What Should We Tell Patients About Physical Activity After a Prostate Cancer Diagnosis?

Figure: The Prostate Cancer Continuum.

Table 1. Selected Observational Studies Measuring Physical Activity After a Diagnosis of Prostate Cancer: An Assessment of the Relationship Between Physical Activity and Disease Progression/Survival

Table 2. Selected Randomized Controlled Trials of Exercise Interventions Prescribed for Men Receiving Radiation Therapy for Prostate Cancer

Table 3. Selected Randomized Trials Showing Benefits of Resistance Exercise for Patients Receiving Androgen Deprivation Therapy (ADT)

Table 4. The “5 A’s” Approach to Promoting Changes in Physical Activity Behavior

"Start Moving and Feel Better!" Patient Education Handout

A number of observational studies and clinical trials have shown that physical activity after a diagnosis of prostate cancer is associated with a decrease in disease progression and an increase in survival, and that specific exercises reduce morbidity from prostate cancer treatments. However, providers need more guidance on what types of physical activity to recommend to patients across different disease states and treatments in prostate cancer, and when and how to initiate the discussion. In addition to evaluating important studies showing benefits of physical activity in patients with prostate cancer, this review suggests some evidence-based methods for incorporating physical activity interventions into clinical practice.

Introduction

The last decade of research indicates that physical activity benefits patients across the prostate cancer continuum (see Figure). To the left of the continuum are men presenting with localized disease, which may be treated with surgery or radiation with or without concurrent androgen deprivation therapy (ADT). Men with recurrent or advanced disease are initially treated with ADT for castrate-sensitive cancer but will require advanced systemic therapies such as novel androgen suppression agents (abiraterone or enzalutamide), immunotherapy, radiopharmaceuticals, or chemotherapy for castrate-resistant metastatic disease. It is estimated that there will be 4 million prostate cancer survivors by the year 2022.[1] Men with localized prostate cancer have a life expectancy of more than a decade,[2] and even men with recurrent or metastatic prostate cancer have life expectancies of 9 and 6 years, respectively,[3,4] making survivorship issues like physical activity important.

The terms “physical activity” and “exercise” are often used interchangeably, but it is important to note that physical activity is broadly defined, referring to all skeletal muscle activities by an individual that result in energy expenditure, whereas exercise is a more specific term encompassing structured, repetitive activity performed with an intent to improve one’s health.[5] This review summarizes studies of both physical activity and exercise that can inform care across the prostate cancer continuum, by answering the following questions:

(1) What is the benefit of physical activity in preventing/delaying prostate cancer progression and improving survival?

(2) What exercise behaviors mitigate the morbidity of treatment across the prostate cancer continuum?

(3) How can we improve the delivery of physical activity and exercise as therapeutic tools?

Physical Activity and Prostate Cancer: Impact on Disease Progression and Survival

The Prostate Cancer Lifestyle Trial suggests that lifestyle changes play a role in preventing disease progression in men with prostate cancer. A total of 93 patients under active surveillance for localized prostate cancer were randomized to an intervention arm (vegan diet, moderate aerobic exercise consisting of 30 minutes of walking 6 days/week, stress management, and supportive care sessions) or a control arm (lifestyle changes recommended by the patient’s own provider). After 2 years, 27% of patients in the control arm underwent further conventional treatment (radiation, surgery, or ADT), compared with only 5% of those in the intervention arm (P < .05).[6] Despite preclinical data suggesting physical activity plays a role in preventing prostate cancer growth by a variety of mechanisms,[7] there is an overall lack of long-term prospective clinical trials examining the effects of physical activity on disease progression and survival.

