Managing Side Effects of Androgen-Deprivation Therapy Increasingly Important

Leonard G. Gomella, MD

Androgen-deprivation therapy (ADT) is a mainstay of treatment for prostate cancer in a number of settings, so managing its side effects is becoming increasingly important for urologists and oncology practitioners in collaboration with primary care physicians.

The issue is of particular concern due to the availability of newer agents that decrease testosterone levels for longer periods of time, and also with the use of ADT in nonmetastatic prostate cancers, which ultimately lengthens the time men spend on antiandrogen drugs, according to Leonard G. Gomella, MD, chairman of the Department of Urology at Thomas Jefferson University Hospital in Philadelphia.

ADT can involve bilateral orchiectomy or the use of estrogens, LHRH agonists or antagonists, antiandrogens, newer agents such as abiraterone, or the secondary administration of ketoconazole, Gomella pointed out.

The strategy, he said, is most appropriately used upon diagnosis of metastatic prostate cancer; with radiation in intermediate- to high-risk prostate cancer; to stimulate volume reduction before brachytherapy; and after treatment failure in localized disease, although the timing in that setting is controversial.

With increased use of the strategy have come growing concerns over side effects, including hot flashes, loss of libido, fatigue, anemia, muscle loss, osteoporosis, and bone fracture. Adverse events can also include depression, memory difficulties, and emotionality, as well as metabolic syndrome.

While giving ADT on an intermittent schedule can help ease these side effects, the jury is still out on whether that method is as effective in treating prostate cancer as continuous therapy, Gomella said.

Metabolic Syndrome

Gomella explained that GnRH agonists increase cholesterol and triglycerides,¹ boost obesity, and heighten insulin resistance² in men with prostate cancer, potentially leading to diabetes mellitus, coronary heart disease, and myocardial infarction.³

To monitor for signs of diabetes, clinicians should conduct blood screens for glycated hemoglobin levels and markers of diabetes and prediabetes in these patients at baseline and then yearly, and should promote weight loss and physical activity,⁴ Gomella suggested.

Tracking potential cardiovascular complications should involve screening for fasting lipoproteins at baseline, 1 year, and then every 5 years, and assigning a target LDL cholesterol level based on major risk factors for coronary heart disease, Gomella said. Prevention in this setting, should focus on the treatment of hypertension, tobacco cessation efforts, the promotion of healthy lifestyle choices, and the use of first-line statins for hyperlipidemia when needed.⁴

Bone Mineral Density

While a normal man loses 0.5% of his bone density in a year,⁵ men on ADT lose 4.6% of their bone density in that period,⁶ a trend that “adds up over the long term and has the potential to cause great morbidity and, in fact, mortality,” Gomella said. After being on these medications for 10 years, 80% of men have osteoporosis,⁷ he added.

One study found that the likelihood of experiencing a bone fracture between 1 and 5 years after treatment with a GnRH agonist increased 6.8%, to a frequency of 19.4%, in patients with prostate cancer who received ADT compared with patients with the disease who were not treated with ADT; in the ADT group versus the non-ADT group, 5.2% versus 2.4% of patients experienced fractures that required hospitalization.⁸ Fractures in areas such as the hip can significantly decrease a patient’s longevity, and men fare much worse in that situation than women do, Gomella noted.⁹

Monitoring bone mineral density (BMD) remains the gold standard for diagnosing osteoporosis in clinical practice, as it is one of the best ways of determining bone strength and predicts fracture as reliably as blood pressure predicts stroke. A DEXA bone scan T-score of <-2.5 indicates osteoporosis, he said. He added that the World Health Organization has a fracture risk assessment questionnaire that practitioners may find helpful.

Preventing/Treating Osteoporosis

One simple tactic for prevention is the administration of vitamin D, which at 700 to 800 IU per day can lower the risk of bone fracture by 26%, Gomella said.¹⁰

Along with that, calcium can help, but in doses above 1000 IU it comes with a side effect of its own—a 20% increased risk of cardiovascular disease mortality in men, Gomella said.¹¹ As a result, he said, it is now considered best for patients to get about 400 mg of calcium from their diets, with supplementation at a dosage of 600 mg daily.

By inhibiting osteoclast activity, bisphosphonates such as zoledronic acid, pamidronate, alendronate, and risedronate, can reduce bone resorption and turnover, slightly increasing bone mineral density (BMD) in the hips and spine and reducing the incidence of vertebral fractures by 40% to 70%, Gomella said. However, these drugs should not be given if a patient’s glomerular filtration rate is <30 mL/min, and a dental exam should be given before starting, and again every 6 months, to limit the risk of osteonecrosis of the jaw, a potential side effect with this drug class. Other side effects can include dysphagia, nausea, uveitis, hypocalcemia, renal impairment, and musculoskeletal pain.

Some bisphosphonates are approved only for women, he added, and drugs in this class that are approved for men tend to be applicable in very specific settings, such as osteoporosis but no metastases, or vice versa.

Also potentially useful in this population is the monoclonal antibody denosumab (Prolia, Xgeva), which can increase bone density at the spine by 6.7% after 2 years and decrease the incidence of vertebral fractures by 68% and hip fractures by 40%, Gomella said.^12,13

Potential side effects include osteonecrosis of the jaw, hypocalcemia, and new primary malignancy, Gomella pointed out.

