There has been a substantial increase in the use of temporary androgen deprivation therapy (ADT) as an adjuvant to radical radiation and surgical therapies for management of prostate cancer[
1,
2] with substantial periods of ADT now routinely applied to improve outcomes at 5, 10 and 15 years post diagnosis[
2‐
4]. More than 2,000 men in Australia[
5] and more than 80,000 in the USA[
6] commence on-going ADT for prostate cancer each year. However, ADT leads to a range of well-established musculoskeletal toxicities including reduced bone mass and increased skeletal fractures[
7,
8] compounded with rapid metabolic alterations including increased body fat, loss of lean mass, insulin resistance and negative lipoprotein profile[
9‐
15]. Recent work, including our own current Australian cohort, suggests an increased incidence of cardiovascular and metabolic morbidity associated with temporary ADT[
16‐
20] and we have also reported significantly increased distress[
21] and reduced quality of life (QOL)[
22,
23]. Our team has shown that even a 9-month exposure to ADT leads to significant reductions in bone mass across different clinical sites concurrent with severe loss of lean mass and increased trunk and whole body fat mass, all surrogate indicators of osteoporosis/skeletal fractures and cardiovascular/metabolic complications[
15]. Currently, there is no established treatment to reverse bone loss and the array of metabolic adverse effects associated with severe hypogonadism from temporary ADT. Preliminary clinical trials by our team[
24‐
26] and others[
27,
28] have suggested high efficacy of exercise for these patients but evidence is limited to only a few studies with men on long-term androgen deprivation[
24,
27‐
29]. We have shown that a combined program of resistance and aerobic exercise leads to a number of significant and clinically meaningful benefits including reversal of muscle loss in men receiving ADT for an average of approximately 14 months[
24]. A critical but as yet unanswered research question is to determine whether it is more efficacious to commence exercise therapy at the onset of androgen deprivation so treatment induced adverse effects can immediately be attenuated or even completely prevented. This has not been addressed in any exercise trials to date and has the potential to prevent much of the ADT toxicities from the outset rather than try to rehabilitate the patient from the effects of long-term ADT later. A recent report[
30] showed that physical function and quality of life are compromised within 3 months of commencing ADT suggesting that up-front exercise interventions are needed to counteract these losses, as well as the marked reductions in bone density and bone strength. Importantly, it appears the initial beneficial effects of resistance and aerobic exercise programs are similar for neuromuscular and physical function regardless of whether patients are on acute (3–6 months) or chronic (>6 months) ADT[
31]. Such preliminary evidence supports the hypothesis that exercise might be best initiated when ADT commences, to enhance physical function, retain structure and improve the patient’s acceptance of hormone therapy. This is an important finding as it suggests that exercise may still benefit men during acute ADT, but no research has trialled this from time zero; that is initiation of ADT. This is a considerable gap in our understanding of the management of prostate cancer and ADT.
Having successfully completed several pilot studies, a randomised controlled trial (RCT) and ongoing RCTs in prostate cancer[
24‐
26,
31‐
34], this trial will drill down to the specifics of exercise as medicine to improve skeletal health, physical function, quality of life and mental health implemented immediately when patients initiate ADT. We propose a RCT with partial crossover to examine the effects of the timing of exercise implementation. We will evaluate the following hypotheses:
1)
It is more efficacious to commence exercise therapy at the onset rather than after six months of ADT; and
2)
ADT side effects, in particular the substantial initial bone loss, can be prevented by a 6-month exercise program concurrently undertaken at the onset of ADT.
The primary endpoint will be spine and hip aBMD determined by DXA. Secondary endpoints will include: 1) volumetric BMD (vBMD) and micro-architecture at the tibia, 2) body composition (lean mass and fat mass/abdominal obesity), 3) blood pathology (glucose metabolism, lipid profile, prostate specific antigen (PSA), testosterone, bone formation and resorption markers), 4) physical function, muscle strength and balance, 5) physical activity level and motivation, and 6) health-related quality of life and psychological distress.
The ultimate outcome will be guidelines for the prescription of exercise for the prevention of ADT toxicities, primarily those related to long-term skeletal health and physical function. This project is unique as it explores a fundamental question of when exercise implementation will be of most benefit to men undertaking ADT. The final outcome may be an adjunct treatment which will prevent major toxicities of ADT, ultimately resulting in reduced morbidity and mortality for men with prostate cancer.