A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group
This article is commented on by the following:
Abstract
Introduction:
To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events.
Methods:
The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers.
Results:
The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications.
Conclusions:
Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.
Prostate cancer (PCa), when diagnosed early, generally has a good prognosis attributable to achievements related to screening, localized interventions, and systemic therapies. One of the first—and most important—advances in the treatment of PCa was the discovery of the androgen-dependent nature of the disease in the 1940s and the subsequent development of androgen deprivation therapy (ADT) to suppress testosterone to castrate levels. Since that time, essentially all systemic treatments for advanced PCa have been developed and approved in the context of concurrent ADT.1
PCa treatment with ADT can relieve symptoms, delay disease progression, and prolong survival.2 However, ADT is also associated with a broad range of adverse events (AEs) that affect cardiometabolic, endocrine, and psychosocial outcomes, among others.2 As a result, people receiving ADT for PCa have been shown to have worse quality of life (QoL) and overall health than those with PCa who are not receiving ADT.3 Fortunately, many ADT-related AEs and their effects on patient QoL can be prevented or mitigated with proactive patient and partner education, appropriate monitoring, and behavioral interventions. In routine clinical practice, however, ADT-related AEs appear to be poorly monitored and managed.4 Research consistently shows that patients do not receive sufficient counseling on ADT side effects and are not provided with the tools necessary to optimize health and QoL during and after ADT treatment.5,6
Urologists and other prescribers of ADT face a combination of challenges in the management of ADT AEs, including time constraints, concerns about costs and reimbursement, lack of awareness and resources, and uncertainty regarding division of responsibilities among health care providers. To promote comprehensive care of patients throughout the ADT prescribing process, a multidisciplinary panel of experts on ADT, PCa, and behavioral and lifestyle interventions was convened. The Prostate Cancer 360 (PC360) Working Group developed a series of clinician-directed recommendations, which we believe to be practical for optimizing the patient-centric management of ADT through patient and partner education and counseling, risk factor monitoring and management, and promotion of evidence-based lifestyle interventions.
Materials and Methods
The PC360 Working Group included community and academic urologists, medical oncologists, primary care physicians, psychology experts, nutrition experts, a cardiometabolic physician, an exercise physiologist, an oncology nurse, and PCa patient representatives. The 14 experts included in the PC360 Working Group had a dedicated interest in PCa and ADT management and/or research. The working group reviewed literature on ADT AEs and management strategies from PubMed searches; PCa guidelines; and other relevant cardiology, endocrine, and cancer guidelines. The PC360 Working Group met in person in November 2022 to review and define challenges associated with ADT AEs and then reconvened virtually in small groups in December 2022 to develop comprehensive care recommendations intended to be practical for ADT prescribers. A final in-person meeting in March 2023 allowed the group to refine and finalize recommendations.
Results
The PC360 Working Group developed overarching recommendations for ADT AE management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle), which are summarized in Table 1. A hyperlinked list of key guidelines, risk assessment tools, and clinician resources that contributed to the development of these recommendations can be found in Supplementary Appendix 1 (https://www.urologypracticejournal.com). Patient-oriented resources with evidence-based information on ADT treatment are listed in Supplementary Appendix 2 (https://www.urologypracticejournal.com) and may be useful during treatment discussions between ADT prescribers and patients.