There are, however, several observational studies (Table 1) indicating that physical activity is associated with reduced disease progression and mortality after a diagnosis of localized prostate cancer.[8-10] Kenfield et al first suggested that physical activity after a prostate cancer diagnosis is associated with reduced mortality; the investigators analyzed questionnaires about leisure-time physical activity that were submitted by 2,705 men from the Health Professionals Follow-Up Study who were alive 4 years after a diagnosis of nonmetastatic prostate cancer.[9] They found that even nonvigorous leisure-time activities such as walking, stair climbing, outdoor work, and weight lifting were associated with mortality benefits. One criticism of the Kenfield et al study[9] is that the observed associations might be due to reverse causation, specifically the fact that mortality is higher in patients with advanced cancer, a population that is inherently more inactive due to disease progression. As a result, the same group examined data from 1,455 men from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database for self-reported physical activity in patients diagnosed with clinically localized prostate cancer; the data also showed physical activity is associated with a decrease in disease progression (identified as biochemical relapse, need for secondary treatments, metastases, or prostate cancer death), an outcome less likely to be subject to reverse causation.[8] Bonn et al recently conducted an observational study of data from a Swedish cohort of 4,623 men; after adjusting for confounding factors, they showed that men diagnosed with localized prostate cancer who self-reported engaging in ≥ 20 minutes of daily walking/bicycling, ≥ 1 hour per day of household work, daily recreational activity (≥ 5 metabolic equivalent of task [MET] hours/day, with MET defined as a rate of oxygen consumption of 3.5 mL/kg/min in adults; see Table 1 for a description of METs), or at least 1 hour of weekly exercise (5.5 METs) had lower mortality.[10] While recognizing that it is difficult to draw conclusions about causation from observational data, these three studies imply that encouraging patients with localized disease to engage in physical activity leads to improvements in prostate cancer progression and survival. It is difficult to make more specific physical activity recommendations for improving disease-specific outcomes in patients after a diagnosis of localized prostate cancer, since the minimum amount of activity associated with benefit varies across these studies.

However, some trends from the observational studies highlighted in Table 1 are important to note. First, some degree of physical activity is likely better than none at all; for instance, after adjusting for confounders, even 5 to < 10 hours per week of nonvigorous activity (< 6 METs) in the study by Kenfield et al[9] and at least 1 hour of daily household activity (~ 2.5 METs) as described in Bonn et al[10] were associated with mortality benefits. These findings suggest that in patients who are not able to undertake vigorous activities, even low-intensity physical activity after a prostate cancer diagnosis might be helpful. The second trend is that accumulating data suggest intensity of activity might be important. For example, in terms of walking behavior, Kenfield et al[9] observed that regardless of patients’ walking duration, mortality was improved by brisk rather than easy-paced walking (hazard ratio [HR], 0.52 [95% confidence interval (CI), 0.39–0.70]), and Richman et al[8] found that the rate of disease progression was lower with brisk vs easy-paced walking (HR, 0.52 [95% CI, 0.29–0.91]). Finally, the Kenfield et al study also suggests that the amount of physical activity matters; although a minimum of 9 MET-hours/week was associated with a mortality benefit, patients engaging in more physical activity of ≥ 24–48 MET-hours/week and ≥ 48 MET-hours/week had progressively higher mortality benefits (P < .001). The benefit of physical activity in improving disease-specific outcomes in patients initially diagnosed with more advanced disease, including metastatic prostate cancer, is yet to be examined. Long-term prospective studies of physical activity and disease-specific outcomes across the prostate cancer continuum are needed before more specific recommendations can be made to patients.

What Exercise Behaviors Reduce Treatment Morbidity in Prostate Cancer?

Exercise to reduce complications of radical prostatectomy

Pelvic floor exercises are hypothesized to improve urinary incontinence after prostatectomy by strengthening supportive muscles around the bladder and preventing urinary leakage. A recent comprehensive Cochrane meta-analysis to assess the effects of conservative management for urinary incontinence after prostatectomy showed mixed results regarding the efficacy of pelvic floor strengthening exercises. While eight trials showed that pelvic floor muscle training provided a benefit in preventing incontinence, there were eight other trials that did not show a clear benefit.[11] Neither pelvic floor strengthening techniques nor aerobic exercise has shown a benefit in improving erectile dysfunction after prostatectomy,[12,13] but increased preoperative physical activity levels have been associated with better quality of life after surgery.[14]

