancer survivors. Detection of frailty is limited to self-report instruments and performance measures, so unbiased tools are needed. We investigated relationships between an unbiased measure – daily life mobility – and ADT history, frailty, falls, and functioning in ADT-treated prostate cancer survivors.
Methods
ADT-treated prostate cancer survivors (N=99) were recruited from an exercise clinical trial, an academic medical center, and the community. Participants completed performance measures and surveys to assess frailty, fall history, and physical functioning, then wore instrumented socks to continuously monitor daily life mobility. We performed a principal component analysis on daily life mobility metrics and used regression analyses to investigate relationships between domains of daily life mobility and frailty, fall history, and physical functioning.
Results
Daily life mobility metrics clustered into four domains: Gait Pace, Rhythm, Activity, and Balance. Worse scores on Rhythm and Activity were associated with increased odds of frailty (OR 1.59, 95% CI: 1.04, 2.49 and OR 1.81, 95% CI: 1.19, 2.83, respectively). A worse score on Rhythm was associated with increased odds of ≥1 falls in the previous year (OR 1.60, 95% CI: 1.05, 2.47). Worse scores on Gait Pace, Rhythm, and Activity were associated with worse physical functioning. Mobility metrics were similar between current and past users of ADT.
Conclusions
Continuous passive monitoring of daily life mobility may identify prostate cancer survivors who have or are developing risk for frailty, falls, and declines in physical functioning.
Importance
The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown.
Objective
To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes.
Design, Setting, and Participants
This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022.
Intervention
Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion.
Main Outcomes and Measures
The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A 1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes.
Results
Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A 1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A 1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes.
Conclusions and Relevance
In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism.
Trial Registration
ClinicalTrials.gov Identifier: NCT03518034
The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer.
We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429.
A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes.
The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)
Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer.
Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement.
After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality.
GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.
Using 1991-92 data for a 5-percent Medicare sample, we develop, estimate, and evaluate risk-adjustment models that utilize diagnostic information from both inpatient and ambulatory claims to adjust payments for aged and disabled Medicare enrollees. Hierarchical coexisting conditions (HCC) models achieve greater explanatory power than diagnostic cost group (DCG) models by taking account of multiple coexisting medical conditions. Prospective models predict average costs of individuals with chronic conditions nearly as well as concurrent models. All models predict medical costs far more accurately than the current health maintenance organization (HMO) payment formula.
Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy.
Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually.
After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome.
Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.
Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.
To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls.
Cohort study of outpatients using administrative data.
3 US Medicaid programmes.
Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis.
Diagnosis of cardiac arrest or ventricular arrhythmia.
Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038).
The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.
Recent reports have suggested that growing numbers of patients with localized prostate cancer are receiving androgen deprivation therapy as primary or neoadjuvant treatment, yet sparse clinical evidence supports the use of such treatment except among patients with high-risk or locally advanced disease receiving external beam radiotherapy. We describe national trends in the use of androgen deprivation therapy for localized disease.
CaPSURE is an observational database of 7195 patients with prostate cancer. This study included 3439 of these patients who were diagnosed since 1989, had clinical staging information available, and were treated with radical prostatectomy, radiation therapy, or primary androgen deprivation therapy (PADT). High-, intermediate-, and low-risk groups were defined by serum prostate-specific antigen level, Gleason score, and clinical tumor stage. Time trends in the use of PADT and neoadjuvant androgen deprivation therapy (NADT) were analyzed. All statistical tests were two-sided.
Rates of PADT use rose sharply between 1989 and 2001, from 4.6% (95% confidence interval [CI] = 3.4% to 5.8%) to 14.2% (95% CI = 12.2% to 16.2%), from 8.9% (95% CI = 7.3% to 10.5%) to 19.7% (95% CI = 17.5% to 21.9%), and from 32.8% (95% CI = 29.9% to 35.7%) to 48.2% (95% CI = 45.1% to 51.3%) (all P<.001) in low-, intermediate-, and high-risk groups, respectively. NADT use also increased in association with radical prostatectomy (2.9% [95% CI = 2.1% to 3.7%] to 7.8% [95% CI = 6.5% to 9.1%] of patients, P =.003) and external beam radiotherapy (9.8% [95% CI = 7.5% to 12.1%] to 74.6% [95% CI = 70.8% to 78.4%], P<.001) across all risk levels combined. Rates of NADT use among patients treated with brachytherapy also increased but not statistically significantly (7.4% [95% CI = 3.5% to 11.3%] to 24.6% [95% CI = 18.2% to 31.0%], P =.100).
Rates of both PADT and NADT are increasing across risk groups and treatment types. Future clinical trials must define more clearly the appropriate role of hormonal therapy in localized prostate cancer, and their results should shape updated practice guidelines.
Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events.
To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer.
A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of AST (n = 102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease.
Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival.
After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P =.04), lower prostate cancer-specific mortality (P =.02), and higher survival free of salvage AST (P =.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group.
The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.
The use of androgen-deprivation therapy for prostate cancer has increased substantially over the past 15 years. This treatment is associated with a loss of bone-mineral density, but the risk of fracture after androgen-deprivation therapy has not been well studied.
We studied the records of 50,613 men who were listed in the linked database of the Surveillance, Epidemiology, and End Results program and Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 1997. The primary outcomes were the occurrence of any fracture and the occurrence of a fracture resulting in hospitalization. Cox proportional-hazards analyses were adjusted for characteristics of the patients and the cancer, other cancer treatment received, and the occurrence of a fracture or the diagnosis of osteoporosis during the 12 months preceding the diagnosis of cancer.
Of men surviving at least five years after diagnosis, 19.4 percent of those who received androgen-deprivation therapy had a fracture, as compared with 12.6 percent of those not receiving androgen-deprivation therapy (P<0.001). In the Cox proportional-hazards analyses, adjusted for characteristics of the patient and the tumor, there was a statistically significant relation between the number of doses of gonadotropin-releasing hormone received during the 12 months after diagnosis and the subsequent risk of fracture.
Androgen-deprivation therapy for prostate cancer increases the risk of fracture.
This study (EORTC 30891) attempted to demonstrate equivalent overall survival in patients with localized prostate cancer not suitable for local curative treatment treated with immediate or deferred androgen ablation.
We randomly assigned 985 patients with newly diagnosed prostate cancer T0-4 N0-2 M0 to receive androgen deprivation either immediately (n = 493) or on symptomatic disease progression or occurrence of serious complications (n = 492).
Baseline characteristics were well balanced in the two groups. Median age was 73 years (range, 52 to 81). At a median follow-up of 7.8 years, 541 of 985 patients had died, mostly of prostate cancer (n = 193) or cardiovascular disease (n = 185). The overall survival hazard ratio was 1.25 (95% CI, 1.05 to 1.48; noninferiority P > .1) favoring immediate treatment, seemingly due to fewer deaths of nonprostatic cancer causes (P = .06). The time from randomization to progression of hormone refractory disease did not differ significantly, nor did prostate-cancer specific survival. The median time to the start of deferred treatment after study entry was 7 years. In this group 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm).
Immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptom-free survival. This must be weighed on an individual basis against the adverse effects of life-long androgen deprivation, which may be avoided in a substantial number of patients with a deferred treatment policy.
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.
Comorbidities may increase the negative effects of specific anticancer treatments such as androgen suppression therapy (AST).
To compare 6 months of AST and radiation therapy (RT) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality.
At academic and community-based medical centers in Massachusetts, between December 1, 1995, and April 15, 2001, 206 men with localized but unfavorable-risk prostate cancer were randomized to receive RT alone or RT and AST combined. All-cause mortality estimates stratified by randomized treatment group and further stratified in a postrandomization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test.
Time to all-cause mortality.
As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1-8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27-1.10; P = .08).
The addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable-risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction.
clinicaltrials.gov Identifier: NCT00116220.
PURPOSEAlthough androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated.MATERIALS AND METHODS
In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm.RESULTSActuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P or = 1 year), the 5-year disease-free surviv...
CONTEXT: Medicare has a legislative mandate for quality assurance, but the effectiveness of its population-based quality improvement programs has been difficult to establish.
OBJECTIVE: To improve the quality of care for Medicare patients with acute myocardial infarction.
DESIGN: Quality improvement project with baseline measurement, feedback, remeasurement, and comparison samples.
SETTING: All acute care hospitals in the United States.
PATIENTS: Preintervention and postintervention samples included all Medicare patients in Alabama, Connecticut, Iowa, and Wisconsin discharged with principal diagnoses of acute myocardial infarctions during 2 periods, June 1992 through December 1992 and August 1995 through November 1995. Indicator comparisons were made with a random sample of Medicare patients in the rest of the nation discharged with acute myocardial infarctions from August 1995 through November 1995. Mortality comparisons involved all Medicare patients nationwide with inpatient claims for acute myocardial infarctions during 2 periods, June 1992 through May 1993 and August 1995 through July 1996.
INTERVENTION: Data feedback by peer review organizations.
MAIN OUTCOME MEASURES: Quality indicators derived from clinical practice guidelines, length of stay, and mortality.