| PC360 recommendations for the comprehensive care of people receiving ADT | Timing | Potential clinical lead(s) | Potential responsibilities of the ADT prescriber | ||
| Before initiation | At initiation | During treatment | |||
| Overarching clinical considerations | |||||
| 1.1 Ensure that patients receiving ADT have PCPsa that they visit routinely | X | X | ADT prescriber, clinical staff | Oversight, patient counseling, referral (if needed), and confirmation of regular PCP visits | |
| 1.2 Inform patients’ PCPs about planned ADT treatment regimen and potential AEs | X | ADT prescriber, clinical staff | HCP-HCP communication, oversight | ||
| 1.3 Facilitate proactive involvement of partners, caregivers, and other trusted support persons in ADT management | X | X | ADT prescriber, PCP, behavioral health specialist | Patient education, referral (if needed) | |
| Cardiometabolic health | |||||
| 2.1 Assess cardiometabolic health and overall cardiovascular risk of all patients receiving ADT | X | X | ADT prescriber, clinical staff, PCP, cardio-oncologist | Oversight, risk factor monitoring, referral | |
| 2.2 Address cardiometabolic risk factors with appropriate interventions, including pharmacotherapy as needed | X | X | ADT prescriber, PCP, cardiologist, cardio-oncologist | Oversight, patient counseling, risk factor management, referral | |
| 2.3 Consider the use of statins for primary prevention in patients with PCa who are receiving ADT, regardless of cardiometabolic risk | X | X | ADT prescriber, PCP, cardiologist, cardio-oncologist | Patient counseling, statin initiation and titration, referral | |
| Bone health | |||||
| 3.1 Assess bone health, and continue monitoring during treatmentb | X | X | ADT prescriber, PCP | Oversight, testing, referral | |
| 3.2 Educate patients about the effects of ADT on bone health and recommendations for optimizing bone health | X | X | ADT prescriber, PCP, clinical staff | Oversight, patient education | |
| 3.3 In patients who are at risk for fracture, mitigate risk with evidence-based strategies, including pharmacotherapy | X | X | X | ADT prescriber, PCP, endocrinologist | Oversight, patient counseling, bone health medication management, referral (if needed) |
| Sexual health | |||||
| 4.1 Assess sexual health and relative importance of maintaining sexual function | X | X | ADT prescriber, clinical staff | Clinical staff training, sexual health assessment, patient education | |
| 4.2 Educate patients and partners about the sexual AEs of ADT, including setting realistic expectations for sexual activity, but also advising that enjoyable sexual activity is still possible while on ADT | X | ADT prescriber | Patient education | ||
| 4.3 Provide patients and partners with the option of interventions to maintain sexual activity during ADT treatment | X | X | ADT prescriber, sexual health therapist, behavioral therapist | Patient education, referral | |
| Psychological health | |||||
| 5.1 Educate patients on the neuropsychiatric changes associated with ADT use | X | ADT prescriber, mental health specialist | Oversight, patient education | ||
| 5.2 Screen patients for depression and anxiety using validated brief tools | X | X | X | ADT prescriber, clinical staff, PCP | Oversight, patient education, referral (if needed) |
| Lifestyle and behavioral health | |||||
| 6.1 Counsel patients on the ADT-associated changes in body composition | X | X | ADT prescriber | Patient education | |
| 6.2 Assess patient activity level to determine optimal physical activity interventions | X | X | ADT prescriber, PCP, clinical staff, exercise physiologist | Oversight, patient counseling, referral (if needed) | |
| 6.3 Educate patients about the importance and recommended amounts of physical activity | X | X | X | ADT prescriber, PCP, clinical staff, exercise physiologist | Oversight, patient education, referral (if needed) |
| 6.4 Assess patients’ eating patterns and counsel them to follow a healthy pattern | X | X | X | ADT prescriber, PCP, clinical staff, nutritionist | Oversight, patient counseling, referral (if needed) |
Discussion
Overarching Clinical Considerations
The health care system in the US places considerable constraints on ADT prescribers and constitutes a major barrier to the implementation of comprehensive care of patients receiving ADT. As such, the PC360 team developed recommendations for ADT prescribers to optimize ADT management through an interdisciplinary, team-based approach. Advanced practice providers and other clinical staff were seen as important members of the care team, supporting ADT prescribers in tasks such as patient counseling and follow-up. To promote coordinated, comprehensive care during ADT treatment, the PC360 Working Group identified 3 key interventions (Table 1, recommendations 1.1-1.3) that form the foundation for the other recommendations herein.
All patients with PCa who are initiating ADT should have a regular primary care provider (PCP) who is prepared to monitor for, and counsel patients about, ADT AEs. Given that one-quarter of US adults do not have a PCP,7 ADT prescribers or their clinical staff should confirm patient access to a current PCP. Any patient without a PCP should be referred to one, and all patients should receive counseling about the importance of staying up to date with primary care visits during ADT treatment. Resources for PCP referral will vary according to region and practice type. Community providers may consider generating and maintaining a list of PCPs according to a patient’s location or health insurance, while academic providers should familiarize themselves with the primary care resources within their health systems. Although ensuring access to primary care is an important first step in optimizing ADT management, many PCPs report inadequate knowledge of ADT and lack confidence in counseling patients about potential AEs.8 To address potential knowledge deficits among PCPs caring for patients starting ADT, the PC360 Working Group recommends providing PCPs with a comprehensive synopsis of their patient’s ADT treatment plan, potential ADT AEs of concern, and any known risk factors. These communications can be brief, and most of the content can be covered using a generic template. An example form letter intended for use by ADT prescribers can be found in Supplementary Appendix 3 (https://www.urologypracticejournal.com).
