A phase II RCT and economic analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy

Prostate Cancer (PC) is the leading cancer diagnosed in North American men [1,2]. With improvements in early diagnosis and treatment, survival has been steadily increasing for this population [2]. One common treatment for men diagnosed with PC is androgen deprivation therapy (ADT), which is estimated to be used in 45% of men with PC [3,4]. Common side effects from ADT are fatigue, decreased muscle strength and cardiorespiratory function, loss of sexual functioning, mood changes, changes in body composition and negative effects on health-related quality of life (QOL) [5-8]. These changes often lead to a decrease in overall physical functioning and individual well-being [6,9]. Modifiable factors that can limit the burden of ADT need to be identified.

Exercise in the form of both resistance and aerobic training provide benefits for individuals with PC on ADT. In a randomized controlled trial (RCT), Segal et al. [10] found improvements in fatigue in the exercise group compared to a worsening of fatigue in the control group. Improvements in QOL were also noted following this in-center, structured exercise program [10]. Galvao et al. [11] found improvements in muscle strength following a 20-week resistance and endurance training program [11]. Improvements in 6-minute walk tests, stair climbing and chair rise fitness measures were also observed. In another study, Galvao et al. found significant improvements in the general health and physical health composite scores on the Medical Outcomes Study 36-item questionnaire (SF-36) for participants who completed a 12-week aerobic and resistance exercise program, compared to usual care [12].

These trials and others have been included in multiple systematic reviews of exercise interventions for individuals on ADT for PC. These reviews have found that, generally, exercise is safe and feasible, and exercise interventions are associated with multiple benefits for this population [9,13-16]. For example, Baumann et al. concluded that exercise interventions led to improvements in fatigue levels, muscular strength, flexibility, aerobic fitness, QOL, and well-being [9]. Santa Mina et al.’s review also found similar results regarding physical functioning and QOL outcomes with the additional finding that exercise program supervision by a certified professional was an important factor in achieving greater health benefits [14]. Altogether, findings from these reviews provide strong evidence of exercise benefits for patients on ADT.

Of interest, Thorsen et al. noted that in two of the studies reviewed, older age was associated with lower levels of participation intention [13]. This may be particularly important since PC is predominantly an older person’s disease, and aging itself is associated with multiple functional declines and sarcopenia [17].

While the most consistent benefits of exercise interventions in men on ADT have been seen with 1:1 supervised programs [15], few studies have directly compared exercise delivery methods. The systematic review by Keogh et al. noted significantly greater improvements in outcomes (physical functioning and QOL) for individuals in group-based supervised training vs. home-based training [15]. However, three important things should be noted. First, the noted improvement with group-based training compared to home-based training was based on indirect study comparisons. Second, home-based training provided significant pre-post increases in aerobic endurance and reduced fatigue. Third, only one RCT has directly compared multiple exercise delivery methods, comparing only 1:1 and group supervised training, but with a small sample size and without a home-based arm [18]. Because in-center, supervised, exercise programs are resource-intensive (and largely inaccessible), the demonstration of similar efficacy in home-based programs to these supervised programs would have important health service delivery implications and economic benefits and may help expand exercise delivery options for men on ADT.

It is also clear that the benefits obtained from an exercise program are maintained only as long as the exercise is maintained; therefore ensuring long term adherence to exercise programming has significant health implications. In RCTs of exercise in PC, adherence responses to exercise interventions are moderate to high but vary by protocol design. Supervised exercise intervention adherence ranged from 79% to 95% (as assessed by attendance at scheduled sessions) in three studies [10,19,20], whereas in a study of group-based training the attendance-based adherence was 94% [11,12]. In three home-based studies, the adherence ranged from 77% to 100% (assessed by way of patient reporting, booster session attendance or weekly group session attendance) [21-23]. In spite of a moderate to high level of adherence for exercise intervention across multiple delivery approaches, only Culos-Reed et al. [21] directly measured changes in activity levels (decreased in strenuous physical activity, however mild and moderate physical activity stayed relatively the same) from post-intervention to subsequent follow-up assessment. Additionally, follow-up assessments of fitness outcomes following the post intervention assessment [20-23] are rarely reported. However, when reported longer-term benefits vary, such that there is evidence of maintenance of intervention-based improvements at 6 months follow up in one study [20] whereas no differences in fatigue levels were found from baseline to the end of a 4-week intervention and again 4 weeks later, between the control and exercise groups [23].Follow-up data post-intervention were not obtained or reported in four of the above studies [10,12,19,22].

Even though multiple rigorous studies have demonstrated improvements in several health outcomes with an exercise intervention, exercise in the oncology setting remains unfunded in most countries by health insurance programs (public and private) and organizations. This contrasts sharply with cardiovascular rehabilitation, which is publicly funded in many jurisdictions, in part due to more advanced, robust evidence demonstrating cost-effectiveness. Indeed, in today’s fiscally strained funding environment, there is an increasing emphasis on demonstrating value (or return) on investment. Demonstration of the cost-effectiveness of exercise programs for men on ADT could lead to larger scale implementation of these programs.

Thus, the primary aims of this phase II non-inferiority RCT are:

This trial is taking place at two experienced academic tertiary care Canadian centers – the Princess Margaret Cancer Centre (Toronto, Ontario), and the Tom Baker Cancer Centre, (Calgary, Alberta). Ethics approval has been obtained at both institutions. All study participants provide written informed consent prior to study enrolment. The trial has been registered at clinicaltrials.gov (Registration # NCT02046837).

Increasing amounts of data from well-designed intervention studies have demonstrated statistically and clinically significant gains in fitness and QOL outcomes with exercise-based interventions [16]. The most robust data support 1:1 supervised programs, but these are resource-intensive and largely inaccessible to most patients. Whether group-supervised or home-based programs, both of which are likely significantly less resource-intensive and more feasible to implement, are equally effective as 1:1 supervised programs remains unclear. Altogether, wider adoption of exercise programs is important as the status quo of the majority of men treated with ADT is that they remain physically inactive and at risk of multiple potentially avoidable side effects [13,61,62]. In addition, longer-term adherence, after completion of acute training programs, is key to ensuring ongoing health benefits, yet few data have been published examining longer-term follow-up adherence with any exercise delivery model. Moreover, little is known about factors predicting long term adherence; such information can be used in enhancing longer-term exercise programming effects. Hence, the goals of this study are a better understanding of health benefits (QOL, physical fitness, and other clinically relevant endpoints) provided through three varying exercise delivery models that include evaluation of the cost-effectiveness of program provision (for men on ADT for PC), and adherence associated with each approach (during and after the formal six-month intervention period).

The current study is designed to address important limitations in prior studies and advance the science of exercise delivery for men on ADT. First, this study is directly comparing the three main exercise delivery models to identify whether less resource-intense approaches are as efficacious as the reference standard of supervised personal training. Second, adherence will be carefully studied during and, more importantly, after the formal six-month intervention period. Moreover, insights will be gained into enabling factors and barriers to exercise adherence. Third, we will formally begin to evaluate the cost effectiveness of each exercise delivery model; such information should ultimately inform health policy. Additional innovations include structured exercise tapering (to facilitate independent exercise), introduction of a smartphone app and health coach support to enhance home-based exercising, and other features.

The evidence-based knowledge gained with this research will provide an understanding of the best (clinically effective, high adherence, cost effective) exercise program for this population and will help strengthen research in this field. Although the results from the phase II trial will not be definitive, this step is foundational and the knowledge that will be generated will be incorporated into the design and execution of a multi-center phase III RCT.