Canadian Urological Association guideline on androgen deprivation therapy: Adverse events and management strategies Flashcards
What is the most common type of malignancy in Canadian men?
Prostate cancer (PCa)
What are the different disease states that are categorized under advanced PCa?
Locally advanced or de novo metastatic disease, recurrent disease following primary treatment, and castrate-resistant prostate cancer (CRPC)
What is the primary treatment method for advanced PCa?
Androgen deprivation therapy (ADT)
What are the uses of ADT in the management of PCa?
ADT is the main treatment for advanced PCa. Additionally, it is used in localized disease among patients treated with radiation therapy.
Is ADT curative for PCa? What are some potential side effects?
No, ADT is not curative. It is associated with significant adverse events that can potentially cause substantial morbidity.
Why is the management and mitigation of ADT-related adverse events important?
Recent advancements in treatment have significantly improved outcomes and prolonged survival in patients with advanced disease. Managing and mitigating ADT-related adverse events is a critical aspect of medical care for these patients.
What are the two main types of androgen deprivation therapy?
Surgical orchiectomy and medical castration.
What are the two methods of medical castration?
Gonadal androgen ablation and androgen receptor antagonists (AA).
Name three types of Leutenizing hormone-releasing hormone (LHRH) agonists used in gonadal androgen ablation.
Leuprolide, goserelin, and triptorelin.
Name two types of LHRH antagonists used in gonadal androgen ablation.
Degarelix and relugolix.
What is the first-generation androgen receptor antagonist?
Bicalutamide.
Name three types of second-generation androgen receptor antagonists.
Enzalutamide, apalutamide, and darolutamide.
What are androgen synthesis inhibitors also known as?
CYP17 adrenal inhibitors.
Name two types of androgen synthesis inhibitors.
Abiraterone acetate and ketoconazole.
What databases were accessed to gather articles for the guidelines on ADT adverse events?
EmBASE and Medline.
What keywords were used in the search strategy for the articles?
“Prostate cancer,” “androgen deprivation therapy,” “complications,” “adverse events,” “side effects.”
Besides database searches, what other sources were consulted to gather data for the guidelines?
Reference lists of review articles and evidence-based guidelines on side effects of ADT.
What was the role of the expert panel in developing the guidelines?
The expert panel, comprised of urologists with significant experience prescribing and managing ADT adverse events, developed the recommendations.
How were the guideline statements assigned a level of evidence?
They were assigned a level of evidence using criteria from the Oxford Center for Evidence-based Medicine.
What determines if a statement is given a strong, moderate, or weak recommendation?
A strong recommendation is supported by high-quality, consistent evidence or unanimous expert consensus. A weak recommendation is supported by low-quality evidence and has a high degree of uncertainty. An “expert opinion” recommendation lacks explicit evidence but has sufficient biological plausibility.
What is the primary result of the castrate levels of testosterone induced by ADT?
The castrate levels of testosterone induced by ADT result in adverse effects that span across various organ systems, leading to potential significant morbidity and alterations in health-related quality of life (HRQOL) in men living with PCa.
Are the complications from ADT typically dose-limiting?
No, most of these complications are not dose-limiting and can be managed through pharmacological or other interventions.
What is the testosterone flare, and how can it be mitigated during the initiation of luteinizing hormone-releasing hormone (LHRH) agonists?
The testosterone flare is an adverse effect associated with the initiation of LHRH agonists. It can be mitigated by the addition of a first-generation anti-androgen (AA) for the first 2–4 weeks of treatment.
What is the overall goal of the urologist when administering ADT for men living with PCa?
The urologist’s goal is to optimize oncological outcomes while maintaining acceptable HRQOL. This requires an in-depth understanding of treatment-related adverse events to offer appropriate patient counselling and manage complications.
What types of ADT does this guideline focus on in relation to adverse effects?
This guideline focuses on adverse effects as a result of the use of LHRH agonists and antagonists.
What three elements follow each ADT-related complication in this guideline?
Each ADT-related complication is followed by a summary of the evidence, a summary of recommendations, and subsequently, a review of the data used to formulate the guideline statements.
What is the term “cardiometabolic health” in the context of androgen deprivation therapy (ADT)?
Cardiometabolic health refers to the effects of ADT on cardiovascular disease (CVD), body composition, and metabolic parameters (including lipid profiles, insulin resistance, and glucose homeostasis).
How does ADT impact cardiac health?
ADT may increase the risk of cardiac complications, especially in patients with pre-existing CVD or a history of major adverse cardiac events (MACE).
What are the potential effects of ADT on thromboembolic and cerebrovascular events?
ADT may increase the risk of venous thromboembolism (VTE) and stroke.