Another component of optimizing ADT management is the early and proactive involvement of partners, caregivers, and/or other trusted support persons. Ideally, this process should begin prior to the initiation of ADT and should continue throughout treatment. The mental, emotional, and sexual AEs associated with ADT can directly impact partner well-being, which in turn negatively affects patient wellbeing.9 Early and ongoing involvement of partners in the ADT treatment process can help both patients and partners prepare for, and adjust to, the effects of AEs. For those patient-partner dyads who are interested and for those with preexisting relational dysfunction, consider referral to a behavioral health specialist for psychosocial interventions.
Cardiometabolic Health
ADT is associated with atherosclerotic, inflammatory, endothelial, glycemic, and body composition changes, all of which contribute to an increased risk of cardiometabolic complications and major adverse cardiovascular events.10,11 In patients with advanced PCa, cardiovascular disease (CVD) is the leading cause of noncancer death, and in patients with localized PCa, cardiovascular deaths are more common than PCa-related deaths.12 ADT use carries the greatest cardiovascular risk in patients who have preexisting cardiometabolic comorbidities13—but prescribing clinicians should be aware that the vast majority of patients initiating ADT have these comorbidities. In one recent study, 99% of patients with PCa had at least 1 uncontrolled cardiovascular risk factor, and 51% had at least 3 uncontrolled risk factors.14 As a result, PC360 endorses cardiovascular risk assessment and mitigation before and during ADT treatment (Table 1, recommendations 2.1-2.3).
Prior to initiating ADT, prescribers should either assess patients for cardiovascular risk or refer them to PCPs or cardiometabolic clinics to receive appropriate assessments (Table 2).15 In addition to evaluation for standard cardiovascular risk factors (eg, dyslipidemia, hypertension, glucose intolerance, diabetes), some patients may benefit from a more thorough assessment of cardiovascular risk using the American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic CVD (ASCVD) risk calculator, which predicts the risk of an ASCVD event in the next 10 years for a patient without baseline ASCVD.16 Although this calculator has not been validated in patients receiving ADT, establishing a baseline risk level can be useful for initial decision making and monitoring.
| Test | First test | Follow-up (PCP, cardiologist, or ADT prescriber) |
| Cardiometabolic | ||
| Family history of CVD | Baseline | N/A |
| Office-based blood pressure | Baseline | Every visit |
| Lipid panel | Baseline | At 3-6 mo and at least annually thereafter |
| eGFR | Baseline | Annually |
| Blood glucose levels (fasting or nonfasting) | Baseline | At 3-6 mo and at least annually thereafter |
| Body weight and BMI | Baseline | Every visit |
| 10-y ASCVD riska | Baseline | At 3-6 mo and at least annually thereafter |
| Bone | ||
| Fracture risk assessment | Baseline | Annually |
| DXA scan | Within 1-6 mo of ADT initiationb | Every 1-3 y |
| Serum vitamin D levels15,a | Baseline | Annually |
| Dental examination | Prior to initiation of antiresorptives | Every 6 mo |
The PC360 Working Group recommends using information from the cardiovascular assessment to risk-stratify patients prior to initiating ADT to allow for appropriate risk management. Given that the greatest risk for cardiovascular events occurs in the first 6 months of ADT use,17 this proactive approach to cardiovascular risk management is critically important. A simple risk stratification schema and corresponding next steps are provided in the Figure. It is important to note that this stratification is based on expert opinion and has not been validated in men receiving ADT; therefore, this risk stratification should serve as a guide only. Prescribers may also wish to consider risk-enhancing factors (eg, high-risk race/ethnicity, albuminuria) described by the ACC/AHA in their 2019 primary prevention guidelines.15 Furthermore, given that ADT initiation itself is a risk factor for ASCVD, the PC360 Working Group felt that no patients receiving ADT could be considered truly low risk.
Figure. Example of cardiovascular risk stratification and subsequent management for patients initiating androgen deprivation therapy (ADT) developed by the Prostate Cancer 360 Working Group. ASCVD indicates atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CVD, cardiovascular disease; MI, myocardial infarction.