RESULTS: Performance on all quality indicators improved significantly in the 4 pilot states. Administration of aspirin during hospitalization in patients without contraindications improved from 84% to 90% (P< .001), and prescription of beta-blockers at discharge improved from 47% to 68% (P < .001). Mortality at 30 days decreased from 18.9% to 17.1% (P = .005) and at 1 year from 32.3% to 29.6% (P < .001). These improvements in quality occurred during a period when median length of stay decreased from 8 days to 6 days. Performance on all quality indicators except reperfusion was better in the pilot states than in the rest of the nation in 1995, and the differences were statistically significant for aspirin use at discharge (P < .001), beta-blocker use (P < .001), and smoking cessation counseling (P = .02). Postinfarction mortality was not significantly different between the pilot states and the rest of the nation during the baseline period, although it was slightly but significantly better in the pilot states during the follow-up period (absolute mortality difference at 1 year, 0.9%; P = .004).
CONCLUSIONS: The quality of care for Medicare patients with acute myocardial infarction has improved in the Cooperative Cardiovascular Project pilot states. Performance on the defined quality indicators appeared to be better in the pilot states than in the rest of the nation in 1995 and was associated with reduced mortality.
Objective
To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls.
Design
Cohort study of outpatients using administrative data.
Setting
3 US Medicaid programmes.
Participants
Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis.
Main outcome measure
Diagnosis of cardiac arrest or ventricular arrhythmia.
Results
Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses 600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038).
Conclusions
The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.
What is already known on this topic
What is already known on this topic
Thioridazine seems to prolong the electrocardiographic QT interval more than haloperidol Although QT prolongation is used as a marker of arrhythmogenicity, it is unknown whether thioridazine is any worse than haloperidol with regard to cardiac safety
What this study adds
What this study adds
Patients taking antipsychotic drugs had higher risks of cardiac events than control patients with glaucoma or psoriasis Overall, the risk of cardiac arrest and ventricular arrhythmia was not higher with thioridazine than haloperidol
Thioridazine may carry a greater risk than haloperidol at high doses
Patients should be treated with the lowest dose of thioridazine needed to treat their symptoms
The role of androgen deprivation therapy in prostate carcinoma is controversial in earlier stages of disease. The authors examined the time trends and patterns of use for androgen deprivation in the form of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy, in population-based tumor registries.Methods
Data were obtained from the linked Surveillance, Epidemiology and End Results-Medicare database. A total of 100,274 men with prostate carcinoma diagnosed from 1991 through 1999 were selected. The main outcome was the proportion of men who received ≥1 dose of a GnRH agonist in the first 6 months of diagnosis. This was plotted by year and stratified for age, grade, stage as well as primary versus adjuvant usage. Multiple logistic regression was used to examine predictors of GnRH agonist use in the subset of patients with localized cancer.ResultsThere was a consistent increase in GnRH agonist use by year for all ages, stages, and grades. Even in men ≥80 years with localized stage and low-to-moderate grade tumors, primary GnRH agonist use increased over the study period, from 3.7% in 1991 to 30.9% in 1999 (P < 0.001). The multivariable analysis showed that significant variability in GnRH agonist use existed among SEER geographic regions.Conclusions
The use of GnRH agonists for prostate carcinoma increased dramatically during the 1990s. This increase occurred across all stages and histologic grades of prostate carcinoma, and was greatest in patients ≥80 years.
Background. Although health claims data are increasingly used in evaluating variations in patterns of cancer care and outcomes, little is known about the comparability of these data with tumor registry information.
Objectives. To evaluate the agreement between Medicare claims and tumor registry data in measuring patterns of diagnostic and therapeutic procedures for older cancer patients.
Research Design. Analysis of a database linking Surveillance, Epidemiology and End Results (SEER) registry data and Medicare claims in patients aged ≥65 years with cancer.
Subjects. 361,255 Medicare patients with invasive breast, colorectal, endometrial, lung, pancreatic, and prostate cancer diagnosed between 1984 and 1993.
Measures. Concordance of SEER files with corresponding Medicare claims.
Results. Medicare claims generally identified patients who underwent resection and radical surgery according to SEER (ie, concordance ≥85%-90%) but less likely biopsy or local excision (ie, concordance ≤50%). In some instances, claims also categorized patients as having more invasive surgery than was listed in SEER and also provided incremental information about the use of surgical treatment after 4 months. SEER files and, to a lesser degree, Medicare claims identified radiation therapy not included in the other data source, and Medicare files also captured a significant number of patients with codes for chemotherapy.
Conclusions. Medicare files may be appropriate for studies of patterns of use of surgical treatment, but not for diagnostic procedures. The potential benefit of Medicare claims in identifying delayed surgical intervention and chemotherapy deserves further study.