How does ADT influence body composition?
ADT is associated with changes in body composition, including increased body weight and fat mass, decreased lean body mass, and decreased muscle mass.
What are the metabolic complications of ADT?
ADT can lead to insulin resistance, glucose intolerance, changes in the lipid profile, increased risk of incident diabetes, and potentially worsen glycemic control in men with a pre-existing diagnosis. ADT may also increase the risk of developing metabolic syndrome.
What lifestyle modifications are recommended for patients on ADT?
Lifestyle modifications such as smoking cessation, dietary modifications, and exercise should be strongly encouraged.
What should be included in the baseline physical examination prior to ADT initiation?
The baseline physical examination should include blood pressure, weight, waist circumference, and calculation of body mass index (BMI).
The baseline physical examination should include blood pressure, weight, waist circumference, and calculation of body mass index (BMI).
Baseline laboratory investigations should include fasting plasma glucose and lipid profile (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol).
What should be done for patients with a history of myocardial infarction (MI) or stroke when initiating ADT?
Patients with a history of MI or stroke should be referred to a cardiologist or cardio-oncologist for assessment and medical optimization at the time of initiating ADT.
What monitoring should all patients receiving ADT undergo?
All patients receiving ADT should undergo a baseline cardiovascular risk assessment and be monitored for cardiovascular complications while receiving therapy.
What is the leading cause of death in men with prostate cancer (PCa) not dying from the disease itself?
Cardiovascular disease (CVD).
How is the link between androgen deprivation therapy (ADT) and CVD supported?
Large, observational cohort studies describe a strong link between ADT and CVD, including coronary artery disease (CAD), myocardial infarction (MI), and sudden cardiac death.
What does MACE stand for in the context of this study?
MACE is a cumulative term for adverse cardiovascular events and is defined as MI, coronary revascularization, stroke, and hospitalization due to heart failure.
What patient population seems to be at the highest risk for developing MACE while receiving ADT?
Men with pre-existing heart disease.
How does the use of a GnRH antagonist compare to a GnRH agonist with respect to the risk profile for CVD and development of MACE?
Some evidence suggests that men with pre-existing CVD treated with a GnRH antagonist were less likely to have a cardiovascular event within one year of beginning ADT compared to men treated with a GnRH agonist. However, these results are still under debate and further research is needed.
What were the results of the HERO clinical trial comparing the oral GnRH antagonist relugolix with leuprolide?
Relugolix was found to be superior to leuprolide in achieving castrate testosterone levels and was associated with a lower incidence of MACE. The decrease in risk was especially pronounced in men with a prior medical history of MACE.
What were the results of the PRONOUNCE trial comparing the effect of degarelix with leuprolide on MACE in patients with prostate cancer and a prior history of atherosclerotic cardiovascular disease (ASCVD)?
The results suggested that there is no added cardiovascular risk in men receiving a GnRH agonist compared to an antagonist. However, the trial had several limitations, including a low accrual rate and a lower than anticipated event rate, which could affect the reliability of the results.
What is the purpose of the ongoing RADICAL-PC trial?
The RADICAL-PC trial aims to assess the impact of systematic lifestyle and cardiovascular risk factor modification in men with prostate cancer, with a focus on ADT.
What is one hypothesized pathophysiological mechanism that connects GnRH agonists with cerebrovascular events?
GnRH agonists may destabilize atherosclerotic plaques.
According to studies, what is the association between ADT use and the risk of deep vein thrombosis (DVT), pulmonary embolus (PE), or arterial embolism?
ADT is associated with an increased risk of DVT, PE, or arterial embolism.
How much more likely are men receiving ADT to be hospitalized with DVT, PE, or both?
Men receiving ADT were 84% more likely to be hospitalized with DVT, PE, or both.
What does the current evidence suggest about the use of VTE prophylaxis in men receiving ADT?
There is currently insufficient evidence to recommend routine use of VTE prophylaxis in men receiving ADT.
According to a large observational study, how does the risk of stroke in men with local or regional prostate cancer receiving GnRH agonist compare to those not receiving treatment?
Men with local or regional prostate cancer receiving GnRH agonist had a significantly increased risk of stroke compared to the no-treatment group (HR 1.22, 95% CI 1.10–1.36).
How does the relative risk of stroke for men treated with a GnRH agonist compare to those without this treatment, according to a meta-analysis of eight observational studies?
The relative risk of stroke for men treated with a GnRH agonist is increased by 51% compared to those without this treatment (RR 1.51, 95% CI 1.24–1.84).
How does the duration of ADT relate to the number of cerebrovascular events?
Longer durations of ADT are associated with an increased number of cerebrovascular events.