When mitigating cardiovascular risk in patients initiating ADT, prescribers have the option of referring for medication management; initiating treatment and referring for ongoing management; or initiating and managing treatment themselves. The best approach for ADT prescribers will depend on their practices and available resources, but in general, the PC360 Working Group advocates an oversight role for the ADT prescriber, using appropriate referral pathways. Prescribers or clinical staff should follow up on these referrals to ensure patient adherence and adequate risk factor management. In general, treatment goals for cardiovascular risk factor management for primary ASCVD prevention are similar to those for the general population (Table 3). In patients not meeting these goals, consider referral back to primary or specialty providers.
| Parameter | Guideline recommendations | ||
| Organization (y) | Patient population | Recommended target | |
| A1C | ADA (2023) | Most adults with T2D and without significant hypoglycemia | <7.0% |
| Older adults with multiple comorbidities or other medical complexities and/or intermediate life expectancy | <8.0% | ||
| Blood glucose (fasting) | ADA (2023) | Most adults with T2D and without significant hypoglycemia | 80-130 mg/dL |
| Older adults with multiple comorbidities or other medical complexities and/or intermediate life expectancy | 90-150 mg/dL | ||
| Blood glucose (nonfasting) | ADA (2023) | Most adults with T2D and without significant hypoglycemia | <180 mg/dL |
| Older adults with multiple comorbidities or other medical complexities and/or intermediate life expectancy | 100-180 mg/dL | ||
| Blood pressure | ACC/AHA (2019) | Adults with baseline hypertension and 10-y ASCVD risk of ≥10% | <130/80 mm Hg |
| Body weight | ACC/AHA (2019) | Adults with BMI 25-29.9 kg/m2 (overweight) or BMI ≥30 kg/m2 (obesity) | 5%-10% reduction from baseline weight |
| LDL-C | ACC/AHA (2019) | Adults aged 40-75 y with baseline LDL-C 70-189 mg/dL and at borderline risk (10-y ASCVD risk, 5%-<7.5%) | Based on risk discussion |
| Adults aged 40-75 y with baseline LDL-C ≥190 mg/dL and at intermediate risk (10-y ASCVD risk, ≥7.5%-<20%) | ≥50% reduction for optimal benefits | ||
Evidence for the cardiometabolic benefits of statins in patients with PCa is accumulating. In a meta-analysis of 25 cohort studies that included 119,878 patients with PCa, concurrent statin use was associated with improved overall survival by 27% and PCa-specific mortality by 35%.19 Furthermore, based on promising data from early-stage trials and observational studies, the effect of atorvastatin on PCa progression during ADT treatment is being investigated in an ongoing randomized placebo-controlled phase 3 trial.20 While high-quality data on the effects of statins on cardiovascular and cancer-related mortality are still needed, the PC360 Working Group felt that the extant effectiveness data and the minimal risks associated with statin use were sufficient to recommend consideration of concurrent moderate-intensity statin initiation in most patients receiving ADT. Moderate-intensity statins are intended to reduce low-density lipoprotein cholesterol levels by 30% to 49% and primarily include atorvastatin 10 mg (optional up-titration to 20 mg) and rosuvastatin 10 mg (optional down-titration to 5 mg).21 For patients who are resistant to statin initiation because of concerns about AEs or a desire to improve cardiovascular risk without pharmacotherapy, consider ordering or referring to cardiology for coronary artery calcium scanning to better ascertain risk for ASCVD.21
Bone Health
Maintenance of bone health is an important component of optimizing care in patients receiving ADT due to the risk of bone mineral density (BMD) loss, osteoporosis, and fractures. In one meta-analysis, the risk of fracture in patients with PCa was 39% higher in those receiving ADT.22 BMD reduction occurs rapidly after ADT initiation, within 6 to 12 months, and in a dose-dependent manner. Furthermore, the risk for fracture persists beyond ADT discontinuation.23,24 Patients with cancer who experience fracture are at elevated risk for mortality. Although mortality risk is greatest in the first year following a major fracture, risk for mortality persists up to 5 years after fracture, highlighting long-term risks of poor bone health in patients with PCa and the need for proactive monitoring and management (Table 1, recommendations 3.1-3.3).25
The PC360 Working Group recommends that ADT prescribers either perform or refer for bone health assessment at the initiation of ADT (Table 2). BMD testing at ADT initiation may decrease the risk of fracture in patients initiating ADT, and yet, dual-energy x-ray absorptiometry (DXA) screening rates are exceedingly low in these patients (<10%).26 Given that many people with advanced PCa have osteopenia or osteoporosis prior to ADT initiation,27 BMD assessment would ideally occur prior to ADT initiation. However, the Working Group recognizes that insurance coverage varies for DXA, and waiting 6 months after ADT initiation (a risk-based indication for DXA) may be the most feasible path. DXA testing should be repeated every 1 to 3 years in patients receiving ADT. Furthermore, patients may be assessed with a validated fracture risk tool (eg, Fracture Risk Assessment Tool [FRAX]). Although FRAX has not been formally validated in patients with PCa who are receiving ADT, studies have shown that FRAX (with or without BMD input) identifies more patients with PCa requiring antiresorptive therapy than BMD alone.28 If using the FRAX algorithm to assess fracture risk, ADT use should be considered “secondary osteoporosis.”27
Antiresorptive therapy is recommended for patients with PCa who have a T-score of −2.5 or less; FRAX score greater than 20% for major fractures; FRAX score greater than 3% for hip fractures; or vertebral fragility fractures.27 Bone-targeted therapies for patients on ADT include weekly oral alendronate (35-70 mg), weekly or monthly risedronate (35 or 150 mg, respectively), yearly intravenous zoledronic acid (5 mg), or subcutaneous denosumab (60 mg) every 6 months.27,29 The optimal duration of antiresorptive therapy for patients with PCa who are receiving ADT has not been established. Therefore, decisions regarding treatment discontinuation or drug holidays may be determined based on ADT duration, baseline fracture risk, and changes in BMD with treatment.
