In this population of men with PCa, men who exercised for ≥ 9 MET-h/wk had a 33% lower risk of death from any cause and a 35% lower risk of PCa-specific death, after adjustment for other risk factors for mortality and prediagnosis physical activity. Both nonvigorous activity and vigorous activity were associated with lower all-cause mortality. Only vigorous activity was associated with reduced PCa mortality, with a suggestion of a reduced risk for longer duration of brisk walking.
We considered the possibility that this association might be caused by undiagnosed metastatic cancer inducing a reduction in physical activity (reverse causation) and addressed this issue by excluding men with metastases at diagnosis and up to 2 years after their first postdiagnostic activity assessment and men who died within 4 years of this assessment. Additionally, we used activity information 4 to 6 years before death. The median time from metastasis to PCa death was 2.1 years, and the median time to death from other causes was also 2.1 years. This suggests that using activity information 4 to 6 years before death avoids much of the potential effect caused by reverse causation. Results were not materially different when using a longer lag time. On the basis of the analysis evaluating change in activity, the degree of reverse causation may not be severe because most of the reduction in risk was a result of men who were consistently high in activity or had moved from a lower category to the highest category and not mainly a result of an excess risk from men who reduced their activity. Additionally, in a sensitivity analysis in which we stopped updating activity before a diagnosis of metastasis, the results remained unchanged (data not shown).
Activity was self-reported and limited to a subset of common activities. However, this physical activity assessment has detected other well-established activity-disease relationships in cardiovascular disease8,9
In addition, our population is homogenous by profession, so leisure time activity will capture most between-person variation in physical activity. Our physical activity assessment is a better measure of vigorous activity than nonvigorous activity10
; nevertheless, we still observed a significant trend with increasing nonvigorous activity for all-cause mortality.
No prior studies have evaluated the relationship between physical activity after diagnosis and survival in men with PCa, but incidence studies suggest that vigorous activity could reduce risk for fatal disease. We previously reported a significant association between high levels of vigorous activity and reduced risk of advanced PCa in men age 65 years or older,7
and several recent cohort studies support an association of recreational or occupational activity with reduced risk of advanced and fatal disease.19–21
Patel et al19
reported a significant 31% reduction in risk of aggressive PCa among men engaged in more than 35 MET-h/wk of activity compared with men reporting no activity, whereas Johnson et al21
reported no association for leisure time activity but a significant inverse association with advanced disease for manual occupational activity in the European Prospective Investigation Into Cancer and Nutrition (EPIC) cohort. Levels of leisure activity were much higher in EPIC compared with our study, with half of the men having ≥ 43 MET-hours of leisure activity per week, reducing the exposure contrast compared with our population.
Physical activity may affect cancer progression and mortality through the insulin/insulin-like growth factor (IGF) axis. The binding of IGFs and insulin to their receptors can influence cell proliferation, differentiation, apoptosis, adhesion, migration, and angiogenesis.22
Physical activity increases insulin sensitivity and may affect IGF-1 bioactivity. Ma et al23
reported that men in the highest quartile of prediagnostic plasma C-peptide (a marker of insulin production) had a 2.4-fold higher risk of dying from PCa compared with men in the lowest quartile. Laboratory studies have reported that exercise resulted in lower serum insulin and IGF-1 and higher IGF binding protein-1 compared with controls, and the serum from men engaged in regular aerobic exercise reduced cell growth, induced apoptosis, and increased p53 protein content in serum-stimulated LNCaP cells in vitro.24,25
Physical activity lowers inflammatory factors, increases anti-inflammatory cytokines, and inhibits the production of proinflammatory cytokines.26–29
In a 12-month randomized controlled trial of a physical activity intervention among elderly persons, Nicklas et al30
reported significantly lower circulating levels of inflammatory cytokine interleukin-6. Strong evidence supports a role of chronic inflammation in prostate carcinogenesis,31
and the degree of inflammation in prostate tumors32
and specific inflammatory markers33
are associated with progression and can improve prediction for biochemical progression.34
Stark et al35
reported that in men with a BMI less than 25 kg/m2
, those with the highest level of IL-6 had an HR of 1.73 (95% CI, 0.86 to 3.51; Ptrend
= .02) for increased risk of lethal PCa compared with men with the lowest IL-6 level. Physical activity also increases adiponectin levels, which has anti-inflammatory and mitogenic actions,36
and men with the highest compared with lowest quintile of adiponectin concentration had a 61% lower risk of PCa mortality (HR, 0.39; 95% CI, 0.17 to 0.85; Ptrend
Physical activity also affects the innate immune system.38
Exercise in patients with breast cancer was associated with improved natural killer cell cytolytic activity,39
and proportion of circulating granulocytes.40
Physical activity may also affect tumor angiogenesis.41
Although previous studies have focused on physical activity and improvement in fatigue, physical functioning, and quality of life,42
we focused on physical activity after PCa diagnosis in relation to overall and PCa-specific mortality. The findings are based on prospective data, with activity data collected every 2 years, before and after diagnosis. Lastly, we had an adequate number of PCa deaths to evaluate this outcome after excluding participants who died within 4 years of diagnosis.
In conclusion, our results suggest that among men with PCa, moderate physical activity may improve overall survival, whereas a greater amount of activity is necessary to improve PCa-specific survival. A modest amount of vigorous activity such as biking, tennis, jogging, or swimming at levels of ≥ 3 h/wk may substantially improve PCa-specific survival. Mechanistic studies and randomized trials of physical activity interventions are needed in PCa survivors to determine whether physical activity reduces PCa progression and what regimens are optimal.