Exercise to alleviate complications during radiation therapy

Fatigue is a major side effect following radiotherapy and presents in 30% to 80% of cancer patients after initiation.[15] The exact mechanism for radiation-induced fatigue is unclear, but in prostate cancer patients radiotherapy may have a systemic effect on neuromuscular efficiency.[16] Three randomized controlled trials (RCTs) showed that aerobic exercise such as regular walking prevents fatigue in men undergoing radiation therapy for prostate cancer.[17-19] In addition to improving fatigue, other benefits of walking interventions shown in RCTs include improvements in physical function, quality of life, cardiac fitness, muscle strength, and flexibility (Table 2). A retrospective analysis of the Windsor et al clinical trial also demonstrated that patients in the walking intervention arm had a decrease in rectal toxicity compared with the control group (P = .004), suggesting that exercise might ameliorate radiation proctitis.[20]

In an RCT, Segal et al first looked at the effects of resistance exercise vs aerobic exercise vs usual care in 121 patients receiving radiation therapy for localized prostate cancer.[21] Of note, 61% of patients in this study were also receiving concurrent ADT. The authors expected that both resistance and aerobic exercise would mitigate fatigue and improve quality of life but would have differing benefits in terms of improving strength and fitness. The results showed that whereas both aerobic and resistance exercise improved short-term fatigue and fitness, resistance exercise also resulted in improvements in long-term fatigue, quality of life, and muscle strength. Table 2 summarizes exercise prescriptions from selected RCTs of patients undergoing radiation therapy, and in general shows that moderate aerobic exercise or a combination of aerobic plus resistance exercise 3 days per week alleviates fatigue and improves other notable patient-reported outcomes.

Exercise to reduce complications of ADT and other advanced systemic therapy

The most well-described benefits of exercise in prostate cancer may be in patients treated with ADT. Patients with localized prostate cancer can be treated with short-term ADT plus radiation therapy, but for men who relapse or have metastatic disease, the ADT treatment duration is usually indefinite (though ADT may be administered intermittently). Surgical castration is an option, but most patients initially undergo chemical castration with gonadotropin-releasing hormone agonists,[22] which can result in metabolic changes like insulin resistance, cardiovascular effects, muscle and bone loss, fatigue, diminished sexual health, and hot flashes.[23] Decreases in muscle strength and bone loss often parallel a decrease in physical functioning, which is associated with an increased risk of falls and fractures.[24] A systematic review indicated that exercise improves strength, cardiorespiratory fitness, functional tasks, lean body mass, and fatigue in men undergoing ADT.[25] More recent RCTs also proposed that exercise might improve psychological distress, social function, mental health, sexual function,[26,27] physical disability,[28] and health-related quality of life,[29,30] as well as facilitate skeletal adaptations that could preserve bone density.[31]

Many clinical trials show that a combination of aerobic and resistance exercise is beneficial to patients receiving ADT.[25] However, there is evidence that men who are advised to exercise prefer aerobic exercise to resistance exercise, because they are more familiar with aerobic activity such as walking.[29] Therefore, providers should be aware of the benefit of emphasizing to patients the particular importance of resistance exercise to combat ADT-related muscle loss, a condition that likely contributes to fatigue, decreased physical function, and falls.[32] Several RCTs looked specifically at the role of resistance exercise during treatment with ADT (Table 3). Two of these studies showed resistance exercise improved both muscle strength and fitness compared with the control arms, which performed stretching exercises[28] or no exercise (with patients randomized to an exercise waiting list).[33] Two more RCTs indicated that resistance exercise mitigates loss in lean body mass, compared with aerobic exercise, and also might be associated with benefits in quality of life.[29,34] Resistance exercise could be especially important in men receiving novel androgen-directed therapy, since complications related to muscle loss are likely more significant than those associated with conventional ADT.[35] For instance, abiraterone is shown to cause considerable muscle loss within 6 months of treatment,[36] and enzalutamide is linked to a significant rate of falls.[37]

Given the heterogeneity of clinical trials in regard to the duration, type, frequency, and degree of supervision with exercise prescriptions, it is difficult to formulate a standard exercise prescription for patients on ADT. Incorporating brisk aerobic exercise and resistance exercise programs involving all major muscle groups several days per week appears to be of benefit.[25] Patients with bone metastases should be cautioned about fracture risk, but with proper guidelines or supervision, exercise is generally considered safe in patients with prostate cancer.[25,38,39] The role of exercise in mitigating morbidity from other advanced systemic treatments for metastatic prostate cancer, including next-generation androgen suppression therapies (abiraterone or enzalutamide), immunotherapy, radiopharmaceuticals, and chemotherapy, is still being explored and represents an important knowledge gap.