As with cardiometabolic risk management, bone health medications may be managed by ADT prescribers or PCPs, with prescriber follow up to ensure adherence and adequate treatment. Regardless of the approach used, ADT prescribers should be familiar with the AE profiles of antiresorptives and recommended monitoring and mitigation strategies. Because antiresorptive medications can cause or worsen hypocalcemia, prescribers should ensure that calcium levels are monitored and managed prior to and during treatment. Osteonecrosis of the jaw (ONJ) and atypical femur fracture (AFF) are rare but serious AEs that have been reported with bisphosphonates and denosumab.29 ONJ has been reported in up to 1.7% of patients with cancer treated with high-dose denosumab.30 To reduce the risk of ONJ, patients with PCa who are receiving bone health therapies should be counseled about the importance of good oral hygiene and the need for routine dental care. Prior to the initiation of any antiresorptive therapy, prescribers should ensure dental examination and clearance and should hold bone health therapies in patients undergoing dental procedures. AFFs tend to be less common than ONJ in cancer patients, but patients on antiresorptives should still receive counseling about the symptoms of AFF (thigh or groin pain) and the need to discuss these symptoms with a provider.29
Regardless of fracture risk or use of bone-targeted pharmacotherapy, all patients should be proactively educated on the importance of bone health maintenance. Recommendations for calcium and vitamin D should be discussed (Table 4), and patients who are at risk for vitamin D insufficiency (<30 ng/mL) should undergo serum vitamin D testing and receive a prescription for vitamin D supplementation, as appropriate.29 As many as 2 of every 3 men with PCa have vitamin D deficiency or insufficiency31; therefore, most patients initiating ADT should also be receiving vitamin D supplementation. For vitamin D deficiency, the typical dose is 50,000 IU once weekly for 5 to 8 weeks followed by maintenance with 1000 to 2000 IU daily.29
| Component of bone health | Goal | Patient counseling points |
| Calcium | Total intake of 1000 mg/d (men aged 50-70 y) or 1200 mg/d (men aged ≥71 y) | • Ideally, calcium should come from a diet rich in calcium-containing foods
|
| Vitamin D | 800-1000 IU/d (serum 25[OH]D levels ∼30 ng/mL) | • Vitamin D can come from sun exposure and from foods such as fortified milk, fortified
breakfast cereals, and saltwater fish
|
| Cigarette and tobacco use | Abstinence | • Tobacco use is detrimental to both bone health and overall health
|
| Alcohol intake | Moderate or less | • Excessive alcohol intake reduces calcium absorption and increases the risk of falls
|
| Weight-bearing, muscle-strengthening activity | Adherence to a multicomponent physical activity program | • Preventing bone loss with exercise is easier than reversing bone loss
|
Sexual Health
As the goal of ADT is to achieve castrate levels of testosterone, sexual function is inherently altered with ADT use. Erectile dysfunction is one of the most common AEs associated with ADT and has been reported in as many as 90% of patients. Other common sexual AEs include reduced sexual desire, inability to achieve orgasm, and reduced penile and testicular size.32 The effects of these AEs on sexual health can be further compounded by body composition changes, such as gynecomastia, weight gain, centralization of body fat, and loss of lean muscle mass. Importantly, the effects of ADT on sexual health can persist even after discontinuation, especially when combined with localized PCa treatments.33 The sexual AEs of ADT negatively affect the QoL of both patients and their partners,34 highlighting the need for ADT prescribers to proactively address these effects with patients and their partners prior to ADT initiation (Table 1, recommendations 4.1-4.3).