BACKGROUND
The role of androgen deprivation therapy in prostate carcinoma is controversial in earlier stages of disease. The authors examined the time trends and patterns of use for androgen deprivation in the form of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy, in population-based tumor registries.METHODS
Data were obtained from the linked Surveillance, Epidemiology and End Results-Medicare database. A total of 100,274 men with prostate carcinoma diagnosed from 1991 through 1999 were selected. The main outcome was the proportion of men who received ≥ 1 dose of a GnRH agonist in the first 6 months of diagnosis. This was plotted by year and stratified for age, grade, stage as well as primary versus adjuvant usage. Multiple logistic regression was used to examine predictors of GnRH agonist use in the subset of patients with localized cancer.RESULTSThere was a consistent increase in GnRH agonist use by year for all ages, stages, and grades. Even in men ≥ 80 years with localized stage and low to moderate grade tumors, primary GnRH agonist use increased over the study period, from 3.7% in 1991 to 30.9% in 1999 (P < 0.001). The multivariable analysis showed that significant variability in GnRH agonist use existed among SEER geographic regions.CONCLUSIONS
The use of GnRH agonists for prostate carcinoma increased dramatically during the 1990s. This increase occurred across all stages and histologic grades of prostate carcinoma, and was greatest in patients ≥ 80 years. Cancer 2005. © 2005 American Cancer Society.
OBJECTIVE: To determine the positive predictive value of ICD-9-CM coding of acute myocardial infarction and cardiac procedures.
METHODS: Using chart-abstracted data as the standard, we examined administrative data from the Veterans Health Administration for a national random sample of 5,151 discharges.
MAIN RESULTS: The positive predictive value of acute myocardial infarction coding in the primary position was 96.9%. The sensitivity and specificity of coding were, respectively, 96% and 99% for catheterization, 95.7% and 100% for coronary artery bypass graft surgery, and 90.3% and 99.7% for percutaneous transluminal coronary angioplasty.
CONCLUSIONS: The positive predictive value of acute myocardial infarction and related procedure coding is comparable to or better than previously reported observations of administrative databases.
Background:
The use of androgen deprivation therapy (ADT) in the treatment of men with prostate cancer has risen sharply. Although cardiovascular disease is the most common reason for death among men with prostate cancer who do not die of the disease itself, data regarding the effect of ADT on cardiovascular morbidity and mortality in men with prostate cancer are limited. In the current study, the authors attempted to measure the risk for subsequent cardiovascular morbidity in men with prostate cancer who received ADT.
Methods:
A cohort of newly diagnosed men in a population-based registry who were diagnosed between 1992 and 1996 were identified retrospectively. A total of 22,816 subjects were identified after exclusion criteria were applied. Using a multivariate model, the authors calculated the risk of subsequent cardiovascular morbidity in men with prostate cancer who were treated with ADT, as defined using Medicare claims.
Results:
Newly diagnosed prostate cancer patients who received ADT for at least 1 year were found to have a 20% higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT. Subjects began incurring this higher risk within 12 months of treatment. However, Hispanic men were found to have a lowered risk for cardiovascular morbidity.
Conclusions:
ADT is associated with significantly increased cardiovascular morbidity in men with prostate cancer and may lower overall survival in men with low-risk disease. These data have particular relevance to decisions regarding the use of ADT in men with prostate cancer in settings in which the benefit has not been clearly established. For men with metastatic disease, focused efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT.
Purpose
Use of androgen deprivation therapy (ADT) may be associated with an increased risk of diabetes mellitus but the risk of both acute myocardial infarction (AMI) and cardiovascular mortality remain controversial because few outcomes and conflicting findings have been reported. We sought to clarify whether ADT is associated with these outcomes in a large, representative cohort.
Methods
Using linked administrative databases in Ontario, Canada, men age 66 years or older with prostate cancer given continuous ADT for at least 6 months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Treated and untreated groups were matched 1:1 (ie, hard-matched) on age, prior cancer treatment, and year of diagnosis and propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. Primary outcomes were development of AMI, sudden cardiac death, and diabetes. Fragility fracture was also examined.
Results
The cohort was observed for a mean of 6.47 years. In time-to-event analyses, ADT use was associated with an increased risk of diabetes (hazard ratio [HR], 1.16; 95% CI, 1.11 to 1.21) and fragility fracture (HR, 1.65; 95% CI, 1.53 to 1.77) but not with AMI (HR, 0.91; 95% CI, 0.84 to 1.00) or sudden cardiac death (HR, 0.96; 95% CI, 0.83 to 1.10). Increasing duration of ADT was associated with an excess risk of fragility fractures and diabetes but not cardiac outcomes.
Conclusion
Continuous ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not AMI or sudden cardiac death.
Primary androgen deprivation therapy (PADT) is frequently used as a sole modality of treatment in men with localized prostate cancer, despite a lack of clinical trial data supporting its use.
To measure the impact of treatment with PADT compared to observation on overall survival in men with organ-confined prostate cancer.