What are the effects of ADT on body composition in men?
ADT treatment in men leads to an increase in body weight and percentage fat mass, primarily due to an accumulation of subcutaneous fat. It also causes a loss of muscle mass, leading to a decrease in percentage lean mass. These changes can occur as early as one month following treatment and may persist up to two years beyond treatment cessation.
What term is used to describe the loss of lean body mass and accumulation of fat mass?
This phenomenon is collectively termed sarcopenic obesity.
This phenomenon is collectively termed sarcopenic obesity.
The decrease in muscle mass leads to reduced grip strength, absolute muscular strength, and gait speed. Moreover, detrimental changes to aerobic fitness and overall physical function can occur. These changes can increase the risk of falls and fractures.
What are the potential risks associated with an elevated BMI in patients treated with ADT?
Elevated BMI may be associated with prostate cancer (PCa) progression and death. There may also be an association between obesity and the development of castration-resistant prostate cancer (CRPC) and metastases in men treated with early ADT.
When do the changes in body composition due to ADT begin to occur and how long can they persist?
These changes are thought to occur soon after initiating therapy, sometimes as early as one month following treatment. They may persist up to two years beyond treatment cessation.
What are the metabolic consequences of Androgen Deprivation Therapy (ADT)?
The metabolic consequences of ADT include insulin resistance, glucose intolerance, and changes to the lipid profile. It is also associated with an increased likelihood of developing incident diabetes.
How does ADT affect men with pre-existing insulin-dependent diabetes?
ADT may worsen glycemic control in men with pre-existing insulin-dependent diabetes.
How does ADT affect the lipid profile?
ADT appears to change the lipid profile, with most studies finding an increase in triglyceride and total cholesterol levels. The cause of this rise (i.e., whether due to HDL or LDL cholesterol) remains to be determined.
What is the metabolic syndrome according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)?
The NCEP ATP III defines metabolic syndrome as meeting three of the following criteria: waist circumference ≥102 cm in men, serum triglycerides ≥1.7 mmol/L, serum HDL cholesterol <1 mmol/L in men, blood pressure ≥130/85 mmHg, fasting plasma glucose ≥5.6 mmol/L, or requirement for medications to treat criteria 2–5 listed above.
How is ADT associated with metabolic syndrome?
ADT is associated with a higher risk of metabolic syndrome compared to controls, with more than 50% of men on ADT meeting criteria for metabolic syndrome. This diagnosis is mainly attributable to an elevation of triglycerides, hyperglycemia, and abdominal obesity.
Why is early identification and intervention necessary for men on ADT who have metabolic syndrome?
Early identification and intervention are necessary as patients with a diagnosis of metabolic syndrome are more likely to develop type 2 diabetes and cardiovascular diseases.
What is the recommended approach for managing men on ADT with regard to cardiovascular disease (CVD) risk?
Adopt the Canadian Cardiovascular Harmonized National Guidelines Endeavour (C-CHANGE) guidelines for both a screening and management strategy. This includes moderating caloric intake, promoting healthy dietary patterns, encouraging smoking cessation, and regulating blood pressure to a target level of <130/80.
What kind of diabetes screening should be performed for patients initiating ADT, and how frequently?
Diabetes screening with a fasting plasma glucose level, hemoglobin A1c, or oral glucose tolerance test should be performed at the time of ADT initiation, and at 6–12-month intervals following the initiation of treatment.
How should lipid profiles be monitored in patients on ADT?
Baseline lipid profiles (triglycerides, LDL cholesterol, HDL cholesterol, and total cholesterol) should be obtained at the start of ADT and monitored throughout the treatment duration. Management of dyslipidemia and lipid targets should be carried out according to the 2021 Canadian Cardiovascular Society guidelines.
What pharmacological therapies may be considered for high-risk individuals receiving ADT, according to the C-CHANGE guidelines?
This includes statins, aspirin, and angiotensin-converting enzyme inhibitors for primary and secondary prevention.
What benefits can exercise offer to PCa patients receiving ADT?
Exercise, particularly a combination of resistance and aerobic training, can prevent muscle loss and decline in lean body mass, improve metabolic indices and body composition, and ameliorate cardiovascular outcomes. It can also enhance overall physical and mental wellbeing.
What are the recommendations for exercise training in cancer survivors according to the 2018 American College of Sports and Medicine Roundtable?
150 minutes of moderate-intensity aerobic exercise spread over 3–5 days in addition to resistance training 2–3 times per week. Resistance training should engage 8–10 muscle groups and include 8–10 repetitions with two sets.
Fig. 1. Multidisciplinary approach to managing patients on androgen deprivation therapy (ADT).