As shown in Table 5, ADT prescribers should be prepared to both assess sexual health and provide patients and their partners with education intended to improve patient-partner adjustment to changes in sexual activity. Inclusion of the partners in this assessment when possible is important, as patients and partners may have different assumptions, expectations, and values. Sexual health and erectile dysfunction experts and specialty centers can also be valuable partners in the management of these AEs.
| Assessment | Patient and partner education |
|
|
One of the most important aspects of sexual health counseling for patients starting ADT is the need to set realistic expectations for sexual activity during ADT treatment. ADT prescribers should keep in mind that realistic expectations include the likely need to modify or redefine sexuality beyond erectile function. Importantly, prescribers should avoid suggesting that sexual activity while on ADT is impossible. For example, implicitly equating erectile function with sexual activity by using wording that implies ADT is the end of a patient’s sex life should be avoided, as this can result in a self-fulfilling prophecy of discontinuing all sexual activity.35,36 Although patients who are interested should be made aware of options for treating erectile dysfunction, patients should also be informed about the risks and relative benefits of these options, including the low levels of success of erectile aids (ie, phosphodiesterase type 5 inhibitors), and the need to address other factors of sexual health beyond erectile function (eg, reduced sexual desire and thus less spontaneous interest in sexual activity).37,38 Most patient-partner dyads report a decrease in intimacy that parallels the decrease in sexual function,39 which can negatively affect relationship quality. Strategic and straightforward interventions that can be delivered by the ADT provider include normalizing the common shift toward nonpenetrative sexual activity associated with aging, and the introduction of the concept of responsive sexual desire (eg, desire that follows the initiation of sexual stimuli).
Psychological Health
ADT use is associated with several psychological changes and comorbidities, including depression, anxiety, emotional lability, and cognitive decline.36,40,41 Psychologic comorbidities can worsen QoL in patients with PCa and may also contribute to other adverse outcomes, including suicidal ideation and suicide.36 The risk of depression increases with longer duration of ADT,41 which is why psychologic health should be evaluated at baseline and throughout ADT. Although psychologic comorbidities would ideally be monitored and managed in the primary care setting, ADT prescribers may consider incorporating brief validated depression and anxiety screens in their standard patient intake forms (Table 1, recommendations 5.1 and 5.2). For example, 2-item versions of the PHQ (Patient Health Questionnaire)-2 and GAD (Generalized Anxiety Disorder)-2 screeners are available and can be administered and scored by clinical staff. In patients who screen positive on these assessments, the more extensive validated tools (eg, PHQ-9 and GAD-7) can then be used to assess the severity of mental health disorders and the need for referral to either primary care or, in patients with severe mental health comorbidities, directly to psychiatry or mental health counseling.
Patient counseling regarding the psychologic AEs of ADT is also important and can alleviate some of the burden on the ADT prescriber by empowering patients and their partners to monitor their own mental health. The risk for mental health comorbidities and other neuropsychiatric changes (eg, cognitive decline) should be discussed at ADT initiation, and patients should be instructed to follow up with their PCPs if they experience changes in their mental state. ADT prescribers may consider showing patients where they can access validated tools for assessing depression, anxiety, and cognition so that they can monitor changes in scores.
Lifestyle Interventions
For all patients receiving ADT, lifestyle interventions focused on healthful behaviors are a key component of management (Table 1, recommendations 6.1-6.4). ADT initiation is associated with changes in body composition, including increased body fat percentage, decreased lean body mass, centralization of body fat, and increased weight and BMI.42 As such, all patients should receive counseling on the potential for body composition changes prior to ADT initiation, and the benefits of lifestyle interventions to prevent or mitigate these changes should be discussed.
