Adverse Effects of Androgen Deprivation Therapy in Men with Prostate Cancer

Submitted by Frances Cusano April 15, 2009:

(Review of “Adverse Effects of Androgen Deprivation Therapy: Defining the Problem and Promoting Health Among Men with Prostate Cancer. Saylor PJ and Smith MR. JNCCN 2010;8)




Androgen deprivation therapy (ADT), which includes bilateral orchiectomies or treatment with a gonadotropin releasing hormone (GnRH agonist), improves overall survival when combined with external beam radiation in patients with locally advanced or high-risk non-metastatic prostate cancer. ADT also improves survival in men with nodal metastases after prostatectomy and pelvic lymphadenectomy. In men with metastatic prostate cancer, ADT decreases pain and modestly improves overall survival.



Because men often live for years with prostate cancer, treatment-related morbidity needs to be monitored. GnRH agonists have been shown to produce detrimental changes in body composition, lipid profile, insulin sensitivity and bone mineral density. As evidence based guidelines for the management of ADT adverse effects do not yet exist, the authors proposed practical management recommendations adopted from available guidelines by the National Osteoporosis Foundation, the American Diabetes Association, the National Cholesterol Education Program Adult Treatment Panel III and the American Heart Association.



Obesity

The first year of ADT causes lean body mass to decrease by about 3%, fat mass to increase by 10% and weight to increase by 2%. ADT-associated redistribution of weight has been shown to favour the accumulation of subcutaneous abdominal fat. Abdominal circumference has been associated with mortality in a large prospective cohort study. There are no evidence based prevention or treatment strategies at this time for ADT-associated changes in body composition. A study that randomized 155 men receiving ADT to a control group or a treatment arm that performed resistance exercise 3 times a week failed to demonstrate a difference in body composition between the two groups.



Lipid Alteration

GnRH agonists cause triglycerides to increase by approximately 26% and total cholesterol to rise by approximately 10%. High density lipoprotein (HDL) increases by about 8 to 11%. For prostate cancer patients who have received ADT, the authors recommend measuring fasting lipoproteins at baseline, within 1 year of ADT initiation, and as clinically indicated after that. Primary prevention guidelines include tobacco cessation and lifestyle changes (reducing dietary saturated fat and cholesterol, increasing physical activity and controlling weight). Statins are recommended as first-line treatment if lifestyle changes do not achieve target low density lipoprotein (LDL).



Insulin Resistance and Diabetes

GnRH agonists have been shown to decrease insulin sensitivity within 12 weeks after ADT initiation in non-diabetic men. Two large database analyses have demonstrated that GnRH agonist treatment is associated with an increased incidence of diabetes. The authors recommend screening with hemoglobin A1c or fasting plasma glucose at baseline and again within 1 year for patients treated with long-term ADT. Diabetes is considered when the hemoglobin A1c is greater than 6.5 % or the fasting plasma glucose is greater than 6.9 mmol/L. Patients with hemoglobin A1c between 6.0 % and 6.5 % or impaired fasting glucose (5.6 – 6.9 mmol/L) are at high risk of developing diabetes and should be counseled to pursue 5 to 10 % weight loss and 150 minutes or more per week of moderate physical activitiy.



Coronary Heart Disease

Data on the increase in risk for cardiovascular events due to ADT therapy is conflicting. Because studies in the general population have shown that patients with fewer known risk factors for cardiovascular disease have a lower incidence of heart disease and stroke, the authors recommend primary prevention. Recommendations include tobacco cessation, treatment of hypertension as per accepted guidelines, lifestyle interventions (reduced intake of saturated fat and cholesterol, increased physical activity and weight control), and low dose aspirin in men with 10-year coronary heart disease risk > 10%.



Osteoporosis and Fracture Risk

ADT has been associated with decreased bone mineral density (BMD) and elevated fracture risk. The authors recommend BMD testing at baseline, after 1 year of ADT, then every 2 years as clinically indicated. The online Fracture Risk Assessment Tool (FRAX) (http://www.shef.ac.uk/FRAX) uses patient factors such as age and use of tobacco and medication to assess the risk of fracture. Guidelines include supplemental calcium and vitamin D for all patients. Drug therapy is recommended for men who have a low T-score (-1.0 to -2.5) and a 10-year risk for hip fracture of at least 3%, or at least 20% for any osteoporosis-related fracture. Bisphosphonates increase BMD, but their impact on preventing treatment-related fractures has not been properly evaluated. Two recent phase III trials have shown that denosumab and toremifene are each effective in fracture prevention in men receiving ADT.



Development of guidelines for the management of adverse effects from ADT therapy give the clinical pharmacist a useful reference in managing prostate cancer patients receiving ADT.