Article

Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational Study of Veterans With Prostate Cancer

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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.

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... We excluded studies that were of low quality. In total, 16 studies were included [4,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Table 2 shows the quality assessment of clinical trials using the Cochrane Risk of Bias Tool. ...
... In total, 14 observational studies and two randomized control trials (RCTs ) were included in the systemic review [4,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. The key characteristics of the investigations (published between 2006 and 2020) that were considered are listed in Table 5. ...
... MI (aHR = 1.28, 95% CI = 1.08-1.5) [23,24]. Oral anti-androgen monotherapy was not linked to any of the outcomes investigated. ...
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The purpose of this study was to investigate the relationship between androgen deprivation therapy (ADT) and cardiovascular events in men with prostate cancer. Cardiovascular disease (CVD) is a primary cause of noncancer mortality in men with prostate cancer. Surveillance, Epidemiology, and End Results (SEER) Medicare-linked data revealed that CVD was responsible for about a quarter of deaths among men with prostate cancer, with a focus on the role of ADT as a contributing cause. We performed a literature search in November 2021 utilizing search engines such as PubMed, Scopus, Science Direct, and Google Scholar. Original publications with data published between 2006 and 2020 were used in the investigation of men with prostate cancer undergoing ADT treatment with a CVD outcome. Two reviewers independently examined the content of the studies and extracted data from the final papers after they had been validated for quality using quality assessment tools. A total of 14 observational studies and two randomized controlled trials are included in this systematic review. Sample sizes in the examined publications varied from 79 to 201,797 individuals. ADT was the intervention in all of the investigations. Seven of the included studies did not identify the type of ADT utilized; instead, they compared the outcomes of individuals who got ADT against those who did not. The specific type of ADT used is mentioned in the remaining nine studies included in the systematic review. Patients who got ADT, such as gonadotropin-releasing hormone (GnRH) agonists, combination androgen blockade, surgical castration, and oral anti-androgen, are compared to those who did not receive ADT to discover who had a better prognosis. In conclusion, even though ADT has several negative metabolic side effects that increase the risk of cardiovascular toxicity, published research utilizing a variety of designs has demonstrated inconsistency in the impact of ADT on cardiovascular outcomes. While the risk of CVD should be considered when prescribing ADT, the findings suggest that it should not be considered a contraindication if the expected benefit is substantial.
... Large, observational cohort studies describe a strong link between ADT and CVD, including CAD, MI, and sudden cardiac death. [11][12][13][14][15] However, ad-hoc analyses from random-ized control trials (RCTs) in the RT literature have failed to consistently demonstrate this association. [16][17][18][19] Several metaanalyses have attempted to address these discrepant findings. ...
... A large observational study of over 37 000 men with local or regional PCa receiving GnRH agonist experienced a significantly increased risk of stroke compared to the no treatment group (HR 1.22, 95% CI 1.10-1.36). 13 Longer durations of ADT were associated with an increased number of these events. A meta-analysis of eight observational studies found a 51% increase in relative risk of stroke for men treated with a GnRH agonist compared to those without (RR 1.51, 95% CI 1.24-1.84). ...
... 12 Two additional population-based studies also demonstrated similar findings, with an increased association of ADT and incident diabetes by 16-28%. 13,51 In addition, use of ADT may worsen glycemic control in men with pre-existing insulin-dependent diabetes. 52 ADT also appears to change the lipid profile, although results describing these changes are conflicting. ...
... ADT is effective in improving patients' quality of life by reducing bone pain, pathological fractures, spinal cord compression, and ureteral obstruction, which are symptoms specific to advanced PC, such as bone metastases or local enlargement of PC [18,44,45]. However, ADT has various adverse effects, such as hot flashes [46][47][48][49][50], sexual dysfunction [46,[49][50][51][52], breast enlargement [48,49,53,54], depression [49,55], dementia [56][57][58][59][60][61], osteoporosis [62][63][64][65][66], obesity [46,67], diabetes [68][69][70][71][72][73], and cardiovascular (CV) toxicity [68,[74][75][76][77][78][79][80]. ...
... ADT is effective in improving patients' quality of life by reducing bone pain, pathological fractures, spinal cord compression, and ureteral obstruction, which are symptoms specific to advanced PC, such as bone metastases or local enlargement of PC [18,44,45]. However, ADT has various adverse effects, such as hot flashes [46][47][48][49][50], sexual dysfunction [46,[49][50][51][52], breast enlargement [48,49,53,54], depression [49,55], dementia [56][57][58][59][60][61], osteoporosis [62][63][64][65][66], obesity [46,67], diabetes [68][69][70][71][72][73], and cardiovascular (CV) toxicity [68,[74][75][76][77][78][79][80]. ...
... Since then, various studies have investigated the association between ADT and CV risk events in patients with PC (Table 6). In a retrospective cohort study of 37,443 patients (older patients accounted for a 60%) with local or regional PC diagnosed by the Veterans Healthcare Administration, CV toxicity was significantly higher in the ADT group [68]. ...
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The recommended treatment for high-risk localized or locally advanced prostate cancer is radical prostatectomy plus extended pelvic lymph node dissection or radiation therapy plus long-term androgen deprivation therapy. However, some patients are treated with androgen deprivation therapy alone for various reasons. In this review, we will discuss the position, indications, complications, and future prospects of androgen deprivation therapy for high-risk localized and locally advanced prostate cancer.
... ADT is recommended alone or in combination with other therapeutic modalities for diseases of intermediate or higher risk [3,4]. Despite its established oncological efficacy, studies have shown associations between ADT and increased risks of diabetes mellitus (DM), cardiovascular mortality, myocardial infarction (MI), and stroke [5][6][7], and among diabetic patients, worsened diabetic control and a higher risk of diabetic complications [8][9][10]. Currently, risk factors and prognosticators for adverse cardiovascular events among patients with PCa receiving ADT remain actively investigated. ...
... We found that VVHV increased after ADT, consistent with prior findings of ADT being associated with poor glycaemic control [6][7][8][9][10]. Previous studies about glycaemic control in patients receiving ADT focused on time pointspecific HbA1c or fasting glucose levels, which capture only a snapshot of a patient's glycaemic metabolism and ignore temporal variations in glycaemic indices. ...
Article
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Background Androgen deprivation therapy (ADT) worsens glycaemic control and cardiovascular outcomes. The prognostic value of visit-to-visit HbA1c variability (VVHV) has been unexplored in prostate cancer (PCa) patients receiving ADT. Objective To explore the effect of ADT on VVHV and the cardiovascular prognostic value of VVHV. Design, setting, and participants PCa patients receiving ADT in Hong Kong between January 1, 1993 and March 31, 2021 were included in this retrospective cohort study. Those with fewer than three HbA1c results available within 3 yr after ADT initiation, <6 mo of ADT, missing baseline HbA1c, prior diagnosis of any component of major adverse cardiovascular events (MACEs), and MACEs occurring within 3 yr were excluded. Patients were followed up until September 31, 2021. Outcome measurements and statistical analysis The outcome was MACEs (composite of heart failure, myocardial infarction, stroke, and cardiovascular mortality). VVHV was calculated from HbA1c levels within 3 yr after and, separately where available, before ADT initiation using coefficient of variation (CV; standard deviation [SD] divided by mean) and average real variability (ARV; average difference between consecutive measurements). Results and limitations Altogether, 1065 patients were analysed (median age 74.4 yr old [interquartile range 68.3–79.5 yr]). In 709 patients with VVHV available before and after ADT initiation, VVHV increased after ADT initiation (p < 0.001), with 473 (66.2%) and 474 (66.9%) having increased CV and ARV, respectively. Over a median follow-up of 4.3 yr (2.8–6.7 yr), higher VVHV was associated with a higher risk of MACEs (adjusted hazard ratio [per SD] for CV 1.21 [95% confidence interval: 1.02, 1.43], p = 0.029; ARV 1.25 [1.06, 1.48], p = 0.008). Limitations included residual confounding and selection bias. Conclusions In PCa patients receiving ADT, VVHV increased after ADT initiation. Higher VVHV was associated with an increased risk of MACEs. Patient summary In prostate cancer patients receiving androgen deprivation therapy (ADT), glycaemic control is less stable after initiating ADT, which was associated with an increased cardiovascular risk.
... Multiple studies have favored long-term over shortterm ADT in patients with HR prostate cancer [4][5][6][7][8][9], and a recent meta-analysis showed that prolonged duration of ADT is associated with improved survival outcomes in patients with Gleason scores of 8-10 [10]. ADT is associated with a variety of adverse effects including sexual dysfunction, hot flashes, osteoporosis and increased risk of fractures, obesity, insulin resistance and a greater risk of diabetes and cardiovascular diseases, among others [11][12][13][14]. The risk of adverse events increases with the duration of treatment which affects patients' well-being and quality of life, and the best way to mitigate the side effects is by shortening the duration of treatment [15]. ...
... However, delivering long term ADT is associated with several clinical and economical challenges. Patients who receive long term ADT are at increased risk for many complications such as anemia, osteoporosis, mood, mental, sexual, and musculoskeletal changes among others [11][12][13][14]. In addition, the cost of these drugs could be prohibitive, particularly in resource-limited settings. ...