Physical activity is not only beneficial for physical function and body composition, but can also improve fatigue, QoL, mental health, and sleep.43,44 In one randomized controlled trial, all forms of exercise improved fatigue, with the greatest benefits reported by patients with the highest levels of baseline fatigue.45 When discussing physical activity with patients, ADT prescribers should consider beginning with an assessment of the patient’s baseline activity level using a brief validated tool (eg, Godin Leisure-Time Exercise Questionnaire or International Physical Activity Questionnaire Short Form). Those patients who are sedentary or inactive are at the highest risk for exercise-related injury and may benefit from referral to an exercise physiology program. Referral should also be considered for any patients who are not safe exercising without professional supervision.44 PC360 recommendations for physical activity are aligned with those developed by the American College of Sports Medicine for patients with cancer (Table 6). Of note, although the ACC/AHA endorses 5% to 10% body weight reduction in people with overweight or obesity, this is likely a challenging target for patients on ADT. For these patients, the focus should be on attainable goals, such as meeting physical activity goals and eating healthfully.
| Healthful behavior | Goal | Patient counseling points |
| Aerobic activity | 30 min at moderate intensity, 3 times per wk | • Moderate-intensity activities are those during which someone can talk but not sing
(eg, brisk walking, jogging, water aerobics, light biking)
|
| Resistance training | 20-30 min, 2 times per wk | • Options for generating resistance include weights, resistance bands, and body weight
|
| Nutrition | Healthful and balanced eating patterns | • Diverse and healthful diets include various fruits, vegetables, whole grains, nuts,
and lean proteins
|
Nutrition is another important counseling point for patients starting ADT. Adherence to a typical Western dietary pattern is associated with a 2.5-fold increase in PCa-related mortality and a 67% decrease in overall survival. In contrast, healthful eating patterns improve overall survival by up to 36%.46 Eating patterns with evidence supporting cardiometabolic health in patients on ADT include low-carbohydrate diets and the Mediterranean diet.47,48 The Mediterranean diet has also been associated with reduced fatigue and improved QoL in patients on ADT.49 Given that there are many dietary patterns associated with healthful eating and no single “ideal” pattern has been identified, the PC360 recommendations focus on shared features of healthy nutrition across various healthful eating patterns (Table 6). For example, patients with PCa should be counseled about the benefits of eating a variety of fruits, vegetables, and unprocessed protein sources, and advised about reducing or avoiding processed foods, trans fats, simple sugars, and excessive alcohol intake.
Poor adherence to lifestyle interventions often presents a challenge. One of the best ways to promote adherence to dietary recommendations is to help patients identify a healthy eating pattern that aligns with their personal preferences. Another resource to promote lifestyle adherence is to refer patients to appropriate specialists (eg, exercise physiologist, registered dietitian or nutritionist), which can improve uptake and alleviate the burden on ADT prescribers. When cost or resources limit referrals, ADT prescribers should be familiar with the provider-supervised and community-based lifestyle and exercise programs available in their areas. Referring patients to vetted online resources with written or video instructions for exercise and nutrition may also be beneficial. As with other components of comprehensive ADT care, ADT prescribers should consider providing lifestyle counseling to both patients and their partners or support providers to promote accountability and joint efforts in health promotion.
When prescribing behavioral changes to patients receiving ADT, practitioners are likely to experience more success when they appeal to the behavior benefits that most align with patient values—as opposed to those that may seem to be important to prescribers. Patients can be encouraged to self-identify why engaging in such changes might be important to them, and prescribers can work to reinforce those reasons for change. This approach is consistent with strategies designed to motivate and sustain health behavior change.50
Conclusions
ADT is a potentially life-extending intervention that is associated with potential short- and long-term AEs. Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, and psychological health. Preemptive patient education is critically important to ensure that patients have the opportunity to proactively engage in lifestyle interventions instead of waiting until comorbidities or complications arise, which often may be too late to meaningfully reduce risk.
Given that ADT prescribers are often juggling several other concerns when treating patients with PCa, ADT AE monitoring and management is frequently suboptimal. In an ideal world, ADT prescribers would have the time and resources to perform thorough risk assessments, refer patients to the appropriate specialists for treatment, and follow up on any missed referrals or remaining uncontrolled risk factors. In the current health care system, however, ADT prescribers will need to rely on a mix of interdisciplinary care, clinical staff, automated processes and procedures (eg, electronic health records systems), and patient engagement to ensure patients are receiving comprehensive care. ADT prescribers should implement or advocate for processes that can offload ordering and following up on tests and interventions that are recommended for all patients. Nonclinical staff can also be valuable for assisting patients who encounter financial barriers to optimal care, including those with high ADT copays and/or socioeconomic barriers to accessing the recommended referrals and resources discussed herein. Offloading these tasks can save more time for patient counseling, which should be provided prior to ADT initiation and should incorporate partners or other trusted support providers. Nurse practitioners, physician assistants, and nurses can all be valuable partners in patient engagement and counseling.
As with all expert recommendations, those included herein should be individualized according to the available practice resources and the needs and preferences of patients and their partners, with the goal of enabling patients to receive the benefits of ADT while reducing the risk of ADT-related morbidity and improving QoL.
