CUA: Androgen Deprivation Therapy: Adverse Events & Management (2021)

See Original Guidelines

*****All of the content below is included in the more comprehensive Hormonal Therapy Chapter Notes*****

• Guidelines are relevant with literature up to December 2020

Complications of Androgen Deprivation Therapy (ADT)

• See Complications of Androgen Ablation section in Hormonal Therapy Chapter Notes
• COACH Wants BDSM From Montreal (9)
  1. Cardiovascular disease
  2. Osteoporosis
  3. Anemia
  4. Cognitive dysfunction
  5. Hot Flashes
  6. Weight gain and fat % mass increase
  7. Breast events
  8. Diabetes
  9. Sexual dysfunction
  10. Muscle % body mass decrease
  11. Fatigue
  12. Metabolic (5):
      1. Insulin resistance
      2. Glucose intolerance
      3. Worsened glycemic control in men with a pre-existing diabetes
      4. Increased triglycerides, low-density lipoprotein (LDL), and total cholesterol levels
      5. Increased risk of metabolic syndrome

Recommended Investigations Prior to ADT initiation

• History and Physical exam (4)
  • 1. History (4)
       1. Cardiometabolic
          1. History of major adverse cardiac events (MACE)
             • MACE is defined as MI, coronary revascularization, stroke, and hospitalization because of heart failure.
          2. Risk factors for cardiac disease
             • Pre-existing heart disease appears to be a major risk factor for development of major adverse cardiac events (MACE) in men receiving ADT.
          3. Previous VTE or stroke
       2. Bone
          1. Falls risk
    2. Physical exam (5)
       1. Cardiometabolic
          1. Blood pressure
          2. Weight
          3. Waist circumference
          4. Calculation of body mass index (BMI)
       2. Bone
          1. Height
• Labs (7)
  1. Cardiometabolic
     1. Diabetes screening (fasting plasma glucose, oral glucose tolerance test, or Hgb A1c level)
     2. Lipid profile:
        1. Triglycerides
        2. Low-density lipoprotein [LDL] cholesterol
        3. High-density lipoprotein [HDL] cholesterol
        4. Total cholesterol
  2. Bone
     1. Calcium
     2. 25-hydroxyvitamin D
• Other (2)
  • Cardiometabolic
    • Referral to a cardiologist or cardio-oncologist may be considered in patients with a history of myocardial infarction (MI) or stroke, for assessment and medical optimization prior to initiating ADT
  • Bone
    • Bone mineral density (BMD) testing using dual energy x-ray absorptiometry (DXA)
      • Using a validated tool, results of BMD testing should be used to calculate a patient’s 10-year risk of a major osteoporotic fracture for consideration of pharmacological therapy.
        • Recommended tools for calculating fracture risk
          • Canadian Association of Radiologists and Osteoporosis Canada
          • Fracture Risk Assessment tool (FRAX) of the World Health Organization (WHO)
• Inform primary care provider that the patient has been initiated on ADT and that there may be adverse events associated with this therapy
• Counsel patient regarding sexual side effects, particularly with respect to body image.