Article
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Abstract Background A nadir Prostate-Specific Antigen (nPSA) of 0.06 ng/mL has been shown to be a strong independent predictor of biochemical recurrence-free survival (bRFS) in patients with intermediate or high-risk (HR) prostate cancer treated with definitive external beam radiation therapy (RT) and androgen deprivation therapy (ADT). We aimed to examine the association between the duration of ADT and bRFS in HR localized prostate cancer, based on nPSA. Methods Between 1998 and 2015, 204 patients with HR localized prostate cancer were identified. Of them, 157 patients (77.0%) reached the desired nPSA of 6 months); (P = 0.043). The presenting T stage was borderline significant (HR 3.074; 95% CI 0.972–9.719; P = 0.056), while PSA at presentation, Gleason Score and age were not. On multivariate analysis, the use of ADT for 12 months (P = 0.012) and tnPSA (P = 0.037) remained significant. In the unfavorable group, receiving ADT beyond 9 and 12 months was associated with improved bRFS (P = 0.044 and 0.019, respectively). However, beyond 18 months, there was no significant difference. Conclusion In HR localized prostate cancer patients treated with definitive RT and ADT, the total duration of ADT may be adjusted according to treatment response using nPSA. In patients reaching a nPSA below 0.06 ng/mL, a total of 12 months of ADT may be sufficient, while in those not reaching a nPSA below 0.06 ng/mL, a total duration of 18 months is required.
... 7 Several observational studies showed that GnRH agonists were related to increased cardiovascular disease risk in patients with prostate cancer. [8][9][10] However, a meta-analysis of randomized trials reported no significant associations between GnRH agonists and the risk of cardiovascular disease. 11 Most evidence suggesting an association between GnRH agonists and cardiovascular disease for male patients with prostate cancer came from population-based studies. ...
... 11 Most evidence suggesting an association between GnRH agonists and cardiovascular disease for male patients with prostate cancer came from population-based studies. 8,9,12,13 Several meta-analyses of observational studies disclosed that GnRH agonists were related to an increased incidence of non-fatal cardiovascular disease. 14, 15 Whether or not GnRH agonists are associated with an excess risk of cardiovascular morbidity remains a highly controversial question. ...
Article
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Background: The risk of ischemic heart disease (IHD) due to the impact of gonadotropin-releasing hormone (GnRH) agonists among female patients with breast cancer remains a controversy. Methods: Information from the Registry for Catastrophic Illness, the National Health Insurance Research Database (NHIRD), and the Death Registry Database in Taiwan were analyzed. Female patients with breast cancer were selected from the Registry for Catastrophic Illness from January 1, 2000, to December 31, 2018. All the breast cancer patients were followed until new-onset IHD diagnosis, death, or December 31, 2018. A Kaplan-Meier survival curve was drawn to show the difference between patients treated with and without GnRH agonists. The Cox regression analysis was used to investigate the effects of GnRH agonists and the incidence of IHD. Results: A total of 172,850 female patients with breast cancer were recognized with a mean age of 52.6 years. Among them, 6071(3.5%) had received GnRH agonist therapy. Kaplan-Meier survival curves showed a significant difference between patients with and without GnRH therapy (log-rank p < 0.0001). Patients who received GnRH therapy had a significantly decreased risk of developing IHD than those without GnRH therapy (HR = 0.18; 95% CI = 0.14-0.23). After adjusting for age, treatment, and comorbidity, patients who received GnRH therapy still had a significantly lower risk of developing IHD (AHR = 0.5, 95% CI = 0.39-0.64). Conclusion: The study showed that the use of GnRH agonists for breast cancer treatment was significantly associated with a reduced risk of IHD. Further research is required to investigate the possible protective effect of GnRH on IHD.
... In fact, in the year 2010, the Food and Drug Administration (FDA) warned patients with prostate cancer treatment who are using GnRH agonists about an increased risk of diabetes while they are receiving these medications [4]. Nevertheless, the effects of GnRH agonists on glucose metabolism were not yet fully understood until the recent literature elucidated these effects [3,5,6]. ...
... Nevertheless, this case is considered the first -to the best of the authors' knowledge -to report HHS as a presenting feature of leuprolide-induced impaired glycemic control in a patient without a previous history of diabetes within a short-term interval following the first injection of leuprolide. Diabetes screening with close glycemic monitoring is recommended for patients receiving leuprolide to minimize the occurrence of serious diabetic complications such as the HSS described in this patient [4]. ...
Article
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We present a novel case of severe hyperosmolar hyperglycemic derangement in an elderly patient-without a known history of diabetes mellitus-after the first injection of leuprolide for the treatment of metastatic prostate adenocarcinoma. Whilst the available literature provided accumulative evidence of an association between insulin resistance and the use of gonadotropin-releasing hormone (GnRH) agonists, the initial presentation of leuprolide-induced impaired glycemic tolerance with a hyperosmolar hyperglycemic state (HHS) represents a clinical rarity that was seldom reported. A literature review was conducted to explore the underlying mechanisms of leuprolide-associated glucose intolerance. Screening for diabetes is recommended for patients receiving leuprolide therapy to identify at-risk patients and close glycemic monitoring is warranted in diabetic patients to minimize serious complications from poor glycemic control induced by leuprolide.
... Surprisingly none of these studies sought to identify which patients with pN1 disease may benefit from immediate ADT versus observation ± deferred ADT, and vice-versa. This is an important consideration given the known heterogeneity that exists among pN1 PCa patients [10,11] and the substantial sideeffects of ADT [12][13][14][15]. Further, these studies did not examine the role of postoperative PSA kinetics in guiding hormonal therapy use. ...
... By doing so, close to 40% (n = 115 of 297) of men may avoid immediate ADT, and over 30% may avoid ADT for life (n = 91 of 297, Supplementary Table 2). This is an important consideration as anti-androgen therapies are well known to cause clinically significant cardiac [13][14][15], cerebrovascular [12], and cognitive [24] adverse events, as well as deterioration in quality-oflife of the PCa survivors [25,26]. Contrarily, we show that patients in whom PSA either remains above 0.2 ng/mL after radical prostatectomy or rises rapidly, i.e. within 6 months, over this level should be managed aggressively with iADT upfront. ...
Article
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Background Optimal postsurgical management of prostate cancer (PCa) patients with nodal metastasis at the time of radical prostatectomy remains unclear. We sought to examine the role of postoperative PSA kinetics and pathologic tumor characteristics in guiding additional hormonal therapy use in pN1 men. Methods In total, 297 pN1 PCa patients treated with radical prostatectomy and ePLND between 2002 and 2018 were identified within our prospectively maintained institutional cancer data-registry. Following surgery, these patients were managed with either immediate androgen deprivation therapy (iADT) or observation with deferred ADT (dADT). The former was defined as ADT given within ≤6 months of surgery and the latter as >6 months. The primary outcome was metastasis. Regression-tree analysis was used to stratify patients into novel risk-groups based on post-prostatectomy tumor characteristics and PSA kinetics and the corresponding metastasis risk. Multivariable Cox regression analyses tested the impact of iADT versus observation ± dADT on metastasis, cancer-specific mortality, and overall mortality within each risk-group separately. Results The median follow-up was 6.1 years (IQR 3.2–9.0). Regression-tree analysis stratified patients into 3 novel risk-groups (Harrell’s C-index 0.79) based on PSA-nadir and time to biochemical failure: group 1 (low-risk) included patients with time to biochemical recurrence >6 months (n = 115), while groups 2 and 3 included patients with biochemical failure within ≤6 months with a postoperative PSA-nadir <1.05 ng/mL (group 2 [intermediate-risk], n = 125) or ≥1.05 ng/mL (group 3 [high-risk], n = 57), respectively. No other patient or tumor characteristics were significant for risk stratification. Within each risk-group, the 10-year metastasis-free survival rates with iADT versus observation ± dADT use were: group 1, 100% versus 95.4% (Log-rank p = 0.738), group 2, 80.6% versus 53.5% (Log-rank p = 0.016), and group 3, 41.5% versus 0% (Log-rank p = 0.015), respectively. Adjusted Cox regression analyses confirmed the benefit of iADT utilization in reducing metastasis in group 2 (p = 0.029) and group 3 (p = 0.008) patients, with no benefit for group 1 patients (p = 0.918). Similar results were noted for cancer-specific and overall mortality. Conclusions Following radical prostatectomy, early postoperative PSA kinetics may provide valuable information for guiding the timing of ADT initiation—this may reduce over- and undertreatment of pN1 PCa men.
... Similarly, in a prospective cohort study, androgen deprivation therapy in men with prostate cancer was associated with QTc prolongation compared with men with prostate cancer not receiving the therapy (475). As QTc prolongation is associated with an increased risk of ventricular tachyarrhythmias (torsades de pointes) and sudden cardiac death (476)(477)(478), it is not surprising that androgen deprivation therapy is associated with a higher risk of arrhythmia, cardiac conduction disturbances and sudden death (479,480). A small case series study and analysis of the European pharmacovigilance database concluded that "conditions or drugs leading to male hypogonadism were associated with torsades de pointes", and "correction of hypogonadism with testosterone replacement therapy can treat or prevent torsades de pointes" (481). ...
... Acute and severe androgen deficiency induced by administration of a GnRH agonist or antagonist worsens measures of insulin sensitivity; acute withdrawal of testosterone therapy in men with idiopathic hypogonadotropic hypogonadism (528) and administration of androgen deprivation therapy in men with prostate cancer is associated with the worsening of insulin sensitivity (452,529,530). Men with prostate cancer who are receiving androgen deprivation therapy are at increased risk of developing type 2 diabetes and metabolic syndrome (479,529,531). In the TIMES2 study (532), men with type 2 diabetes mellitus and/or metabolic syndrome were randomized to either 2% testosterone gel or placebo gel for 6 months. ...