Acknowledgments
The subject matter of this manuscript was discussed and refined during 2 roundtable discussions and small group advisory meetings on the topic of ADT lifestyle management, with organizational and logistical support provided by Tolmar Inc. The authors developed the manuscript independently without contribution or oversight of the content by the sponsor. Tolmar Inc funded independent medical writing support but had no role in the manuscript content or approval. Jessica Martin, PhD, and Fallon Medica LLC provided medical writing, editing, referencing, and graphic support at the direction of the authors.
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Support: Tolmar Inc provided organizational and logistical support for the roundtable meeting and funded independent medical writing support; Tolmar Inc had no role in the manuscript content or approval.
Conflict of Interest Disclosures: E.D.C.: consultant/advisor: Janssen, Bayer, MDx, Tolmar; meeting participant: Pfizer, Astellas; owner: 3D Bx; leadership position: Carden Jennings Publishing. R.H.E.: consultant: Tolmar. M.M.M.: consultancy fee: Halozyme, Tolmar. S.J.F.: consultant: Astellas, Bayer, Janssen, Pfizer, Merck, Astra Zeneca, Sanofi, Myovant. R.K.P.: advisor/consultant: Astra-Zeneca, Bayer, Blue Earth Diagnostics, BMS, Dendreon, EMD Serono, Exelixis, Genentech/Roche, Janssen, Merck, Pfizer, Sanofi, Tolmar; steering committees: Ambrx, BMS; IP/licensing: Tempus Labs; research funding: BMS, Genentech/Roche, Exelixis, Pharmacyclics. R.J.W.: As a co-lead of the Canadian Androgen Deprivation Therapy Educational program, receives financial support for the program in the form of unrestricted educational grants from a consortium of pharmaceutical industry sponsors, including Astellas, Bayer, Novartis, Pfizer, and Tolmar; has also received speaker honorarium from Tolmar and Bayer for talks on androgen depression therapy. M.T.R.: consultant: OPKO, Astellas, Urovant, Sunovion. L.M.W.: As a co-lead of the Canadian Androgen Deprivation Therapy Educational program, receives financial support for the program in the form of unrestricted educational grants from a consortium of pharmaceutical industry sponsors, including Astellas, Bayer, Novartis, Pfizer, and Tolmar; has also received speaker honorarium for talks on assessing and managing sexual health from Merck and Astra Zeneca. J.M.H.: consultant/advisor: Astellas, Dendreon, Eli Lilly and Company, Immunis AI, Janssen Biotech, Myriad Genetics, Myovant Sciences, Pfizer, Urogen, Promaxo, Lynx DX; meeting participant/lecturer: Astellas, Amgen, Bater, Blue Earth Diagnostics, Dendreon, Janssen Biotech, Lantheus, Merck, Myriad Genetics, Myovant Sciences, Pfizer, Procept-Biorobotic, Progenics, Tolmar, Urogen; scientific study/trial: Astellas, Bayer, Dendreon, Janssen Biotech, Lipella, Merck, miR Scientific, Myriad Genetics, Myovant Science, Nucleix, Pfizer. M.B.G., C.F., T.C., M.C., and P.-H.L. have no conflicts of interest to disclose.
Ethics Statement: This study was deemed exempt from Institutional Review Board review.
Author Contributions: Conception and design: E.D.C., M.B.G., M.M.M., R.K.P., R.J.W., L.M.W., C.F., T.C.; Idea generation & critical review: E.D.C., C.F.; Data analysis and interpretation: E.D.C., M.B.G., R.H.E., M.M.M., S.J.F., R.K.P., R.J.W., M.T.R., L.M.W., P.H.L., J.M.H., M.C.; Critical revision of the manuscript for scientific and factual content: E.D.C., M.B.G., R.H.E., M.M.M., S.J.F., R.K.P., R.J.W., M.T.R., L.M.W., M.C., P.H.L., J.M.H.; Drafting the manuscript: E.D.C., M.B.G., R.H.E., C.F., T.C.; Draft and review of CVD and metabolic impact of ADT: E.D.C., M.B.G., R.H.E., M.M.M., R.J.W., M.T.R., L.M.W., C.F., M.C., J.M.H., P.H.L.; Statistical analysis: M.B.G., M.C.; Supervision: E.D.C., M.B.G., M.M.M., S.J.F., R.K.P., M.T.R., L.M.W., C.F., T.C., P.H.L., J.M.H.
