Management of complications of androgen deprivation therapy in the older man

Prostate cancer is the most common malignancy in older men. With the aging of the population, the number of older men with prostate cancer will grow rapidly. Androgen deprivation therapy (ADT) is the mainstay of treatment for men with systemic disease and is increasingly utilized as primary therapy or in combination with other therapies for localized disease. Side effects of therapy are multifold and include hot flashes, osteoporosis, and adverse psychological and metabolic effects. Recent research has illustrated that ADT can negatively impact the functional, cognitive, and physical performance of older men. Patients with prostate cancer, despite recurrence of the disease, have a long life expectancy and may be subjected to the side effects of ADT for many years. This review highlights the complications of ADT and approaches to management. We also provide recommendations for assessment and management of ADT complications among the most vulnerable and frail older male patients.     

Quality of life in prostate cancer patients taking androgen deprivation therapy

OBJECTIVES: To examine the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL), self-reported HRQOL was compared in prostate cancer patients receiving short- (< 6 months) or long-term (> or = 6 months) ADT and healthy controls. DESIGN: Cross-sectional study. SETTING: Academic medical center in Pittsburgh, Pennsylvania. PARTICIPANTS: Ninety-six men, including those with prostate cancer receiving short-term, long-term, and no ADT and healthy controls. Men taking medications or having diseases known to affect bone mineral metabolism were excluded. MEASUREMENTS: The 36-item Short Form Medical Outcomes Study Health Survey (an HRQOL assessment) and a comorbidity index were administered to each participant. Characteristics, including body composition (assessed using dual-energy x-ray absorptiometry) and gonadal status (serum total and free testosterone) were measured approximately 3 months or less before the HRQOL assessment. RESULTS: As expected, men receiving ADT had significantly lower levels of testosterone, free testosterone, and lean body mass, as well as greater body fat and comorbidity index (all P<.01) than men not receiving ADT (i.e., men with prostate cancer and healthy controls). Participants receiving ADT reported significantly poorer QOL in the areas of physical function (P<.001), general health (P<.001), and physical health component summary (P<.001) than men not receiving ADT. There were no significant differences in HRQOL outcomes between participants receiving short- or long-term ADT. Comorbidity and testosterone levels were associated with several QOL scales. After controlling for the significant joint predictors of comorbidity and total testosterone using hierarchical regression analysis, ADT was no longer a significant predictor, and only comorbidity and total testosterone contributed to the explanation of the variance of the physical health component summary. Comorbidity alone contributed to the explanation of the variance in physical function, bodily pain, general health, and vitality. CONCLUSION: Patients with prostate cancer who were receiving ADT experience worse HRQOL than those not receiving ADT, but duration of ADT was not a contributing factor. After controlling for comorbidity, total testosterone level rather than ADT accounted for a small yet statistically significant percentage of the total variance of the physical health component summary. These findings have important clinical implications regarding the decision to treat prostate cancer patients with ADT.     

Changes in body composition during androgen deprivation therapy for prostate cancer

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.     

The influence of androgen deprivation therapy on metabolism in patients with prostate cancer

The effects of androgen deprivation therapy (ADT) include not only suppression of tumor growth, but also adverse effects on various bodily functions. The aim of this study was to determine the metabolic effects of ADT in patients with nonmetastatic prostate cancer. Forty-nine men with prostate cancer were treated with ADT before beginning radical therapy for 6 months. Body weight, peripheral red blood cell counts, hemoglobin, hematocrit, fasting blood sugar, serum total cholesterol, blood urea nitrogen, uric acid, compensated calcium, inorganic phosphorus, bone-specific alkaline phosphatase, urinary deoxypyridinoline, and radial bone density determined using dual energy x-ray absorptiometry were examined before and 6 months after ADT treatment. Body weight (P = 0.037) and the levels of fasting blood sugar (P = 0.014), serum total cholesterol (P = 0.017), blood urea nitrogen (P = 0.030), compensated calcium (P < 0.001), inorganic phosphorus (P < 0.001), bone-specific alkaline phosphatase (P < 0.001), and compensated urinary deoxypyridinoline (P < 0.001) increased significantly. Peripheral red blood cell counts (P < 0.001), hemoglobin level (P < 0.001), hematocrit (P < 0.001), uric acid (P < 0.001), and radial bone density (P = 0.023) decreased significantly. These effects of ADT on various bodily functions warrant systematic study in clinical trials. We should be aware of the far-reaching consequences of ADT and incorporate strategies for preventing and managing adverse effects into routine practice.     

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.     