Chapter
In male mammals, changes at all levels of the hypothalamic-pituitary-testicular axis, including alterations in the GnRH pulse generator, gonadotropin secretion, and testicular steroidogenesis, in addition to alterations of feed-forward and feed-back relationships contribute to the age-related decline in circulating testosterone concentrations. The rate of age-related decline in testosterone levels is affected by the presence of chronic illness, adiposity, medication, sampling time, and the methods of testosterone measurement. Epidemiologic surveys reveal an association of low testosterone levels with changes in sexual function, body composition, physical function and mobility, and increased risk of diabetes, late life persistent depressive disorder (dysthymia), unexplained anemia of aging, osteoporosis and bone fractures. Age-related decline in testosterone should be distinguished from classical hypogonadism due to known diseases of the hypothalamus, pituitary, and the testis. In young hypogonadal men who have a known disease of the hypothalamus, pituitary, and testis, testosterone therapy is generally beneficial and has been associated with a low frequency of adverse events. However, neither the long-term benefits in improved health outcomes nor the long-term risks of testosterone therapy are known in older men with age-related decline in testosterone levels. Well-conducted randomized trials have found that testosterone replacement of older men with unequivocally low testosterone levels improves sexual desire, erectile function, and overall sexual activity; lean body mass, muscle strength and some measures of physical function and mobility; areal and volumetric bone density and bone strength; depressive symptoms; and corrects anemia of aging. Testosterone treatment does not worsen lower urinary tract symptoms but the effects of long-term testosterone treatment on the risk of prostate cancer and major adverse cardiovascular events remain unknown. Although testicular morphology, semen production, and fertility are maintained up to a very old age in men, there is clear evidence of decreased fecundity with advancing age and an increased risk of specific genetic disorders related to paternal age among the offspring of older men. Thus, reproductive aging of men is emerging as an important public health problem whose serious societal consequences go far beyond the quality-of-life issues related to low testosterone levels. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
... В исследовании N.L. Keating и соавт. (2006) [21] с участием 73 000 пациентов с раком простаты, которые получали агонисты гонадотропин рилизинг-гормона, описано увеличение риска ИБС на 16 %, ИМ на 11 %. При ретроспективном анализе C.S. Saigal и соавт. ...
Article
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In the second part of the review, the analysis of modern literature data demonstrating the pathophysiological mechanisms of the development of cardiovascular complications of chemo- and radiation therapy in oncological patients should be continued.
... It is also an adjuvant to radiation treatment in patients with locally advanced illnesses and those with unwanted intermediate-risk or high-risk local sicknesses. ADT's goal is hypogonadism, which can be achieved surgically with bilateral orchidectomy or therapeutically with luteinizing hormone-releasing hormone agonists (LHRHa) or LHRH antagonists [3]. Nonetheless, ADT causes side effects such as libido loss, hot flashes, bone weakness, exhaustion, loss of lean body mass, anemia, gynecomastia, and progression of the metabolic condition [4,5]. ...
Article
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Introduction: Dyslipidemia is the primary cause of hospitalization and death in men with advanced prostate cancer. Our goal was to examine how androgen deprivation therapy (ADT) affects lipid profiles in Indian men with locally progressed or metastatic prostate cancer. Methods: this multi center study was conducted in LRH urology department From jan 2020 to jan 2021 Patients with prostate cancer who received ADT and for whom lipid account data from the first two years of ADT treatment was available were split into two groups for retrospective analysis. Members of Group A had bilateral orchidectomy, whereas those in Group B were given a luteinizing hormone-releasing hormone agonist (LHRHa). The information considered are quality standards, prostate-specific antigen (PSA), and lipid profiles. Results: 69 eligible patients were divided evenly between teams A (29) and B (40). After starting ADT, the median blood PSA level dropped significantly in both groups and remained low until 24 months. At six months, there was a statistically insignificant decline in all lipid profile parameters in team A patients except for high-density lipoprotein cholesterol.
... With respect to metabolic consequences, a large U.S. study showed patients on ADT were 44% more likely to develop diabetes with a 16% increased risk of sudden cardiac death compared with patients with PCa not receiving ADT. 28 Overall, literature reports a 14-39% increased risk of fracture in patients exposed to ADT compared with unexposed controls. 29,30 Alternatives to TTh for treatment of hypogonadal sequelae of ADT have been explored such as manipulating ADT administration protocols, using therapies to target specific side effects, and nonpharmacology therapies. ...
Article
Androgen deprivation therapy is a mainstay of advanced prostate cancer (PCa) but the resulting low testosterone levels leave men susceptible to a multitude of adverse effects. These can include vasomotor symptoms, reduced sexual desire and performance, and mood changes. Testosterone therapy (TTh) in advanced PCa has historically been contraindicated since Huggins and Hodges reported that testosterone activates PCa. Although TTh has been demonstrated to be safe in patients who have undergone treatment for localized PCa, there is extremely limited evidence on its safety in advanced PCa. Despite the lack of evidence, some men with advanced PCa still inquire about TTh, and recent publications have described its use. In this article, we review the potential implications of TTh in men with advanced PCa, defined here as biochemical recurrence after localized therapy or metastatic PCa that is either hormone sensitive or castration resistant.
... 62 Decreased muscle loss has also been linked with lowered levels of testosterone, and this can lead to significant fatigue and overall weakness. 64 There is also a proposed increased risk of diabetes mellitus and cardiovascular disease (CVD), as well as risk of death from CVD. [65][66][67][68] Cormie et al. found that combined aerobic and resistance exer-cise prevented weight gain; improved cardiovascular fitness, muscular strength, and lower body function; improved high density lipoprotein to cholesterol ratios; and improved sexual, psychological, and social functioning. 69 They advised the initiation of supervised exercise programs to all patients receiving ADT to minimize the morbidity associated with the potential severe hypogonadism. ...
... Although continuous ADT shows therapeutic efficacy in prostate cancer, toxicity must be considered with respect to quality of life, including sexual dysfunction, hot flashes, osteoporosis, sarcopenia, and cardiovascular adverse events [30][31][32][33][34][35][36]. In that sense, intermittent ADT may be a good alternative as it delays androgen resistance and can improve quality of life. ...
Article
Biochemical recurrence (BCR) is common after radical prostatectomy, but effective treatment options for men with BCR after curative treatment remain controversial. Although prostate-specific antigen is widely used as a surrogate marker for prostate cancer survival, it cannot fully differentiate between prostate-cancer-specific survival and overall survival. Thus, it is challenging for physicians to determine the timing of treatment to halt or slow the clinical progression of disease in patients with BCR while avoiding overtreatment for patients whose disease may not progress beyond BCR. Adjuvant therapy for radical prostatectomy or radiotherapy in intermediate- or high-risk localized prostate cancer has a benefit in terms of disease progression and survival but is not recommended in low-risk prostate cancer because of the significant adverse effects related to radiotherapy and androgen-deprivation therapy (ADT). Salvage radiotherapy (SRT) is also recommended for patients with BCR after radical prostatectomy. Several options for management of BCR after radical prostatectomy include SRT to the prostatic bed and/or pelvis, continuous or intermittent ADT, or observation. Patients' comorbidity, preferences, and cancer-related factors must be considered when deciding the best management strategy. Modern imaging technology such as positron emission tomography imaging of prostate-specific membrane antigen-positive regions enables earlier detection of disease progression, thus enhancing decision making for future disease management.
... Comparing the risk of complications as well as cancer control is essential in treatment optimization, especially for elderly men, since tolerability may have deteriorated in this segment of the population and intervention may accelerate the vulnerability. For instance, androgen deprivation therapy (ADT) is known to increase the risk of bone fracture [26], diabetes [27,28], and cardiovascular disease [29,30], although there are some ways to mitigate these concerns [31]. Since testosterone has a neuro-protective effect including the improvement of energy metabolism and reduction of oxidative stress in neurons [32], ADT may deteriorate cognitive function [33] and may increase the risk of dementia as well [34]. ...
Article
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Robot-assisted radical prostatectomy (RARP) has now become the gold standard treatment for localized prostate cancer. There are multiple elements in decision making for the treatment of prostate cancer. One of the important elements is life expectancy, which the current guidelines recommend as an indicator for choosing treatment options. However, determination of life expectancy can be complicated and difficult in some cases. In addition, surgical tolerability is also an important issue. Since frailty may be a major concern, it may be logical to use geriatric assessment tools to discriminate ‘surgically fit’ patients from unfit patients. Landmark studies show two valid models such as the phenotype model and the cumulative deficit model that allow for the diagnosis of frailty. Many studies have also developed geriatric screening tools such as VES-13 and G8. These tools may have the potential to directly sort out unfit patients for surgery preoperatively.
... There are risk factors present in cancer patients that can make them at higher risk of CVD morbidity and mortality, including smoking, hypertension, and advanced age, as well as sustained inflammation and cardiotoxicity from chemotherapy and radiotherapy [11]. There is also evidence for a possible increased risk of CVD from androgen deprivation therapy used in some groups of PCa patients [36][37][38]. However, these factors are not necessarily an issue in the majority of PCa patients. ...
Article
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Introduction: There is limited knowledge about the use of invasive treatment and mortality after acute myocardial infarction (AMI) in prostate cancer patients. We therefore wanted to compare rates of invasive treatment and 30-day mortality between AMIs in patients with prostate cancer (PCa) and AMIs in the general Norwegian male population. Methods: Norwegian population-based registry data from 2013-2019 were used in this cohort study to identify AMIs in patients with a preceding PCa diagnosis. We compared invasive treatment rates and 30-day mortality in AMI patients with PCa to the same outcomes in all male AMI patients in Norway. Invasive treatment was defined as performed angiography with or without percutaneous coronary intervention or coronary artery bypass graft surgery. Standardized mortality (SMR) and incidence ratios (SIR), and logistic regression were used to evaluate the association between PCa risk groups and invasive treatment. Results: In 1018 patients with PCa of all risk groups, the total rates of invasive treatment for AMIs were similar to the rates in the general AMI population. In patients with ST-segment elevation AMIs, rates were lower in metastatic PCa compared to localized PCa (OR 0.15, 95% CI 0.04-0.49). For non-ST-segment elevation AMIs there were no differences between PCa risk groups. The 30-day mortality after AMI was lower in PCa patients than in the total population of similarly aged AMI patients (SMR 0.77, 95% CI 0.61-0.97). Conclusion: Except for patients with metastatic PCa experiencing an ST-segment elevation AMI, PCa patients were treated as frequent with invasive treatment for their AMI as the general AMI population. 30-day all-cause mortality was lower after AMI in PCa patients compared to the general AMI population.