The design was for an observational cohort from Surveillance, Epidemiology, and End Results (SEER) Medicare data. The cohort consisted of 16,535 men aged 65-80 yr at diagnosis with organ-confined well-differentiated or moderately differentiated prostate cancer who survived >1 yr past diagnosis and did not undergo treatment with prostatectomy or radiation therapy within 6 mo of diagnosis. They were diagnosed between 1991 and 1999 and followed until death or until the end of the study period (December 31, 2002).
Study subjects were selected to receive PADT alone if they received luteinizing hormone-releasing hormone agonists or bilateral orchiectomy in the first 6 mo after diagnosis, and they were selected to be observed if they did not have claims for PADT during the same interval.
Overall survival.
After adjusting for potential confounders (ie, tumor characteristics, comorbidities, and demographics), patients who received ADT had a worse overall survival rate than patients who were observed (hazard ratio: 1.20; 95% confidence interval: 1.13-1.27). In observational studies there may be unmeasured differences between the treated and untreated groups. The SEER database does not provide information on prostate-specific antigen levels.
This large, population-based study suggests that PADT did not improve survival in men with localized prostate cancer, but it suggests that PADT may instead result in worse outcomes compared with observation. Patients and physicians should be cognizant of the potential long-term side effects of ADT in a patient population for which expectant observation is an acceptable treatment strategy.
Gonadotropin-releasing hormone (GnRH) agonists are the mainstay of treatment for recurrent and metastatic prostate cancer. GnRH agonists are also an important part of therapy for many men with localized or locally advanced prostate cancer. Although GnRH agonists improve survival in certain settings, they involve adverse effects including vasomotor flushing, obesity, and osteoporosis. This article describes the evidence that GnRH agonists increase risk for diabetes and cardiovascular disease and reviews the potential mechanisms for treatment-related morbidity.
Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated.
In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm.
Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03).
Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.
We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer.
From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin.
Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001).
Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.
Medicare has a legislative mandate for quality assurance, but the effectiveness of its population-based quality improvement programs has been difficult to establish.
To improve the quality of care for Medicare patients with acute myocardial infarction.
Quality improvement project with baseline measurement, feedback, remeasurement, and comparison samples.
All acute care hospitals in the United States.
Preintervention and postintervention samples included all Medicare patients in Alabama, Connecticut, Iowa, and Wisconsin discharged with principal diagnoses of acute myocardial infarctions during 2 periods, June 1992 through December 1992 and August 1995 through November 1995. Indicator comparisons were made with a random sample of Medicare patients in the rest of the nation discharged with acute myocardial infarctions from August 1995 through November 1995. Mortality comparisons involved all Medicare patients nationwide with inpatient claims for acute myocardial infarctions during 2 periods, June 1992 through May 1993 and August 1995 through July 1996.
Data feedback by peer review organizations.
Quality indicators derived from clinical practice guidelines, length of stay, and mortality.
Performance on all quality indicators improved significantly in the 4 pilot states. Administration of aspirin during hospitalization in patients without contraindications improved from 84% to 90% (P< .001), and prescription of beta-blockers at discharge improved from 47% to 68% (P < .001). Mortality at 30 days decreased from 18.9% to 17.1% (P = .005) and at 1 year from 32.3% to 29.6% (P < .001). These improvements in quality occurred during a period when median length of stay decreased from 8 days to 6 days. Performance on all quality indicators except reperfusion was better in the pilot states than in the rest of the nation in 1995, and the differences were statistically significant for aspirin use at discharge (P < .001), beta-blocker use (P < .001), and smoking cessation counseling (P = .02). Postinfarction mortality was not significantly different between the pilot states and the rest of the nation during the baseline period, although it was slightly but significantly better in the pilot states during the follow-up period (absolute mortality difference at 1 year, 0.9%; P = .004).
The quality of care for Medicare patients with acute myocardial infarction has improved in the Cooperative Cardiovascular Project pilot states. Performance on the defined quality indicators appeared to be better in the pilot states than in the rest of the nation in 1995 and was associated with reduced mortality.
The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.
The accuracy and completeness of the SEER-Medicare data for measuring cancer-related therapy have not been extensively evaluated.
To investigate the best method for measuring cancer-related surgery among patients in the SEER-Medicare database.
A total of 149,970 incident cases of breast, colorectal, endometrial, lung, pancreatic, and prostate cancer diagnosed between 1991 and 1993.MEASURES The most invasive surgical procedure identified through Medicare's inpatient, physician, and hospital outpatient claims was compared with corresponding data from the SEER files.
Agreement between the SEER and Medicare files was generally highest for resection and radical surgery (eg, kappa 0.70-0.90). While there was less agreement regarding no surgical therapy and biopsy individually, the concordance of the two sources in excluding cancer-directed surgery was high. Compared with inpatient data alone, using the combined inpatient, physician, and outpatient data increased concordance between SEER and Medicare for less invasive procedures.
