With ADT in PC, Managing Side Effects 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 in collaboration with oncologists and 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 non-metastatic 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, luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, antiandrogens, newer agents such as abiraterone, or the secondary administration of ketoconazole, said Gomella, who addressed the topic during the 7th Annual Interdisciplinary Prostate Cancer Congress, held March 15 in New York City. 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, which comprises obesity/sarcopenia, diabetes, and cardiovascular disease. 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

He suggested that urologists enlist the help of primary-care physicians in monitoring the possible development of ADT side effects by referring patients to be followed with screenings.Gomella explained that gonadotropin-releasing hormone (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, urologists or primary-care physicians should conduct blood screens for glycated hemoglobin, diabetes, and pre-diabetes on 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, he said, 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 said.

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 as compared to 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, the doctor said, 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 physicians might find helpful.

In general, he said, osteoporosis prevention should start with “the easy stuff” before more complicated interventions are used.

Preventing/Treating Osteoporosis

Vitamin D

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 600 mg daily.

Bisphosphonates

By inhibiting osteoclast activity, bisphosphonates such as zoledronic acid, pamidronate, alendronate, and risedronate can reduce bone resorption and turnover, slightly increasing BMD in the hips and spine and reducing the incidence of vertebral fractures by 40-70%, Gomella said. However, these drugs should not be given if a patient’s glomerular filtration rate is <30, 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, Gomella said.

Some bisphosphonates are approved only for women, he cautioned, 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.

Monoclonal antibody

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 Drugs 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.

Recommendations

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 age ≥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

Gomella concluded his talk with a discussion of hot flashes, which 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 FDA-approved 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.

References

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