... In animal models, androgen deprivation via orchiectomy results in function and structural changes to the internal pudendal arteries, resulting in vascular endothelial dysfunction as well as reduced NO activity, which is reversed by replacement of testosterone. 84 In humans, studies analyzing the effects of androgen-deprivation therapy for prostate cancer have demonstrated increased risk of incident diabetes, myocardial infarction, CVD, 85 and vascular stiffness 86 across the range of different androgen-deprivation modalities including gonadtrophin-releasing hormone agonists, antagonists, androgen blockage, and CYP17 inhibitors, as discussed in a recent meta-analysis by Hu et al. 87 Basal testosterone levels are inversely related to mortality because of CVD in adult men. 88 All-cause mortality is increased in hypogonadal men and testosterone therapy reduces mortality to 8.4% compared with 19.2% in untreated groups. ...
Article
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Androgens, including testosterone and its more potent metabolite, dihydrotestosterone, exert multiple actions in the body. Physiologically they play a critical role in male sex development. In addition, they influence vascular function including arterial vasodilation and mediation of myogenic tone. Androgens are produced from 9 weeks gestation in the human fetal testis, as well as in small amounts by the adrenal glands. Serum concentrations vary according to age and sex. The vasculature is a target for direct actions of androgens, which bind to various sex hormone receptors expressed in endothelial and vascular smooth muscle cells. Androgens exert both vasoprotective and vasoinjurious effects depending on multiple factors including sex-specific effects of androgens, heterogeneity of the vascular endothelium, differential expression of androgen and sex hormone receptors in endothelial and vascular smooth muscle cells and the chronicity of androgen administration. Chronic administration of androgens induces vasoconstriction and influences endothelial permeability, while acute administration may have opposite effects. At the cellular level, androgens stimulate endothelial cell production of nitric oxide and inhibit pro-inflammatory signaling pathways, inducing vasorelaxation and vasoprotection. However androgens also activate endothelial production of vasoconstrictors and stimulate recruitment of endothelial progenitor cells. In humans, both androgen deficiency and androgen excess are associated with increased cardiovascular morbidity and mortality. This review discusses how androgens modulate vascular sex differences across the lifespan by considering the actions and production of androgens in both sexes and describes how cardiovascular risk is altered as levels of androgens change with aging.
... The relationship between ADT (GnRH agonists) and an increased risk of diabetes mellitus, coronary heart disease (CHD), myocardial infarction (MI), and sudden cardiac death was first observed in the above-mentioned SEER-Medicare database [39]. Subsequent observational studies and randomized controlled trials (RCTs) have not been able to find a clear association between ADT and increased CV risk, probably due to several study limitations and biases, although meta-analyses of observational studies have shown positive associations with CV events and CV death [40,41]. ...
Article
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Introduction Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) are frequently poly-medicated due to age-related and androgen deprivation therapy (ADT)-derived comorbidities. In high-risk patients, androgen receptor inhibitors (ARIs) have shown to delay disease progression; however, drug–drug interactions (DDIs) with preexisting medications may impact the therapeutic effect and safety of these and of the ARIs themselves. Areas covered We review the potential comorbidity burden of nmCRPC patients on the basis of epidemiologic studies on age-related comorbidities, the impact of ADT and specific studies analyzing this topic. Using the DDIs compendia Lexicomp® and Drugs.com®, we provide a scenario of the potential DDIs between common mediations used to treat these comorbidities and the three currently available ARIs: apalutamide, enzalutamide and darolutamide. Expert opinion In high-risk nmCRPC patients to be treated with an ARI, careful multidisciplinary evaluation of potential DDIs is a fundamental component in the clinical-decision making. The lower potential for DDIs, the lower need for dose adjustment or change of current comedications and of patient monitoring, and safer introduction of new comedications. To optimize this step, an effort is still needed to determine the clinical relevance of DDIs and to harmonize their definition and classification among the different compendia.
... The current research emulates a randomized comparative safety study, the PRONOUNCE trial (12,13), which was designed to evaluate the comparative risk of major adverse cardiovascular events (MACE), defined as a composite of allcause mortality, nonfatal myocardial infarction, or nonfatal stroke, among advanced prostate cancer patients treated with androgen deprivation therapy. The trial was intended to address conflicting reports of increased cardiovascular risk among patients treated with gonadotropin-releasing hormone agonists vs antagonists (14)(15)(16)(17)(18)(19). Using a previously described approach to clinical trial emulation, we aimed to predict the findings of the PRONOUNCE trial before trial results were published (10). ...
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Background Medical and regulatory communities are increasingly interested in the utility of real-world evidence (RWE) for answering questions pertaining to drug safety and effectiveness but concerns about validity remain. A principled approach to conducting RWE studies may alleviate concerns and increase confidence in findings. This study sought to predict the findings from the PRONOUNCE trial using a principled approach to generating RWE. Methods This propensity-score (PS) matched observational cohort study utilized 3 claims databases to compare the occurrence of major adverse cardiovascular events (MACE) among initiators of degarelix vs. leuprolide. Patients were included if they had history of prostate cancer and atherosclerotic cardiovascular disease. Subjects were excluded if they didn’t have continuous database enrollment in the year prior to treatment initiation, were exposed to androgen deprivation therapy or experienced an acute cardiovascular event within 30 days prior to treatment initiation, or had a history or risk factors of QT prolongation. Results There were 12,448 leuprolide and 1,969 degarelix study-eligible patients before matching, with 1,887 in each arm after PS-matching. The results for MACE comparing degarelix to leuprolide in the observational analysis (hazard ratio= 1.35; 95% confidence interval = 0.94–1.93) was consistent with the subsequently released PRONOUNCE result (hazard ratio = 1.28; 95% confidence interval = 0.59–2.79). Conclusions This study successfully predicted the result of a comparative cardiovascular safety trial in the oncology setting. Although the findings are encouraging, limitations of measuring cancer stage and tumor progression are representative of challenges in attempting to generalize whether claims-based RWE can be used as actionable evidence.
... However, an aggregation of observational reports suggested that LHRH agonists may induce cardiovascular (CV) toxicity. 1,2 The American Heart Association and the US Food and Drug Administration subsequently expressed concerns over this potential risk, but its clinical significance has been debated. 3 Until recently, additional studies were conducted, but a definitive conclusion has remained elusive because of mixed results, a lack of high-quality data, and a possible overestimation of induced CV events (CVE). ...
Article
In this article, we address the timely unresolved issue: Should Prostate Cancer Patients with History of Cardiovascular Events Be Preferentially Treated with Luteinizing Hormone-Releasing Hormone Antagonists?
... Androgen deprivation therapy is usually combined as adjuvant treatment with EBRT in localized and locally advanced prostate cancers (8). Although it is effective in reducing tumor mass and prostate-specific antigen (PSA) levels (9), limitations to the use of adjuvant ADT in these localized tumors mainly derive from the short-and long-term adverse effects (AEs), which may worsen the quality of life of the patient or be potentially harmful (10)(11)(12). ...
Article
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Background Intermediate-risk prostate cancer (PCa) is usually treated by a combination of external beam radiation therapy (EBRT) and a short course of androgen deprivation therapy (ADT). ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, anti-androgen monotherapy is generally better tolerated in spite of higher rates of gynecomastia. Objective This study assessed the effectiveness of enzalutamide monotherapy combined with hypofractionated EBRT (Hypo-EBRT) for treating intermediate risk prostate cancer. Method This trial was a multicenter, open-label phase II study of 6 months of enzalutamide monotherapy combined with Hypo-EBRT for intermediate-risk prostate cancer. Hypo-EBRT was initiated 8–12 weeks after initiating enzalutamide. The primary endpoint was PSA decline >80% measured at the 25th week of enzalutamide administration. Secondary end-points included assessment of toxicity, changes in anthropomorphic body measurements, sexual hormones, and metabolic changes. Results Sixty-two patients were included in the study from January 2018 to February 2020. A PSA decline of >80% was observed in all evaluable patients at the end of enzalutamide treatment and 92% achieved PSA values under 0.1 ngr/ml. All patients remain in PSA response (<80% reduction of the initial values) 6 months after the end of enzalutamide treatment. The most frequent adverse events were hypertension, asthenia, and gynecomastia. There were no significant changes in bone density, body mass index (BMI), or patient-reported outcomes (PROs). Conclusion Enzalutamide monotherapy is very effective along with hEBRT in reducing PSA levels for patients with intermediate-risk prostate cancer. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials.
... 10,11 A recent population-based study suggested an association between ADT and Alzheimer's disease 12 ; together with an aberrant increase in the folded β-amyloid (Aβ) protein. 13,14 Both testosterone concentration and ADT increases the risk of cardio-metabolic diseases, 15 which are known risk factors for all-cause dementia. 16 Therefore, examination of the relationship of ADT with Alzheimer's disease and general dementia is critical to fully understand the molecular effects of this association. ...
Article
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Background: Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment likely develops side-effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses. Methods: Gene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database. Results: A total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine-cytokine signaling with an over representation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T-cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL-17A, CCL2, IL-10, IL-6, IL-1RN, LIF/LIFR were further validated by quantitative RT-PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen-responsive prostate cancer cells, compared to no-androgen antagonist treatment. Conclusions: Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.
... According to one research, the subjects received ADT were correlated to higher incidence of ischemic stroke and coronary arterial diseases [8]. Besides, the rate of sudden cardiac death was significantly higher in patients received the ADT [10]. In addition to the above disorders, the ADT is associated with the development of deep vein thrombosis [11]. ...