The agreement of SEER and Medicare data appears to be good for major surgical procedures and for excluding persons who did not undergo cancer-directed surgery. Both the SEER and the Medicare data captured a small number of surgeries not reported in the other file. Therefore, where possible, using both data sources will enhance identification of surgeries. Because the analysis was performed with linked data, the accuracy of surgical claims in Medicare data alone cannot be assessed.
Objectives. Health care organizations often measure processes of care using only administrative data. We assessed whether measuring processes of diabetes care using administrative data without medical record data is likely to underdetect compliance with accepted standards for certain groups of patients.
Data Sources/Study Setting. Assessment of quality indicators during 1998 using administrative and medical records data for a cohort of 1,335 diabetic patients enrolled in three Minnesota health plans.
Study Design. Cross-sectional retrospective study assessing hemoglobin A1c testing, LDL cholesterol testing, and retinopathy screening from the two data sources. Analyses examined whether patient or clinic characteristics were associated with underdetection of quality indicators when administrative data were not supplemented with medical record data.
Data Collection/Extraction Methods. The health plans provided administrative data, and trained abstractors collected medical records data.
Principal Findings. Quality indicators that would be identified if administrative data were supplemented with medical records data are often not identified using administrative data alone. In adjusted analyses, older patients were more likely to have hemoglobin A1c testing underdetected in administrative data (compared to patients <45 years, OR 2.95, 95 percent CI 1.09 to 7.96 for patients 65 to 74 years, and OR 4.20, 95 percent CI 1.81 to 9.77 for patients 75 years and older). Black patients were more likely than white patients to have retinopathy screening underdetected using administrative data (2.57, 95 percent CI 1.16 to 5.70). Patients in different health plans also differed in the likelihood of having quality indicators underdetected.
Conclusions. Diabetes quality indicators may be underdetected more frequently for elderly and black patients and the physicians, clinics, and plans who care for such patients when quality measurement is based on administrative data alone. This suggests that providers who care for such patients may be disproportionately affected by public release of such data or by its use in determining the magnitude of financial incentives.
To assess the effects of androgen deprivation therapy on body composition in men with nonmetastatic prostate cancer.
In a multicenter study, men with Stage M0 prostate cancer were prospectively evaluated during initial androgen deprivation therapy (gonadotropin-releasing hormone agonist or bilateral orchiectomy). The main outcomes were changes in weight, percentage fat mass, and percentage lean mass from baseline to 12 months.
Seventy-nine subjects were assessed. Serum testosterone concentrations decreased by 79.7% +/- 3.0% (P <0.001). Weight increased by 1.8% +/- 0.5% (P <0.001). The percentage fat mass increased by 11.0% +/- 1.7%, and the percentage lean mass decreased by 3.8% +/- 0.6% (P <0.001 for each comparison).
Androgen deprivation therapy increased weight and fat mass and decreased lean mass in men with nonmetastatic prostate cancer.
Health care organizations use many strategies to influence physician behavior and the care delivered, but the effect of such strategies on quality is not known.
We sought to assess the influence of practice management strategies and financial arrangements on the quality of diabetes care.
This was a retrospective cohort study including medical record reviews and a physician survey.
Patients with diabetes mellitus (n=652) enrolled in 3 health plans located in Minnesota and 399 physicians in 135 practices who cared for them participated in this study.
Our main outcome measures was a quality score indicating receipt of care in accordance with 6 accepted quality indicators.
The mean quality score was 2.4 (SD 1.2) on a 6-point scale. Only a small proportion of the variation in quality was attributed to characteristics of physicians' practices (5%). Quality scores tended to be higher for patients whose physicians received quality performance reports or utilization profiles from more than 1 source (P=0.08), routinely enrolled diabetic patients in disease-management programs (P=0.06), or received diabetes-specific reports (P=0.06). Quality scores were lower for patients whose physicians were paid according to fee-for-service compared with salary (P=0.04) and served as gatekeepers for >50% of their patients (P=0.06). However, these findings were all of borderline statistical significance, and the absolute differences in quality were small.
Current practice management strategies and financial arrangements have a limited impact on the quality of care for patients with diabetes. These findings suggest that other strategies may be necessary for health care organizations to improve care for patients with diabetes.
To compare patients treated for acute myocardial infarction (AMI) in a Veterans Health Administration (VHA) facility to similar patients treated under Medicare.
Administrative data on 13,129 elderly male veterans hospitalized for AMI in a VHA facility between October 1, 1996, and September 30, 1999, and a matched set of male Medicare beneficiaries with AMI treated in a non-VHA facility during the same time period.
We conducted a retrospective cohort study using propensity score methods to identify a matched set of male elderly AMI patients treated either in a VHA facility or in a non-VHA facility under Medicare. We compared the two groups of patients according to characteristics of the admitting hospital, distances traveled for care, the use of invasive procedures, and mortality. We assessed the robustness of our conclusions to biases arising from unmeasured confounders using sensitivity analyses.