Other potential treatments for bone metastases and/or osteoporosis include the parathyroid hormone teriparatide, although it is not appropriate for men who have undergone radiation and is typically not used in urology; estrogen or testosterone, which are not FDA-approved in these settings and are controversial; and the nonsteroidal antiestrogen toremifene, which is not FDA-approved for use in men, Gomella said.

To best prevent and track osteoporosis in men taking ADT, doctors should conduct BMD testing on all such patients at baseline, after 1 year of treatment, and then every 2 years, Gomella recommended.

He said that prevention and early treatment should include exercise, prevention of falls, smoking cessation, decreased alcohol intake, 1000 mg a day of calcium, and 1000 IU a day of vitamin D3. Drug therapy should be considered in patients who are aged ≥50 years and fit at least one of the following categories: history of hip or vertebral fracture; T-score of ≤-2.5 at the femoral neck or spine; a 10-year ≥3% probability of hip fracture according to the World Health Organization’s questionnaire; or a 10-year ≥20% probability of a major osteoporosis fracture according to that scale.⁴

Hot Flashes

Hot flashes affect 50% to 80% of men taking ADT. Palliative measures should include suggesting that men identify and avoid their hot-flash triggers and keep their environment cool, Gomella said. He added that reassuring patients that hot flashes may subside over time “usually does a lot of good.” While hot flashes can interfere with a patient’s daily activities, Gomella continued, they are difficult to treat because there are no FDAapproved medications for this condition in men, and many of the therapies that are available can result in side effects.

Megestrol acetate at 20 mg/d¹⁴ and medroxyprogesterone acetate at 400 mg/d¹⁵ have been fairly effective, but cause weight gain, Gomella said. Other treatments being tested or used in this setting include estrogens, antidepressants, neuromodulators, and acupuncture, which so far seems promising for its efficacy and lack of side effects, Gomella said. He added that soy products contain phytoestrogens that might decrease hot flashes and improve cardiac and bone health.

Reference

• Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603.
• Smith MR, Lee H, Nathan DM, et al. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308.
• Keating NL, O’Malley AJ, Smith MR, et al. Diabetes and cardiovascular disease during androgen deprivation for prostate cancer. J Clin Oncol. 2006;24:4448-4456.
• Saylor PJ, Keating NL, Smith MR, et al. Metabolic complications of androgen deprivation therapy for prostate cancer. J Gen Intern Med. 2009;24(Suppl 2):S389-S394.
• Kanis JA. Osteoporosis. Blackwell Healthcare Communications Ltd; 1997:22-55.
• Maillefert JF, Sibilia J, Michel F, et al. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol. 1999;161:1219-1222.
• Morote J, Morin JP, Orsola A, et al. Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology. 2007;69:500-504.
• Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154- 164.
• Trombetti A, Herrmann F, Hoffmeyer P, et al. Survival and potential years of life lost after hip fracture in men and age-matched women. Osteoporos Int. 2002;13:731-737.
• Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B, et al. JAMA. 2005;293(18):2257-2264.
• Larsson, SC. Are calcium supplements harmful to cardiovascular disease? Comment on “Dietary and supplemental calcium intake and cardiovascular diseases mortality: the National Institutes of Health- AARP diet and health study.” JAMA Intern Med. 2013;173(8):647-648.
• Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Eng J Med. 2009;361(8):756-765.
• Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Eng J Med. 2009;361(8):745-755.
• Irani J, Salomon L, Oba R, Bouchard P, Mottet N, et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropinreleasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol. 2010;11(2):147-154.
• Jones JM, Kohli M, Loprinzi CL, et al. Androgen deprivation therapyassociated vasomotor symptoms. Asian J Androl. 2012;14(2):193-197

Nurse Perspective

Frank delaRama, RN, MSN, AOCNS

Clinical Nurse Specialist Oncology Genomics

Prostate Cancer Nurse Navigator

Palo Alto Medical FoundationPalo Alto, CA

Prostate cancer treatment can last years to even decades. The best case scenario is when curative treatment with surgery or radiation is successful, never needing anything more than just yearly PSA checks. On the other hand, prostate cancer that is aggressive or recurrent may need ongoing treatment to keep it under control, similar to managing a chronic disease like diabetes. Thankfully, the current state of prostate cancer treatment is often so successful with respect to overall survival, allowing us to turn our attention to maximizing opportunities to improve quality of life.

Androgen-deprivation therapy (ADT) is a common tool used in the prostate cancer care continuum, with disease ranging from localized, intermediate-risk to recurrent or metastatic. The article here provides the oncology nurse some key points on which to focus our ongoing assessment and care for patients on ADT. With metabolic syndrome, bone health, and hot flashes, there are many nursing and medical interventions that are relatively simple, yet with great impact on quality of life.

Basic nursing assessments usually include reviewing lab values, as well as trends in weight and blood pressure. Also integral to nursing intervention are tasks such as educating our patients on healthy diet and lifestyle, encouraging smoking cessation, and management of treatment side effects. Given the findings outlined in this review, there are modifiable risk factors where oncology nurses can have a great impact on patient’s overall health and quality of life, as opposed to medication side effect management alone.

In much of cancer treatment and follow-up care, patients have a relatively passive role, completing imaging and blood tests, or receiving injections and infusions. With teaching points on diet, exercise, and nonpharmacologic side effect self-management, our patients with prostate cancer on ADT can feel more in control—taking an active role within their treatment plan&mdash;thanks in part to the nurse.