Article
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This study aimed to investigate the influence of androgen deprivation therapy (ADT) for the development of dry eye disease (DED) in subjects with prostate cancer via the use of national health insurance research database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients were selected as prostate cancer with ADT according to diagnostic and procedure codes. Each participant in that group was then matched to one patient with prostate cancer but without ADT and two subject s without prostate cancer and ADT. And a total of 1791, 1791 and 3582 participants were enrolled in each group. The primary outcome was set as the DED development according to the diagnostic codes. Cox proportional hazard regression was applied to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT and other parameters for DED development. There were 228, 126 and 95 new events of DED developed in the control group, the prostate cancer without ADT group and the prostate cancer with ADT group. The rate of DED in the prostate cancer with ADT group (aHR: 0.980, 95% CI: 0.771-1.246, P= 0.8696) and Prostate cancer without ADT group (aHR: 1.064, 95% CI: 0.855-1.325, P= 0.5766) were not significantly different compared to the control group. In addition, the patients aged 70-79 years old demonstrated a significantly higher incidence of developing DED compared to those aged 50-59 years old (aHR: 1.885, 95% CI: 1.188-2.989, P= 0.0071). In conclusion, the use of ADT did not alter the incidence of subsequent DED.
... Around 2002, the negative impact of ADT on cognition came to the attention [18]. In 2006, an increased risk of diabetes and cardiovascular disease was found [19,20] and confirmed by subsequent studies [21]. In addition, more recent studies showed an increased risk of dementia [22]. ...
Article
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Background: Guidelines on androgen deprivation therapy (ADT) for prostate cancer (PCa) arise from a critical appraisal of scientific evidence, which is a costly effort. Despite these efforts and the side effects of ADT, guidelines may not always be adhered to. Objective: To determine ADT overtreatment in PCa patients compared to the European Association of Urology (EAU) guidelines, and to identify predictors and physicians' motivations for this overtreatment. Design setting and participants: Men were included from the European Randomised study of Screening for Prostate Cancer (ERSPC) Rotterdam who were diagnosed with PCa between 2001 and 2019, and received ADT <1 yr after diagnosis. Outcome measurements and statistical analysis: Patients were categorised into the concordant ADT or discordant ADT group following the EAU guidelines. Physicians' motivations for discordancy were reported. Multivariable logistic regression was performed to identify predictors for guideline-discordant ADT including the nonlinear fit of the year of diagnosis. Results and limitations: Of 3608 PCa patients, 1037 received ADT <1 yr after diagnosis. Adherence improved gradually over the study period, resulting in overall discordancy of 15%. A patient diagnosed in 2011 had 3.3 times lower risk on guideline-discordant ADT than a patient diagnosed in 2004 (odds ratio [OR] 0.30; 95% confidence interval [CI] 0.18-0.50). The most common reason for discordancy was unwillingness or unfitness for curative treatment of asymptomatic patients. Age (OR 1.19; 95% CI 1.15-1.24) and Gleason score ≥4 + 3 (OR 1.70; 95% CI 1.06-2.74) were associated with guideline-discordant ADT. Conclusions: In a Dutch cohort, slow adaptation of the EAU guidelines on ADT for PCa patients between 2001 and 2019 resulted in overall overtreatment of 15%, mostly in asymptomatic patients who were unfit or unwilling for curative treatment. Clear, structured presentation, or integration of these tailored guidelines into the electronic health record might accelerate the adaptation of future guidelines. Patient summary: Slow adaptation of the guidelines on hormonal therapy resulted in overtreatment in 15% of prostate cancer patients, mostly in asymptomatic patients who were unfit or unwilling for curative treatment.
... A large population-based cohort study including 73,196 patients reported a significantly increased risk of cardiac events among patients on LHRHa; however, in contrast, orchidectomy did not significantly alter the risk of cardiac events [8]. Hence, there is a possibility that orchidectomy could be associated with fewer adverse effects on multiple health domains compared to longterm LHRHa use. ...
Article
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Background Dyslipidemia is directly related to morbidity and mortality in elderly prostate carcinoma patients. The purpose of this study was to evaluate the effects of androgen deprivation therapy (ADT) on the lipid profile among Indian patients with locally advanced and metastatic prostate carcinoma. Methods The prospective database of prostate carcinoma patients, who received ADT and whose lipid profile data for the first two years of treatment with ADT was available, were divided into two groups for retrospective analysis: Group A patients are those who had undergone bilateral orchidectomy, while group B patients received luteinizing hormone-releasing hormone agonist (LHRHa). The data analyzed include baseline characteristics, prostate-specific antigen (PSA), and lipid profile. Results A total of 69 eligible patients were divided into two groups: group A—29 patients and group B—40 patients. Patients of both the groups reported a significant decrease in the mean serum PSA level from the commencement of ADT and remained close to nadir level till 24 months. In the group A patients, lipid profile parameters except high-density lipoprotein cholesterol showed statistically insignificant deterioration with maximum impact at 6 months. Among the group B patients, the total cholesterol (11.9%), triglycerides (22.2%), and low-density lipoprotein cholesterol (21.1%) increased significantly at 6 months and returned to the near baseline at 12 months and thereafter persisted at the similar level. The mean very low-density lipoprotein level (15.5%) also increased significantly at 6 months and then showed a gradual decline till 24 months of follow-up. Conclusions LHRH agonist used as ADT for prostate carcinoma leads to a statistically significant but clinically insignificant temporary worsening in the lipid profile.
... A common adverse effect of ADT is obesity-related comorbidity such as cardiovascular disease and diabetes. 24 Although the underlying biological mechanisms of this link are not fully understood, the widespread use and clinical benefit of ADT require strategies to be developed to counteract these common side effects of treatment. Studies have indicated that structured exercise may represent a promising approach in this regard. ...
Article
PURPOSE Androgen-deprivation therapy in patients with prostate cancer (PCa) is associated with considerable side effects and secondary comorbidities such as overweight/obesity and cardiovascular disease. The aim of this study was to investigate the effectiveness of an industry-led, treatment-integrated, community-based exercise program on outcomes of body weight, cardiovascular health, and physical function. PATIENTS AND METHODS PCa patients with locally advanced, relapsed, or metastatic disease receiving leuprorelin acetate were enrolled across multiple sites in Australia and assigned supervised group exercise undertaken weekly or biweekly (ie, 16 exercise sessions in total) for 10-18 weeks, consisting of aerobic and resistance training performed at moderate-to-vigorous intensity. RESULTS Between 2014 and 2020, 760 participants completed the baseline and follow-up assessment. Participants were age 48-94 years, and most were either overweight (42.1%) or obese (38.1%). Program compliance was high, with 90% of participants completing all 16 exercise sessions. There was a small but significant reduction in waist circumference (–0.9 cm; 95% CI [–1.2 to –0.5]; P < .001) and no change in weight or body mass index. Systolic (–3.7 mmHg; 95% CI [–4.8 to –2.6]; P < .001) and diastolic (–1.7 mmHg; 95% CI [–2.3 to –1.0]; P < .001) blood pressure were significantly lower after the program. Furthermore, significant improvements were seen in cardiorespiratory fitness and muscle strength ( P < .001). For most of the investigated outcomes, participants with poorer initial measures had the greatest benefit from participating in the program. CONCLUSION The community exercise program was feasible and effective in preventing weight gain, reducing blood pressure, and improving physical function in patients with PCa on androgen-deprivation therapy.
... It is GnRH agonist treatment that has specifically been associated with increased CV morbidity and mortality in several observational studies [2,[6][7][8]. Among them, a population-based study using data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database demonstrated an increased risk of coronary heart disease, myocardial infarction (MI), and sudden cardiac death [7,9] with GnRH agonist use, but not with bilateral orchiectomy. While both treatments may increase CV risk due to the lack of testosterone, GnRH agonists further increase the risk of thromboembolic events. ...
Article
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Background: Cardiovascular disease (CVD) is a common comorbidity in patients with prostate cancer. In this review, we summarize the published literature on the association of cardiovascular risk with androgen deprivation therapy (ADT) treatment and explore the potential differences between the gonadotropin-releasing hormone (GnRH) agonists and antagonists and the molecular mechanisms that may be involved. We also provide a practical outlook on the identification of underlying CV risk and explore the different stratification tools available. Results: While not definitive, the current evidence suggests that GnRH antagonists may be associated with lower rates of certain CV events vs agonists, particularly in patients with preexisting CVD. Risk reduction strategies such as lifestyle advice, consideration of ADT modality, and comedications may help to reduce CV risk factors and improve outcomes in prostate cancer patients receiving ADT. Conclusions: Given all the data that is currently available, identification of baseline CV risk factors may be key to risk mitigation in patients with prostate cancer receiving ADT.
... Prostate cancer (PCa) patients have increased risk of developing cardiovascular disease (CVD) and are more likely to die from non-PCa specific causes, mainly cardiovascular related, than from PCa 1,2 There is evidence that androgen deprivation therapy (ADT), a common treatment for more aggressive PCa, may increase the risk of cardiovascular morbidity and mortality, as well as all-cause mortality. [2][3][4][5][6] However, there have been contradictory findings of the relationship between PCa treatment and CVD. [7][8][9][10] Contradictory findings come mainly from randomised controlled trials which historically include healthier patients than the general population and may not reflect real-world experiences. ...
Article
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Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all‐cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008‐18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke, and heart failure, in addition to atrial fibrillation and all‐cause mortality, were explored using time‐varying Cox regression models. We included 30,923 PCa patients, of whom 8,449 (27%) received primary ADT. Mean follow‐up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05‐1.21), myocardial infarction (1.18: 1.05‐1.32), stroke (1.21: 1.06‐1.38), heart failure (1.23: 1.13‐1.35) and all‐cause mortality (1.49: 1.39‐1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than seven months. A relationship between ADT and composite CVD and all‐cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all‐cause mortality within the context of treatment guidelines and benefits of ADT. This article is protected by copyright. All rights reserved.