VHA patients were significantly less likely than Medicare beneficiaries to be admitted to high-volume facilities (for example, 25 percent versus 46 percent in 1999, p<0.001) or facilities with the capability to perform invasive cardiac procedures. Compared to Medicare patients, VHA patients traveled almost twice as far to their admitting hospital. The VHA patients were significantly less likely to undergo coronary angiography or revascularization in the 30 days following their AMI (p<0.001 for all comparisons). Veterans treated in the VHA had significantly higher mortality at one-year in all years studied (for example, 35.2 percent versus 30.6 percent in 1999). The proportion of elderly VHA patients admitted to high-volume facilities increased and 30-day mortality rates decreased between 1997 and 1999. Using sensitivity analyses to assess possible effects of unmeasured confounders, we could explain some but not all of the observed mortality differences.
We observed differences in the way care for AMI patients was structured, in the use of invasive therapies, and in long term mortality between patients treated in VHA hospitals and those treated in non-VHA facilities under Medicare. Future research should focus on explanations for the differences between the two systems and for the reduction in short-term mortality among VHA patients. Further study of these differences both between and within the systems of care may help identify cost-effective strategies to improve care in both sectors.
Meta-analyses have shown an excess of vascular deaths in women with breast cancer given radiotherapy (RT). In women with breast cancer, RT to the supraclavicular lymph nodes gives a substantial radiation dose to the proximal carotid artery. RT is known to increase the risk of carotid stenosis and ischaemic stroke in head and neck cancer. A study base of 25,171 women with breast cancer was defined. A linkage between the study base and the Hospital Discharge Register yielded 1766 women who were diagnosed with a stroke after a breast cancer. The observed number of strokes was compared with the expected number in the background population. The Relative Risk (RR) of stroke in the study group with breast cancer was 1.12 (95% Confidence Interval (CI)=1.07-1.17). The increased risk was confined to the subtype cerebral infarction, RR=1.12 (95% CI=1.05-1.19). A statistically significant increase in the risk of stroke was seen among women with a history of breast cancer. Whether this risk is associated with the breast cancer disease per se or related to any treatment requires further study.
Rapid and accurate evaluation of stroke subtypes is crucial for optimal treatment and outcomes. This study assessed factors associated with the likelihood of an "ill-defined" diagnosis for stroke hospitalizations.
We examined all hospital claims for stroke among Medicare beneficiaries aged > or =65 years in 2000. Stroke subtypes included hemorrhagic (International Classification of Diseases, Ninth Revision, Clinical Modification codes 430 to 432), ischemic (433 to 434), ill-defined (436 to 437), and late effects of cerebrovascular disease (438).
Among 445 452 hospital claims for stroke, 65.3% were ischemic, 20.9% were ill defined, 11.9% were hemorrhagic, and 1.9% were late effects of cerebrovascular disease. After controlling for age, women (odds ratio [OR],1.30; 95% CI, 1.28 to 1.32), blacks (OR, 1.31; 95% CI, 1.28 to 1.33), and Hispanics (OR, 1.27; 95% CI, 1.20 to 1.34) were more likely to receive a discharge diagnosis of ill defined compared with men and whites, respectively. Differences in age, sex, emergency room presentation, and evidence of diagnostic procedures accounted for some but not all racial disparities. In 14 states, ill-defined strokes constituted > or =25% of all stroke diagnoses.
The high proportion of stroke patients who receive an ill-defined diagnosis on discharge suggests a continued need for improvements in early response and prompt evaluation of strokes. Findings of geographic, gender, and racial disparities in ill-defined stroke diagnosis warrant further investigation. Reimbursement practices and public health efforts that promote hospital stroke policies are critical to improve disease reporting as well as clinical outcomes.
GnRH agonists markedly increase fat mass in men with prostate cancer, but little is known about the effects of treatment on insulin sensitivity.
The objective of the study was to assess the effects of short-term GnRH agonist treatment on insulin sensitivity.
This was a prospective 12-wk study.
The study was conducted at a general clinical research center.
We studied 25 men with locally advanced or recurrent prostate cancer, no radiographic evidence of metastases, no history of diabetes mellitus, and no evidence of diabetes mellitus at baseline visit.
Leuprolide depot and bicalutamide were used in the study.
Oral glucose tolerance tests and body composition assessment by dual-energy x-ray absorptiometry were performed at baseline and wk 12. The primary study outcome was change in insulin sensitivity index.
Mean (+/- se) percentage fat body mass increased by 4.3 +/- 1.3% from baseline to wk 12 (P = 0.002). Insulin sensitivity index decreased by 12.9 +/- 7.6% (P = 0.02). Insulin sensitivity by homeostatic model assessment decreased by 12.8 +/- 5.9% (P = 0.02). Fasting plasma insulin levels increased by 25.9 +/- 9.3% (P = 0.04). Mean glycosylated hemoglobin also increased significantly (P < 0.001).