Prevention & Management of Complications on ADT

• Cardiometabolic
  • Encourage lifestyle modifications (smoking cessation, dietary modifications, exercise)
    • Patients should be encouraged to attend supervised exercise programs using a combination of resistance and aerobic training
      • Supervised exercise therapy in men with PCa is superior to self-implemented exercise regimens
      • Benefits of exercise in males on ADT (10)
        • Physical domains (5):
          1. Prevention of muscle loss and resultant decline in lean body mass
          2. Decreased body mass index
          3. Improved muscle strength
          4. Improvements in peak oxygen consumption and endothelial function
          5. Improved overall physical function
        • Functional domains (2):
          1. Lower levels of fatigue
          2. Decreased risk of falls and fractures
        • Endocrine domains (2):
          1. Improved insulin and glucose homeostasis
          2. Improved in lipid profile
        • Multiple health-related quality of life domains
  • Monitor blood pressure and treat hypertension for a target of <130/80
  • Diabetes screening and lipid profile (see above) assessments should be continued at 6–12 month-intervals throughout treatment duration
    • Dyslipidemia should be treated according to current best practice guidelines
  • In males with a prior history of MI or stroke, consider use of a gonadotropin-releasing hormone (GnRH) antagonist
    • Secondary analyses of randomized trials sugest that those with pre-existing CVD treated with a GnRH antagonist were 56% less likely to have a cardiovascular event within 1 year of beginning ADT compared to treatment with a GnRH agonist.
    • HERO trial comparing oral GnRH antagonist, relugolix, with leuprolide in males with advanced prostate cancer found that the incidence of MACE was more common among those treated with leuprolide.
• Bone health
  • Lifestyle changes, including smoking and alcohol cessation
    • Smoking and alcohol use are associated with bone loss and fractures
  • Patients should be encouraged to participate in exercise therapy using a combination of resistance and aerobic training, preferably in a supervised setting
    • Exercise may preserve BMD in men receiving ADT
  • Calcium intake (1200 mg daily total from diet and supplements) and vitamin D supplementation (800–2000 IU daily)
    • No evidence that shows this decreases risk of BMD loss or fractures in men receiving ADT but have been shown to prevent fractures in the general population age > 50
  • Pharmacotherapy
    • See Bone Health section in Castrate-Resistant Prostate Cancer Chapter Notes
    • Indications for pharmacotherapy (4):
      1. Osteoporosis
      2. History of fragility fractures in the hip or spine
      3. History of multiple fragility fractures
      4. Moderate or high 10-year fracture risk
  • Surveillance DXA (until treatment cessation)
    • Every 2–3 years in low 10-year fracture risk
    • Every 1-2 years in
      • Osteopenia
      • Moderate or high risk for fractures
    • Patients started on pharmacological therapy should have followup DXA to assess for treatment response.
• Hot flashes
  • Lifestyle changes including avoidance of potential patient-identified triggers, commonly heat or spicy foods
  • Pharmacotherapy (5) (none are Health Canada-approved for hot flashes):
    1. Medroxyprogesterone acetate (Provera) 20 mg orally daily
    2. Megestrol acetate (Megace) 20 mg orally twice daily
    3. Cyproterone acetate (Androcur) 50–100 mg orally daily
    4. Gabapentin (Neurontin) 900 mg orally daily
    5. Venlafaxine (Effexor) 75 mg orally daily
    • The best pharmacological therapy to treat hot flashes remains unclear; medroxyprogesterone and cyproterone appear to be more effective than venlafaxine.
  • Intermittent ADT improves hot flashes and should be considered in appropriately selected patients
  • Acupuncture may have a beneficial effect and can be considered in patients unwilling or unable to use pharmacotherapy.
• Breast events
  • Both tamoxifen and RT are effective prophylactic treatments for breast events
    • Prophylaxis for the prevention of gynecomastia in men receiving ADT is not currently recommended
  • Both tamoxifen or RT may be used for treatment of breast events in men receiving bicalutamide monotherapy;
    • Tamoxifen is more effective than a single 12-Gy fraction of RT
    • Surgical management for select patients
• Cognitive function
  • Monitor for cognitive decline and depression throughout duration of treatment
• Fatigue
  • Best treated with exercise therapy
• Anemia
  • Mild in most cases and often does not warrant treatment.
  • Indications for hematology referral (2):
    1. Severe anemia
    2. Decline in hemoglobin that exceeds the expected response to ADT alone
• Sexual function and body image

• • Referral to a sex therapist for multimodal treatment should be considered in males desiring improved sexual function,
  • Erectile dysfunction may be treated with various interventions, including phosphodiesterase inhibitors; however, treatment efficacy may be poor without adequate mental and physical arousal
  • Intermittent ADT may improve libido and erectile function and should be considered in appropriately selected patients
• Health related quality of life
  • Exercise therapy should be encouraged to improve HRQOL during treatment
  • Intermittent ADT improves HRQOL and should be considered in appropriately selected patients.
    • In general, men with non-metastatic PCa are likely to benefit from intermittent ADT without major concern for compromised oncological outcomes, while those with metastatic PCa should be considered for intermittent therapy with caution.

References

• Kokorovic, Andrea, et al. "Canadian Urological Association guideline on androgen deprivation therapy: Adverse events and management strategies." Canadian Urological Association journal= Journal de l'Association des urologues du Canada 15.6 (2021): E307-E322.