... Cardiovascular deaths were not correlated with the addition of ADT or its duration (from 3 to 36 months) [45]. Indeed, the higher risk of cardiac toxicity induced by ADT is controversial and occurs especially in patients with pre-existing cardiovascular comorbidities such as heart failure or myocardial infarction [46,47]. Metabolic consequences are better established with metabolic alterations such as insulin resistance and dyslipidemia [33,34]. ...
Article
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Purpose To analyze the literature that addresses radiation therapy for intermediate and high-risk prostate cancer (PC) in the elderly. Patients and methods A PubMed literature search was conducted including articles from 01/01/2000 to 30/06/21, with the following keywords: PC, radiotherapy/brachytherapy and elderly. The analysis mainly focused on the issue of under-treatment in the elderly and the benefit/risk balance of irradiation. Results Of the 176 references analyzed, 24 matched the selection criteria. The definition of “elderly patient” varied from 70 to 80 years. The analysis was impacted by the inhomogeneous primary end points used in each cohort. Age was often an obstacle to radical treatment, with a subsequent risk of under-treatment, particularly in patients with a poorer prognosis. However, comparable elderly oncological outcomes were compared to younger patients, both with external beam radiotherapy alone or combined with brachytherapy boost. Late toxicity rates are low and most often comparable to younger populations. However, a urinary over- toxicity was observed in the super-elderly (>80 years) after brachytherapy boost. The use of ADT should be considered in light of comorbidities, and may even be deleterious in some patients. Conclusion Due to the increase in life expectancy, the management of PC in the elderly is a challenge for patients, clinicians and health insurance payers. Except for unfit men, elderly patients remain candidates for optimal curative treatment (i.e. regardless of age) after oncogeriatric assessment. More solid data from prospective trials conducted specially in this population will provide better guidance in our daily clinical practice.
... Such treatment is highly effective for arresting tumor growth but has numerous adverse effects, including fatigue, loss of muscle mass, vasomotor instability, bone loss, and metabolic abnormalities. Androgen deprivation therapy is also associated with an elevated risk for cardiovascular disease and diabetes (1)(2)(3). In the past decade, 2 novel hormonal agents, abiraterone and enzalutamide, have greatly expanded treatment options for prostate cancer. ...
... ADT can be administered by surgery (surgical castration) or medication (gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, oral antiandrogens, or a combination of GnRH analogues and antiandrogens in some clinical cases) [3]. Despite its proven survival benefit, hypogonadism, which is produced by ADT, leads to several adverse effects, such as atherosclerosis, type 2 diabetes, obesity, arterial hypertension, anemia, impotence, reduced quality of life, cognitive dysfunction and psychiatric effects, reduced bone mineral density, and increased risk of cardiovascular diseases [4][5][6][7][8]. ...
Article
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Background: The aim of this study was to assess the association between androgen deprivation therapy (ADT) and the risk of inflammatory rheumatic diseases in men with prostate cancer. Methods: Patients with prostate cancer between 2012 and 2016 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database, on the basis of rheumatic diseases diagnoses and information on prescriptions for androgen deprivation therapy. Cox proportional hazard models were used to estimate hazard ratios (HR) to compare the risks of rheumatic diseases caused by androgen deprivation therapy exposure in groups of prostate cancer patients. Results: A total of 12,505 prostate cancer patients were included in this study, out of whom 3070 were ADT users and 9390 were ADT non-users. We observed a higher risk of rheumatic diseases in the cohort of prostate cancer patients treated with ADT compared with ADT non-users (HR 1.55, 95% confidence interval (CI) 1.01-2.28). Detailed risk by cumulative use of ADT was performed for rheumatoid arthritis, and a statistically significant higher risk was found in the group with longest cumulative ADT exposure (>105 weeks) (HR 3.18, 95% CI 1.39-7.29). Conclusions: Our study suggests that ADT usage could be associated with increased risk of rheumatoid arthritis, adding to the many known side effects of ADT.
... Moreover, these events have been associated with poorer prognostic outcomes in terms of both short-and long-term morbidity and mortality 39 . Thromboembolic event onset is believed to be caused as a result of a variety of factors, such as ongoing androgen deprivation therapy and co-existing co-morbidities such as dyslipidemia, diabetes, and increased fat mass quantity [41][42][43] . Consequently, anticoagulant and/or antiplatelet drugs are commonly used to manage this increased risk 44,45 . ...
Article
Objective: Robot-assisted prostatectomy is commonly performed for the management of prostate cancer. The literature has noted that prostate cancer patients are often prone to increased risk for thromboembolic complications. Normally, such situations call for long-term anticoagulant/antiplatelet therapy. However, the administration of these drugs is usually contraindicated prior to surgical intervention to limit intra- and post-operative hemorrhagic complications. Despite some recent evidence that continued administration of anticoagulant/antiplatelet drugs does not impact intra- and post-operative outcomes, no consensus in the literature exists concerning the influence of anticoagulant and antiplatelet drug administration on intra- and post-operative outcomes for robot-assisted prostatectomy. Our aim is to evaluate the influence of perioperative administration of anticoagulant and antiplatelet drugs in patients undergoing robot-assisted prostatectomy in terms of bleeding complication incidence, blood transfusion rate, blood loss, and hospital stay duration. Materials and methods: The academic literature was systematically searched according to the PRISMA guidelines across five databases (Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE). Through this, we conducted a random-effect meta-analysis to evaluate the influence of perioperative administration of anticoagulant and antiplatelet drugs in patients undergoing robot-assisted prostatectomy in terms of bleeding complication incidence, blood transfusion rate, blood loss, and hospital stay duration. Results: From 993 studies, eight eligible studies containing 2516 patients (mean age: 65.7± 3.6 years) were selected for inclusion. Meta-analysis revealed a higher bleeding complication prevalence for patients receiving anticoagulants (event rate: 10.6%) compared to those receiving antiplatelets (3.4%). We also noted longer hospital stay durations for anticoagulant group patients (Hedge's g: -0.30) compared to antiplatelet group counterparts (g: -0.01). Conclusions: The study provides preliminary evidence that anticoagulant drug administration results in higher bleeding complication incidence and longer hospital stay durations in patients undergoing robot-assisted prostatectomy relative to antiplatelet drug administration.
... Given the higher age of many men with PCa, associations between low muscle mass and poor survival have also been reported [5,6]. More commonly, PCa patients on ADT are at increased risk of sarcopenic obesity [7,8], diabetes and cardiovascular disease [9][10][11]. Consequently, this emphasizes the need for strategies to offset the detrimental effects of ADT, particularly on body composition. ...
Article
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Background: Loss of muscle mass and muscle function is a common side effect from androgen deprivation therapy (ADT) for prostate cancer (PCa). Here, we explored effects of heavy-load resistance training (RT) on lean body mass and muscle strength changes reported in randomized controlled trials (RCTs) among PCa patients on ADT and in healthy elderly men (HEM), by comparison of results in separate meta-analysis. Methods: RCTs were identified through databases and reference lists. Results: Seven RCTs in PCa patients (n = 449), and nine in HEM (n = 305) were included. The effects of RT in lean body mass change were similar among PCa patients (Standardized mean difference (SMD): 0.4, 95% CI: 0.2, 0.7) and HEM (SMD: 0.5, 95% CI: 0.2, 0.7). It is noteworthy that the within group changes showed different patterns in PCa patients (intervention: 0.2 kg; control: -0.6 kg) and HEM (intervention: 1.2 kg; control: 0.2 kg). The effects of RT on change in muscle strength (measured as 1 RM) were similar between PCa patients and HEM, both for lower body- (PCa: SMD: 1.9, 95% CI: 1.2, 2.5; HEM: SMD: 2.2, 95% CI: 1.0, 3.4), and for upper body exercises (PCa: SMD: 2.0, 95% CI: 1.3, 2.7; HEM: SMD: 1.9, 95% CI: 1.3, 2.6). Conclusions: The effects of RT on lean body mass and 1 RM were similar in PCa patients on ADT and HEM, but the mechanism for the intervention effect might differ between groups. It seems that RT counteracts loss of lean body mass during ADT in PCa patients, as opposed to increasing lean body mass in HEM.
... По този начин те могат да предизвикат инсулинова резистентност, което влошава гликемичния контрол. Лечението с тях е свързано с повишен риск от диабет (28%) и сърдечно-съдови заболявания (27). След 12-месечно лечение на рак на простатата се отчитат значимо повишаване нивата на кръвната захар, индекса на телесната маса, лептина и се наблюдава инсулинова резистентност (5). ...
Article
Introduction Androgen deprivation therapy (ADT) is the key of medical treatment for advanced prostate cancer (PCa), especially in elderly patients. However, the adherence of ADT prescription to current guidelines is not optimal and must be balanced against possible side effects. Aim of this study was to evaluate the prescriptive appropriateness of ADT and ADT-related adverse events in a referral center for PCa. Methods Five hundred fifty six patients who received an outpatient prescription for ADT from 2014 to 2018 were retrospectively identified from an administrative database. Only standard ADT was considered, including GnRH agonists, GnRH antagonists, and antiandrogens. Prescriptive appropriateness was defined according to the last European Association of Urology (EAU) guidelines. Our cohort was stratified according to age categories and patient follow-up was updated. Results Four hundred twenty five patients were available for analysis. Mean age was 80 years; 96.3% of our patients fell in the “elderly” category. There was a predominance of GnRH agonists over the antagonists (84.9% vs 13%). 15.5% of ADTs did not have an appropriate indication according to guidelines. Patient compliance to ADT was evaluated as good in 372 (87.5%) cases. ADT-related complications were detected in 166 (39%) patients: bone, cardiovascular, and other complications were reported in 7.3%, 8.9%, and 19% of patients. Progression of disease was noted in 165 (38.8%) cases during ADT. At last follow-up, 124 (30.1%) patients were deceased. Conclusions In a referral center, most ADT prescriptions followed EAU guidelines, but a non-negligible proportion still did not fall within these indications, exposing patients to unnecessary side effects. Compliance to ADT was generally good with a predominant use of GnRH agonists. Tolerance to ADT was fair, even if standardized reports were lacking.