Risk of the "androgen deprivation syndrome" in men receiving androgen deprivation for prostate cancer

BACKGROUND: Androgen deprivation therapy for prostate cancer has been associated with a spectrum of adverse effects, such as depression, memory difficulties, and fatigue, termed the androgen deprivation syndrome. Primary care physicians providing follow-up care for men with prostate cancer will be faced with managing these effects. We therefore sought to estimate the incidence of these effects and, by using a control group, ascertain whether these effects were related to androgen deprivation itself. METHODS: We assessed the risk of physician diagnoses of depression, cognitive impairment, or constitutional symptoms in Medicare data following androgen deprivation using a sample of 50 613 men with incident prostate cancer and 50 476 men without cancer, from 1992 through 1997, in the linked Surveillance, Epidemiology, and End Results-Medicare database. Cox proportional hazards regression was used to adjust for confounding variables. RESULTS: Of men surviving at least 5 years after diagnosis, 31.3% of those receiving androgen deprivation developed at least 1 depressive, cognitive, or constitutional diagnosis compared with 23.7% in those who did not (P<.001). After adjustment for variables such as comorbidity, tumor characteristics, and age, the risks associated with androgen deprivation were substantially reduced or abolished: relative risk (RR) for depression diagnosis, 1.08 (95% confidence interval [CI], 1.02-1.15); RR for cognitive impairment, 0.99 (95% CI, 0.94-1.04); and RR for constitutional symptoms, 1.17 (95% CI, 1.13-1.22). CONCLUSION: Depressive, cognitive, and constitutional disorders occur more commonly in patients receiving androgen deprivation, but this appears to be primarily because patients receiving androgen deprivation are older and have more comorbid conditions and more advanced cancers.     

Cardiovascular risks in spondyloarthritides

PURPOSE OF REVIEW: Spondyloarthritides are associated with increased cardiovascular risks, which can only partly be explained by traditional risk factors. It is likely that the chronic inflammatory state is involved. In this review, novel findings regarding cardiac and vascular pathologies and potential overlapping mechanisms will be discussed. RECENT FINDINGS: Cardiac pathologies in spondyloarthritides are conduction disturbances and valvular heart diseases. Recent studies have also focused on vascular pathologies and showed impaired endothelial function, suggesting that atherosclerotic alterations could also be involved in increased cardiovascular mortality. Novel findings suggest that chronic systemic inflammation is involved in these cardiac and vascular pathologies. Thus, spondyloarthritides and ankylosing spondylitis are associated with increased levels of circulating inflammatory mediators such as C-reactive protein. Interestingly, ankylosing spondylitis patients may also have an atherogenic lipid profile and disturbances in their T-helper lymphocyte subsets, which may be involved in cardiovascular disease development. The beneficial effects of statin treatment on circulating inflammatory mediators and atherogenic lipid profiles may reveal new therapeutic options for patients with spondyloarthritides. SUMMARY: Recent studies have highlighted that the chronic, systemic inflammatory condition of patients with spondyloarthritides may be involved in the development of cardiac and vascular pathologies.     

The case for dose escalation versus adjuvant androgen deprivation therapy for intermediate risk prostate cancer

Patients with intermediate-risk prostate cancer have a significant risk of biochemical failure after treatment with external beam radiation therapy. Two strategies to improve outcomes are radiation dose escalation and androgen deprivation therapy (ADT). This article discusses the evidence in favor of dose escalation. The case for radiation dose escalation has been established by several randomized studies, which show improved biochemical control (bNED) rates. Although late toxicity was also increased, it remains at clinically acceptable levels. The use of more focal methods of radiation, such as proton therapy and intensity modulated radiation therapy (IMRT), allows safe dose escalation to 80 Gy. The role of adjuvant ADT is most clearly established in high-risk disease. Advantages in the intermediate-risk group are less pronounced. It is probable that therapeutic gain seen from dose escalation in intermediate-risk patients might allow them to be spared the toxicity of ADT and yet achieve good PSA and clinical control rates. Further randomized trials comparing and or combining the two treatment strategies are required.     

Cardiovascular symptoms and risks of subclinical dysthyroidism

PURPOSE: To clarify the importance of cardiovascular symptoms and risks in subclinical dysthyroidism in order to define the best way of treatment and follow-up. CURRENT KNOWLEDGE AND KEY POINTS: Subclinical dysthyroidism is defined by abnormal circulating TSH values in face and normal free thyroid hormones levels, in asymptomatic individuals. If the cardiovascular effects of overt hyperthyroidism are well documented, the relation between subclinical dysthyroidism and the heart is not well established. Subclinical hyperthyroidism may be caused by the same thyroid disorders that results in overt hyperthyroidism, but the most common cause is excessive dosage in levothyroxine. The most frequent cardias complication of subclinical hyperthyroidism is atrial fibrillation. Recently minimal alterations of myocardial function have also been described. In most patients, one tries to return to euthyroidism in order to prevent cardiovascular complications. Subclinical hypothyroidism is 3 to 10 times more frequent, especially in women after 60 years. Subtle modifications of cardiac function and lipid metabolism and an increased risk of atherosclerosis have been described in this condition. There is still debate about the decision to treat or not to treat these patients. FUTURE PROSPECTS AND PROJECTS: Until now, treatment of subclinical dysthyroidism is mainly based upon experiences and convictions to physicians. Prospective studies are necessary to assess the true benefits and risks of either early treatment or therapeutic abstention with regular clinical and biological follow up. In such studies, patients should be separated according to age and the nature (endogenous or exogenous) of dysthyroidism.