Exercise for prostate cancer patients after completion of treatment

Patients who complete treatment for prostate cancer often experience significant long-term side effects, including fatigue and physical disability. Furthermore, men with prostate cancer are often sedentary after treatment. In a study by Galvão et al, 100 prostate cancer survivors previously treated with radiation and ADT were randomized to a 6-month supervised resistance-plus-aerobic exercise intervention followed by a 6-month unsupervised home maintenance program, or a control group receiving only printed educational materials.[40,41] Benefits in the intervention arm included improvements in physical and social functioning, health-related quality of life, cardiorespiratory fitness, and muscle strength. Prostate cancer survivors-especially those who are sedentary or fatigued, or have reduced physical functioning-should be assessed and considered for exercise interventions even after completing active treatment.

How Can We Improve the Delivery of Physical Activity and Exercise as Therapeutic Tools?

As the body of evidence for the benefits of physical activity and exercise grows, we need to improve the mechanisms for delivering physical activity and exercise as therapeutic tools. Because many patients may not be able to afford or access supervised programs, delivery of physical activity and exercise will need to be made scalable from the supervised environments of most clinical trials to home-based programs. Therefore, providers need to be aware of strategies to encourage physical activity and exercise in the clinic.

Addressing physical activity can take just a few minutes of a busy provider’s time. Providers need a general framework in which to structure conversations with patients about physical activity. One approach is to follow the “5 A’s” checklist (ask, advise, assess, assist, and arrange), which has an evidence base in the setting of smoking cessation and is beginning to be applied to conversations related to physical activity (see Table 4).[42] This involves asking patients about their physical activity, advising patients to stay physically active with a strong recommendation, assessing a patient’s current willingness to be more active, assisting him in taking steps toward achieving activity goals, and arranging a follow-up time to discuss goals.

Providers should make it a point to ask about physical activity during clinic visits. However, it can be difficult to quantify a patient’s level of physical activity based solely on inquiry from the healthcare provider. The American Heart Association has published a scientific statement on the assessment of physical activity.[43] Methods of assessing physical activity are categorized broadly into subjective methods (questionnaires) or objective methods (heart rate monitors, pedometers, wearable accelerometers [eg, those made by Fitbit, Jawbone, Misfit, etc], and direct observation). Validation studies generally show that subjective questionnaires are the easiest tools to implement, and tend to correlate better with quantifying moderate to intense activities rather than light-intensity activities.[43] Global physical activity questionnaires are short and simple surveys that provide a quick overview of physical activity behavior, especially when providers feel that time constraints prohibit discussion of physical activity with prostate cancer patients.[44] Well-known global physical activity questionnaires that estimate activity in MET-hours/week include the Godin Leisure-Time Exercise Questionnaire (based on responses to four questions) and the European Prospective Investigation into Cancer (EPIC)-Norfolk Physical Activity Questionnaire (also a four-question survey). The Exercise Vital Sign (EVS) is a more recent two-item questionnaire that takes less than 1 minute to complete (Table 4); the answers to the two questions in this survey are multiplied together to estimate the number of minutes of “moderate to strenuous” activity performed per week.[45] This survey was administered to a large group of patients (> 1.7 million) and was used to classify patients into groups who were not active (0 minutes of exercise per week), insufficiently active (0 to < 150 minutes of exercise per week), or sufficiently active (≥ 150 minutes of exercise per week). This survey is acknowledged for its simplicity and discriminate validity, with the ability to identify particularly inactive vs active groups of patients. Although not validated specifically in patients with prostate cancer, it provides a rapid assessment tool for providers to begin asking patients about, and quantifying, their activity. Another novel aspect of this tool is that it was built in an attempt to standardize physical activity assessment and streamline it into clinical practice, given that it was designed to automatically incorporate patient answers into the vital sign assessments (ie, appearing next to blood pressure, heart rate, and body mass index) in their electronic medical record.