Article
Background Evidence-practice gaps exist in urology. We previously surveyed European Association of Urology (EAU) guidelines for strong recommendations underpinned by high-certainty evidence that impact patient experience for which practice variations were suspected. The recommendation “Do not offer neoadjuvant androgen deprivation therapy (ADT) before surgery for patients with prostate cancer” was prioritised for further investigation. ADT before surgery is neither clinically effective nor cost effective and has serious side effects. The first step in improving implementation problems is to understand their extent. A clear picture of practice regarding ADT before surgery across Europe is not available. Objective To assess current ADT use before prostate cancer surgery in Europe. Design, setting, and participants This was an observational cross-sectional study. We retrospectively audited recent ADT practices in a multicentre international setting. We used nonprobability purposive sampling, aiming for breadth in terms of low- versus high-volume, academic, versus community and public versus private centres. Outcome measurements and statistical analysis Our primary outcome was adherence to the ADT recommendation. Descriptive statistics and a multilevel model were used to investigate differences between countries across different factors (volume, centre type, and funding type). Subgroup analyses were performed for patients with low, intermediate, and high risk, and for those with locally advanced prostate cancer. We also collected reasons for nonadherence. Results and limitations We included 6598 patients with prostate cancer from 187 hospitals in 31 countries from January 1, 2017 to May 1, 2020. Overall, nonadherence was 2%, (range 0–32%). Most of the variability was found in the high-risk subgroup, for which nonadherence was 4% (range 0–43%). Reasons for nonadherence included attempts to improve oncological outcomes or preoperative tumour parameters; attempts to control the cancer because of long waiting lists; and patient preference (changing one’s mind from radiotherapy to surgery after neoadjuvant ADT had commenced or feeling that the side effects were intolerable). Although we purposively sampled for variety within countries (public/private, academic/community, high/low-volume), a selection bias toward centres with awareness of guidelines is possible, so adherence rates may be overestimated. Conclusions EAU guidelines recommend against ADT use before prostate cancer surgery, yet some guideline-discordant ADT use remains at the cost of patient experience and an additional payer and provider burden. Strategies towards discontinuation of inappropriate preoperative ADT use should be pursued. Patient summary Androgen deprivation therapy (ADT) is sometimes used in men with prostate cancer who will not benefit from it. ADT causes side effects such as weight gain and emotional changes and increases the risk of cardiovascular disease, diabetes, and osteoporosis. Guidelines strongly recommend that men opting for surgery should not receive ADT, but it is unclear how well the guidance is followed. We asked urologists across Europe how patients in their institutions were treated over the past few years. Most do not use ADT before surgery, but this still happens in some places. More research is needed to help doctors to stop using ADT in patients who will not benefit from it.
Article
Background: Androgen deprivation therapy (ADT), a backbone treatment for advanced prostate cancer (PC), is known to have a variety of metabolic side effects. We conducted an updated meta-analysis to quantify the metabolic risks of ADT. Materials and methods: We searched PubMed, Web of Science, and Scopus in May of 2022 for studies investigating the risk of metabolic syndrome (MetS), diabetes, and hypertension from ADT in PC patients using keywords. Only full-length studies with a control group of PC patients not on ADT were included. All results compatible with each outcome domain in each included study were sought. For included studies, relative risk (RR) was pooled using a random effects model and a trim-fill approach was used to adjust for publication bias. Results: 1,846 records were screened, of which 19 were found suitable for data extraction. Five studies, including 891 patients, were evaluated for MetS as an outcome, with the random effects model showing a pooled RR of 1.60 ([95% Confidence Interval (CI), 1.06-2.42]; P=0.03) for patients on ADT while twelve studies, including 336,330 patients, examined diabetes as an outcome, and the random effects model showed a RR of 1.43 ([95% CI, 1.28-1.59]; P< 0.01). After adjustment for publication bias, ADT was associated with a 25% increased risk for diabetes but was not associated with MetS. 4 studies, including 7,051 patients, examined hypertension as an outcome, and the random effects model showed a RR of 1.30 ([95% CI, 1.08-1.55]; P=0.18) in ADT patients. Conclusion: In patients with PC, ADT was not associated with MetS and the association with diabetes was not as strong as previously reported. Our novel meta-analysis of hypertension showed that ADT increased the risk of hypertension by 30%. These results should be understood in the context of collaborating care between a patient's oncologist and primary care provider to optimize care.
Article
Background: Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC. Methods: In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan-Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks. Results: The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79-2.12) for CVD, 2.08 (95% CI: 1.70-2.53) for fracture, and 2.00 (95% CI: 1.31-3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84. Conclusions: In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls.
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The most at risk for occupational toxicity brought on by exposure to heavy metals and PAHs among various vocations are gas station attendants and auto workers. The gonadal and its regulating hormonal pattern were identified in the current investigation in gas station attendants and car employees. Objective: This study's goal is to ascertain the impact of various occupational toxicants on the ovarian health of gasoline station attendants (PPA) and car technicians (AMM). Gonadal steroids and the hormones that control them were examined for this reason and their relationship to gonadal function was established. Methods: For this, blood samples from 19 gas station attendants and 29 auto mechanics were obtained from various gas stations and car shops, respectively. The University of the Punjab in Lahore provided the blood samples for the 24 controls. Using commercially available ELISA kits, the levels of serum estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were examined. The significance of changes was evaluated using the one-way ANOVA test. Results: When compared to the control group, there was a little decrease in the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, and testosterone among fuel station attendants and car employees. Conclusions: Pertinently, reduced reproductive and their regulatory hormonal levels predispose future risk of manifesting reproductive health issues.
Chapter
Cancer of the prostate is the most commonly diagnosed nonskin neoplasm and the second leading cause of cancer‐related mortality in men in the United States. Considerable advances have been made in screening, diagnosis, and therapy options, particularly in advanced disease, but controversies about the diagnosis and management of prostate cancer, especially in the areas of screening and choice of therapy, continue to evolve. Research initiatives in advanced disease have shifted from prognostication to prediction, and current treatment considerations are focused on optimization of therapy sequence, development of rational combinations, biomarker‐driven patient selection, determining the role of local disease control in patients with metastases, and bone targeting therapies. Despite progress, prostate cancer survival has not improved at the same pace as other cancer subtypes. It is anticipated that addressing knowledge gaps will lead to the development of novel agents with unique mechanisms of action and optimization of integrated strategies (surgical, radiation, and medical) to improve overall survival. Prostate cancer awareness, clinical application of improved biopsy schemes, and advances in imaging combined with the widespread use of prostate‐specific antigen (PSA) have resulted in increased detection of early prostate cancer. The question of whether PSA screening would reduce mortality from prostate cancer has now been tested in the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial first published in 2009. Though many of the apparent discrepancies between these trials can be accounted for by trial design and patient cross‐contamination, they brought to the forefront the dilemma of overdiagnosis and overtreatment, as well as the heterogeneous nature of prostate cancer and the urgent need to improve the accuracy of identifying clinically significant early disease with lethal potential. It is hoped that enhancing the current morphologic and anatomic classification of prostate cancer with a better understanding of the molecular underpinnings of diverse disease states will lead to a more refined taxonomy of prostate cancer and ultimately improve outcomes while minimizing treatment‐related morbidity. Salient features that distinguish prostate cancer from other malignancies and frame the dilemmas surrounding it are its striking age‐dependent incidence, with progressively increasing frequency with increasing age, a strong familial and hereditary component, the variable lethality of morphologically identical cancers, the central role of androgen signaling, the preponderance of bone‐forming metastases, and metabolic derangements contributing to lethal progression. Important advances made in each of these areas will modify the approaches currently used to prevent, prognosticate, predict, and treat prostate cancer.
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Purpose: The main purpose of this study was to evaluate the risk of CVD mortality in the national cohort of patients diagnosed with prostate cancer and treated with ADT compared with the ADT non-users. Materials and methods: We performed a retrospective cohort study of patients aged 40–79 years and diagnosed with prostate cancer between 1 January 2012 and 31 December 2016 using the Lithuanian Cancer registry data. In total, 13 343 prostate cancer patients were included in the final study cohort who exclusively used gonadotropin-releasing hormone agonists. The primary outcomes that were registered during the follow-up of this study were overall CVD death. Results: There was a higher risk of CVD death in the cohort of patients treated with ADT than in ADT non-users (HR 2.14, 95% CI [1.86–2.45], p < 0.001). Moreover, there was an increased risk of death from ischemic heart disease and stroke (HR 1.42, 95% CI [1.16–1.73] and 1.70, 95% CI [1.18–2.45], respectively) among ADT users. Finally, the risk of CVD-related mortality was highest in the 70–79 age group of ADT users (HR 4.78, 95% CI [3.79–6.04]). Conclusions: This study shows that ADT usage is associated with increased CVD-related mortality risk for patients diagnosed with prostate cancer compared with ADT non-users. The highest mortality risk was found for ischemic heart disease and stroke. CVD-related mortality was increased in the elder group of patients also.
