The role of physical activity and structured exercise for physical fitness and immune function in men on androgen deprivation therapy for prostate cancer

Metastatic prostate cancer is commonly treated with androgen deprivation therapy (ADT). While ADT effectively slows disease progression, it is associated with severe adverse effects, including musculoskeletal, cardiovascular and metabolic impairments, that compromise the physical fitness and function. The physical decline may be aggravated in advanced disease by the use of secondary treatments, such as androgen receptor inhibitors (ARI). Physical activity has been identified as a modifiable lifestyle factor, with benefits for physical health, prostate cancer progression and survival. These effects may be partially modulated by an anti-inflammatory immune response that is stimulated as a result of muscle activation. Structured exercise in particular is thought to promote favourable health outcomes, including fitness improvements and reductions in systemic inflammation, but studies have reported conflicting results of exercise interventions during ADT. Overall, the physiological adaptations and, particularly, the immune response to physical activity and exercise in the context of ADT are not well understood. The aim of this thesis was therefore to analyse associations of habitual physical activity with physical fitness and immune function in men treated with ADT for prostate cancer, and to investigate changes in physical fitness and immune function following a chronic, structured exercise intervention.
Two cross-sectional studies were performed using baseline data from participants of a multi-centre, randomised, controlled trial for men with advanced metastatic prostate cancer treated with ADT. Study 1 examined levels of self-reported physical activity and adherence to physical activity guidelines, as well as the association between self-reported physical activity with fitness outcomes, in a large multi-centre sample (140 participants). Study 2 expanded on this analysis by investigating levels of accelerometer-derived physical activity, determining their agreement with self-reported estimates, and analysing the association of accelerometer-derived physical activity with physical fitness and immune parameters in a German subsample (27 participants). Both studies included a between-group analysis of physical activity and fitness according to ARI use. Additionally, a longitudinal study (Study 3) of data collected at the baseline and 6-month testing visits of the trial was performed, which analysed changes in physical fitness and immune parameters in participants completing a structured exercise programme of aerobic and resistance exercise compared to the control arm (19 participants; 8 intervention, 11 control).
Habitual physical activity levels were below the recommended level according to self-reported estimates, with only 29% of participants adhering to the guidelines for aerobic physical activity, whereas accelerometer-derived physical activity estimates demonstrated substantially higher physical activity levels. The agreement between the two measurement methods was poor. Higher levels of self-reported moderate-to-vigorous physical activity (MVPA) were significantly associated with a higher maximal oxygen consumption (VO2peak)
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and a faster 400 m walk time in non-users but not in ARI users. Accelerometer-derived data confirmed the association between MVPA and walk time, but showed that VO2peak was positively associated with light activity and not MVPA. There were no associations between strength outcomes for self-reported MVPA, although higher accelerometer-derived light activity and MVPA were linked to increased maximal strength of the lower body. Among immune parameters, higher light physical activity was associated with decreased monocyte and increased regulatory T cell proportions, while decreased sleep time was associated with increased neutrophil proportions.
After 6 months of the structured exercise intervention, maximal lower body strength increased in the intervention arm, while handgrip strength increased in both arms, with a larger effect in the intervention arm. Aerobic fitness outcomes and blood levels of immune parameters remained mostly unaltered except for an increase in lymphocyte proportions, with no differences observed between the intervention and control arm. Regarding the effects of exercise dose, higher levels of completed aerobic exercise were associated with lower natural killer cell counts in the intervention arm. Overall, the uptake of the exercise intervention varied substantially, with the highest adherence noted for resistance exercise.
The results of this thesis indicate that higher habitual physical activity and reduced sedentary behaviour are associated with improved physical fitness in men with advanced prostate cancer. Furthermore, the findings suggest a potential decrease in systemic inflammation, as demonstrated by reduced blood levels of tumour-promoting monocytes, in more active men. Treatment with ARIs may attenuate the benefits of physical activity, although the findings regarding their effects on physical activity levels and fitness outcomes are inconclusive. Because older cancer survivors spend a large share of their time performing habitual, low intensity activities that are disproportionately affected by recall bias, self-reported data may provide biased estimates and objective measurement methods may be more suited to capture this activity. Nonetheless, baseline physical activity levels, especially resistance exercise participation, were concerningly low in some participants. Interestingly, after 6 months of the structured exercise intervention, the highest adherence was recorded for the resistance exercise prescription. This indicates that men with advanced prostate cancer, despite compromised bone and muscle health, are able to perform intense resistance exercise, which is in turn associated with benefits for neuromuscular fitness. Finally, the chronic exercise programme elicited minimal changes in circulating immune parameters, and their significance for the anti-tumour immune response in prostate cancer remains to be investigated.