Short-term treatment with leuprolide and bicalutamide significantly increased fat mass and decreased insulin sensitivity in men with prostate cancer. These observations suggest that GnRH agonists may increase the risk of diabetes mellitus and cardiovascular disease in older men.
Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease.
Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death.
More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P < .001), coronary heart disease (adjusted HR, 1.16; P < .001), myocardial infarction (adjusted HR, 1.11; P = .03), and sudden cardiac death (adjusted HR, 1.16; P = .004). Men treated with orchiectomy were more likely to develop diabetes (adjusted HR, 1.34; P < .001) but not coronary heart disease, myocardial infarction, or sudden cardiac death (all P > .20).
GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease. The benefits of GnRH agonist treatment should be weighed against these potential risks. Additional research is needed to identify populations of men at highest risk of treatment-related complications and to develop strategies to prevent treatment-related diabetes and cardiovascular disease.
We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of androgen suppression therapy (AST).
The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Gray's regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Gray's k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST.
Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not receive AST (P = .017) and men younger than 65 years (P = .016). No significant difference (P = .97) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of AST compared with 3 months of AST.
The use of AST is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST.
We investigated whether androgen deprivation therapy (ADT) use is associated with an increased risk of death from cardiovascular causes in patients treated for localized prostate cancer.
From the Cancer of the Prostate Strategic Urologic Research Endeavor database, data on 3262 patients treated with radical prostatectomy and 1630 patients treated with external beam radiation therapy, brachytherapy, or cryotherapy for localized prostate cancer were included in this analysis. Competing risks regression analyses were performed to assess whether use of ADT was associated with a shorter time to death from cardiovascular causes after controlling for age (as a continuous variable) and the presence of baseline cardiovascular disease risk factors. All tests for statistical significance were two-sided.
The median follow-up time was 3.8 years (range = 0.1-11.3 years). Among the 1015 patients who received ADT, the median duration of ADT use was 4.1 months (range = 1.0-32.9 months). In a competing risks regression analysis that controlled for age and risk factors for cardiovascular disease, both ADT use (adjusted hazard ratio [HR] = 2.6; 95% confidence interval [CI] = 1.4 to 4.7; P = .002) and age (adjusted HR = 1.07; 95% CI = 1.02 to 1.1; P = .003) were associated with statistically significantly increased risks of death from cardiovascular causes in patients treated with radical prostatectomy. Among patients 65 years or older treated with radical prostatectomy, the 5-year cumulative incidence of cardiovascular death was 5.5% (95% CI = 1.2% to 9.8%) in those who received ADT and 2.0% (95% CI = 1.1% to 3.0%) in those who did not. Among patients 65 years or older treated with external beam radiation therapy, brachytherapy, or cryotherapy, ADT use was associated with a higher cumulative incidence of death from cardiovascular causes, but the difference did not reach statistical significance.
The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer.
Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer.
From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-4, prostate-specific antigen [PSA] <150 ng/ml) received RT and 4 mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage.
After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray's p=0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR]=1.09; 95% confidence interval [CI], 0.81-1.47; p=0.58; when censoring at time of salvage goserelin, HR=1.02, 95%CI, 0.73-1.43; p=0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality.
Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer.
Measuring the quality of diabetes care-comparison of administrative data and medical record data
- Keating Nl
- Landrum
- Landon Be Mb
- Borbas C Ayanian Jz
- Guadagnoli
Keating NL, Landrum MB, Landon BE, Ayanian JZ, Borbas C, Guadagnoli E. Measuring the quality of diabetes care-comparison of administrative data and medical record data. Health Serv Res. 2003 ; 38 : 1529 – 1545.
The infl uence of physi-cians ' practice management strategies and fi nancial arrangements on
- Keating Nl
- Landrum
- Mb
- Landon
- Be
Keating NL, Landrum MB, Landon BE, et al. The infl uence of physi-cians ' practice management strategies and fi nancial arrangements on
Risk of fracture after androgen deprivation for prostate cancer
- Vb Shahinian
- Yf Kuo
- Jl Freeman
- Js Goodwin
Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after
androgen deprivation for prostate cancer. N Engl J Med. 2005 ; 352 ( 2 ):
154 – 164.
Care following acute myocardial infraction in the Veterans Health Administration: a comparison with Medicare
- MB Landrum
- E Guadagnoli
- R Zummo
- D Chin
- BJ McNeil
Improving the quality of care for Medicare patients with acute myocardial infarction: results from the Cooperative Cardiovascular Project
- TA Marciniak
- EF Ellerbeck
- MJ Radford