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There are nearly 17 million cancer survivors in the United States, including those who are currently receiving cancer therapy with curative intent and expected to be long-term survivors, as well as those with chronic cancers such as metastatic disease or chronic lymphocytic leukemia, who will receive cancer therapy for many years. Current clinical practice guidelines focus on lifestyle interventions, such as exercise and healthy eating habits, but generally do not address management strategies for clinicians or strategies to increase adherence to medications. We discuss 3 cardiometabolic comorbidities among cancer survivors and present the prevalence of comorbidities prior to a cancer diagnosis, treatment of comorbidities during cancer therapy, and management considerations of comorbidities in long-term cancer survivors or those on chronic cancer therapy. Approaches to support medication adherence and potential methods to enhance a team approach to optimize care of the individual with cancer across the continuum of disease are discussed.
Article
Introduction: Androgen-deprivation therapy (ADT), with or without palliative local treatments, is the standard of care for many patients with locally-advanced and/or metastatic prostate cancer. However, the possible cardiovascular (CV) risks associated with gonadotropin-releasing hormone (GnRH) antagonists and agonists continue to be the subject of concern, especially in a patient population that may already be at increased CV risk. Evidence acquisition: The present review provides a narrative summary of the evidence regarding the CV risks associated with GnRH antagonists and agonists from randomized clinical trials (RCTs), real-world evidence, and meta-analyses. Evidence synthesis: From RCTs, it appears clear that there is a direct class effect for CV risk in patients with prostate cancer being administered GnRH agonists and antagonists, with the latter being associated with reduced CV risk. Real-world data and the available meta-analyses largely indicate that CV risk is lower with GnRH antagonists than with GnRH agonists. Conclusions: A review of the pathophysiological mechanisms of gives further support to the possibility that GnRH antagonists are associated with lower CV risk than agonists. It can be highlighted that when treating patients with advanced or metastatic prostate cancer it is important to screen for underlying comorbidities prior to choosing the most appropriate therapy; moreover, patients should be closely monitored for factors associated with CV risk in order to optimize outcomes. Further studies are needed to define the most appropriate treatment according to the individual patient characteristics.
Article
Objectives: In the era of dose-escalated prostate radiation therapy (RT), the use of androgen deprivation therapy (ADT) is undefined for intermediate-risk (IR) prostate cancer. There is growing concern of the risk of ADT to be detrimental to quality of life. This single-institution retrospective analysis aimed to evaluate outcomes of IR patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with or without concurrent/adjuvant short-term ADT. Materials and methods: Data was collected from 260 consecutive patients treated with dose-escalated IMRT with daily image-guided RT for newly diagnosed IR prostate cancer. Biochemical recurrence-free survival (BCRFS), distant metastasis-free survival, prostate cancer-specific survival, and overall survival (OS) were calculated using Kaplan-Meier methodology. Results: Median follow-up was 93 months. A total of 181 patients had unfavorable IR disease, and 36.2% (N=94) received ADT, with median ADT duration of 6 months. Seven-year BCRFS was 94.1% vs. 86.2% (P=0.067), for ADT and no ADT, respectively, and no difference in distant metastasis-free survival or prostate cancer-specific survival was observed. ADT was associated with significantly worse 7-year OS (80.0% vs. 91.3%, P=0.010). Analysis of the unfavorable IR cohort alone, showed similar results; 7-year BCRFS and 7-year OS in patients who received ADT versus no ADT were 93.7% vs. 85.9% (P=0.093), and 79.0% vs. 90.6% (P=0.019), respectively. Conclusions: In our 15-year experience treating IR prostate cancer with dose-escalated IMRT with daily image-guided RT, short-term concurrent ADT was associated with a statistically significant worse OS. Additional studies are needed to determine if ADT is beneficial or detrimental for patients with IR prostate cancer treated with dose-escalated radiation.
Article
Background: Cancer survivors face an increased risk of non-cancer-related deaths, particularly associated with metabolic syndrome. With increased cancer survivors having metabolic syndrome, health-related quality of life beyond cancer diagnosis and treatment has assumed greater importance. Objective: This study evaluated the prevalence rate of metabolic syndrome in cancer survivors. It examined the correlation between health-related quality of life and influencing factors according to the prevalence of metabolic syndrome. Methods: This is a cross-sectional national study using secondary data from the 2010-2018 Korean National Health and Nutrition Examination Survey by the Korea Disease Control and Prevention Agency. We analyzed a final sample of 1293 cancer survivors using multiple regression. Results: The prevalence rate of metabolic syndrome in cancer survivors was measured at 32.1%. Cancer survivors with metabolic syndrome had a lower health-related quality of life than those without it. The difference was statistically significant. Compared with cancer survivors without metabolic syndrome, those with it experienced substantial negative effects from stress, reducing health-related quality of life. Walking and muscle-building workouts had a positive effect on stress and improved quality of life. Conclusions: Cancer survivors' metabolic syndrome should be monitored closely. Development of a customized intervention program including stress management and physical activities improves their health-related quality of life. Implications for practice: Stress management and physical activities increase health-related quality of life among cancer survivors with metabolic syndrome; thus, healthcare providers should implement intervention programs that promote exercise engagement and stress management for this population.
Article
Aims Female sex has been proposed to be cardioprotective per se. Studies with myocardial ischaemia/reperfusion and infarct size as endpoint have demonstrated cardioprotection in female, castrated male and male pigs. These studies are difficult to compare, given the different pig strains, models, durations of ischaemia and methods of infarct size quantification. The few studies using both female and male pigs reported no differences in infarct size and cardioprotection. We therefore prospectively compared infarct size in Göttingen minipigs undergoing ischaemia/reperfusion (I/R) without and with ischaemic preconditioning (IPC) between female, castrated male and male pigs. Methods and Results In a prospective, randomised approach, 28 Göttingen open-chest, anaesthetised minipigs underwent 60 min ischaemia by distal left anterior descending artery (LAD) occlusion and 180 min reperfusion without and with IPC by 3 cycles of 5 min LAD occlusion/10 min reperfusion. Infarct size with I/R was not different between female, castrated male and male pigs (45±8 vs. 45±13 vs. 41±9% area at risk), as was the reduction in infarct size with IPC (25±11 vs. 30±8 vs. 19±10% area at risk). Also, the area of no-reflow was not different between female, castrated male and male pigs with I/R (57±13 vs. 35±7 vs. 47±26% infarct size) or IPC (4±10 vs.12±20 vs. 0±0% infarct size). Phosphorylation of signal transducer and activator of transcription 3 was increased at 10 min reperfusion by IPC but not by I/R to the same extent in female, castrated male and male pigs (198±30 vs. 230±165 vs. 179±107% of baseline). Conclusion Our data do not support the notion of sex- or castration-related differences in infarct size, coronary microvascular injury and cardioprotection by ischaemic preconditioning. Translational perspective The translation of successful preclinical studies on cardioprotection to the benefit of patients with reperfused myocardial infarction has been difficult. The difficulties have been attributed to confounders such as co-morbidities and co-medications which patients typically have but animals don´t, but also to age and sex. Notably, female sex has been considered as protective per se. We have now, using our established and clinically relevant pig model of reperfused acute myocardial infarction and ischaemic preconditioning as the most robust cardioprotective intervention looked for sex-related differences of infarct size, no-reflow and cardioprotection by ischaemic preconditioning in a prospectively powered approach but found none such difference.
Article
The purpose of this study is to provide certain data on clinical outcome of primary androgen deprivation therapy in men over 80 years of age with localized high-risk prostate cancer. This study included 54 Japanese super-elderly men with high-risk prostate cancer treated with primary androgen deprivation therapy between 2005 and 2015. The median overall survival was 9.1 years (95% confidence interval, 8.1-10.1) and no patient died from prostate cancer. Overall, 51.9% of patients experienced any grade of adverse events following androgen deprivation therapy. Associations between clinicopathological factors including comorbidity count at initial diagnosis and overall survival were investigated. On multivariate analysis, only comorbidity count at initial diagnosis [≥2 vs. ≤1; hazard ratio, 5.34 (95% confidence interval, 1.55-18.49); P = 0.003] was an independent risk factor for overall survival. Our findings suggest that comorbidity count at initial diagnosis is robustly prognostic for overall survival. For super-elderly men with localized high-risk prostate cancer, comorbidity count at initial diagnosis should be emphasized when deciding whether primary androgen deprivation therapy is necessary or not.
Article
Background: Androgen deprivation therapy (ADT) is the major treatment for metastatic prostate cancer (PCa), but few studies have investigated the effects of ADT on thyroid diseases. Methods: This population-based, nationwide cohort study utilized the Taiwan National Health Insurance Research Database (NHIRD) with 17,192 PCa patients between 1997 and 2013. We used the Cox proportional hazards models and propensity score-matched analysis to analyze the association between ADT and the development of thyroid diseases. Results: A total of 17,192 newly diagnosed men with PCa were selected from the NHIRD. There were 6200 ADT users and 6200 non-ADT users after 1:1 propensity score matching. There was a significantly decreased risk of thyroid diseases among ADT users compared with non-ADT users (adjusted hazard ratio (aHR): 0.79, 95% confidence interval (CI): 0.65-0.95, p < 0.001). Further analysis showed a significantly decreased risk of thyroid diseases with increasing ADT duration (p < 0.001). Conclusions: The result showed that ADT use in men with PCa was associated with a decreased risk of thyroid disease development.
Article
In parallel with increased survival rates, quality of life (QoL) has become of growing importance in the management of young cancer survivors. Several surveys have indicated that in those subjects, the issue of reproductive function is considered as one of the main QoL aspects. In this article, we summarize the current evidence, as well as gaps of knowledge and research needs, regarding the impact of cancer and cancer treatment on testicular function-including fertility and androgen production. Also, pre and posttherapy clinical management of reproductive issues in male cancer survivors, are given.
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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.)
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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...
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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.
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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.
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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.
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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.
Article
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.
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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.
Article
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.
Article
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.
Article
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.
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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.
Article
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.