Asking about and quantifying physical activity behavior is the important first step. The next step involves advising patients on the importance of physical activity. A lack of patient education is shown to be a barrier to physical activity in men with prostate cancer.[46] When patients hear about the importance of physical activity from their provider, they are more likely to try to become active. When providers do not address it, patients do not think it is important. Providers can reinforce their message by giving patients simple printed educational materials highlighting the benefits of exercise and safe ways to initiate exercise; examples of useful educational materials available online are guidelines published by the National Comprehensive Cancer Network and the American Cancer Society.[47,48] At Duke, we have created a patient education handout (called “Start Moving and Feel Better!” and included in this article) to provide guidance about physical activity and exercise following a diagnosis of prostate cancer.

After giving advice to be active, providers can assess to what degree an individual patient with prostate cancer wants to be more physically active. Depending on how he answers, providers can assist in discussing how to increase motivation to be more active (if he does not want to be more active) or in planning how to be more active (if he wants to increase his activity level). Eliciting motivation to change and helping patients to articulate and resolve their own ambivalence is a motivational interviewing strategy that is more effective than direct persuasion in promoting physical activity.[49] In the past decade, motivational interviewing has become a standard of care for behavior change counseling in primary care and is recommended by several expert committees as the gold standard for counseling about behavior change.

When patients are interested in exercising, referral to a supervised exercise program is ideal, and when feasible, is often preferred by patients and providers.[44] Otherwise, having knowledge of behaviors that help promote and maintain physical activity will allow providers to help patients to be active. A recent Cochrane review suggests that exercise interventions that encourage cancer patients to set goals, prompt practice, self-monitor physical activity, and develop techniques to generalize behavior from supervised to unsupervised settings may be more likely to promote habitual exercise.[50] A novel method to promote self-monitoring of physical activity, which predicts behavior change, is to use commercially available electronic activity trackers made by companies such as Fitbit, Jawbone, Misfit, or others. These devices are easily worn accelerometers (wrist bands, clips, necklaces, etc) that can continuously monitor motion and often automatically provide feedback (via Bluetooth) to a patient’s smartphone or computer; importantly, they can be programmed to motivate people to stay active. A recent study found that 13 commercially available electronic activity trackers had incorporated at least 5 to 10 out of 14 important behavioral factors known to promote physical activity-including self-monitoring, goal setting, and feedback.[51] These devices do, however, need proper validation for routine clinical use in patients with prostate cancer. Another novel method of promoting behavior change may be action-oriented community activities such as community-based soccer games, recently shown in an RCT to be effective in mitigating side effects of ADT.[52] Providers should also be aware of other comorbid medical conditions to address, such as depression, anxiety, and incontinence, which have been linked to inactivity in patients with prostate cancer.[46,53] Finally, providers should arrange a follow-up meeting with the patient to discuss setting physical activity goals to be evaluated at future clinic visits.

In summary, there is ample evidence suggesting that physical activity and exercise can be therapeutic tools for patients with prostate cancer. Patients diagnosed with localized disease should be advised to stay physically active; furthermore, patients who are undergoing radiation therapy and/or treatment with ADT appear to benefit from regular aerobic and resistance exercise to alleviate side effects. Patients who are willing and able to engage in a supervised exercise program should be referred to do so. In the meantime, providers need to know how to discuss physical activity in the clinic and should continue to develop novel strategies to improve the delivery of physical activity, so patients can enjoy the many benefits of exercising and staying physically active.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgments:Dr. Zullig is supported by a VA Health Services Research and Development (HSR&D) Career Development Award (CDA 13-025).

The authors are grateful to Laura Fish, PhD, and Katherine Zeph, from the Duke Cancer Institute’s Behavioral Health and Survey Research Core, for their assistance in developing the patient handout. Dr. Fish and Ms. Zeph also provided help with literacy level testing and pilot testing the handout for readability, using several test subjects.

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