Physical activity and dietary considerations for prostate cancer risk

The 2018 Physical Activity Guidelines Advisory Committee Scientific Report chapter on cancer⁽⁶⁾ was informed by a systematic review, which synthesised current evidence on exercise and risk of the common cancers^{(Reference McTiernan, Friedenreich and Katzmarzyk7)}. Although there is evidence that habitual physical activity is associated with a 12–25 % reduced risk of seven cancer types, there is no convincing evidence of an inverse association between a physically active lifestyle and risk of developing prostate cancer. A systematic review and meta-analysis of forty-eight cohort studies and twenty-four case-control studies also reported no clear association between habitual physical activity and prostate cancer risk, with point estimates for individual studies indicating risk reductions and increased risk^{(Reference Benke, Leitzmann and Behrens8)}. However, supplementary data from this meta-analysis showed that long-term (>10 years), occupational physical activity significantly reduced total prostate cancer incidence by 17 % and long-term recreational physical activity significantly reduced the risk of advanced prostate cancer by 25 %^{(Reference Benke, Leitzmann and Behrens8)}. As these results were based on a relatively low number of studies, more research is needed to consolidate these findings.

Regarding dietary influences on risk, the World Cancer Research Fund and American Institute for Cancer Research Continuous Update Project focuses on associations between exercise, diet and cancer risk. Although their previous report^{(Reference Wiseman9)} suggested that diets high in calcium increased prostate cancer risk, in their most recent update, the Expert Panel concluded there was no strong evidence linking any individual food group to the risk of prostate cancer⁽¹⁰⁾. However, the report did state there was limited, but suggestive evidence that dairy products, diets high in calcium and low plasma alpha-tocopherol or selenium concentrations may increase risk, but with further research on these dietary constituents being required. The report also found a significant link between prostate cancer risk and BMI, which has dietary implications, with each additional 5 kg/m² BMI increment increasing the risk of advanced prostate cancer by 8 % and prostate cancer mortality by 11 %. The World Cancer Research Fund and American Institute for Cancer Research dietary recommendations⁽¹⁰⁾ are therefore mainly focused on helping individuals maintain a healthy weight, as a result of consuming a diet high in wholegrains, vegetables, fruits and beans, reducing the consumption of sugar-sweetened drinks, and avoiding processed foods high in fat or sugar.

Overall, while current evidence suggests that exercise and dietary habits may not directly lower an individual's risk of prostate cancer, an active lifestyle and healthy eating behaviours increase the likelihood of maintaining a healthy weight and, therefore, could indirectly reduce the risk of advanced prostate cancer, and potentially have important implications for prostate cancer survival.

Physical activity and dietary considerations for prostate cancer survival

Previous research^{(Reference McTiernan, Friedenreich and Katzmarzyk7,Reference Richman, Kenfield and Stampfer11,Reference Friedenreich, Wang and Neilson12)} has suggested there may be a link between physical activity and survival outcomes for prostate cancer patients. A prospective study of 1455 prostate cancer patients found patients who completed brisk walking for >3 h per week had a 57 % lower rate of disease progression than patients who walked at an easy pace for <3 h per week^{(Reference Richman, Kenfield and Stampfer11)}. Other research has reported similar findings, with prostate cancer patients in the highest quartile of postdiagnosis physical activity having a 42 % reduced risk of all-cause mortality compared with the lowest quartile^{(Reference Friedenreich, Wang and Neilson12)}. Furthermore, a review found a 38 % reduction in risk of prostate cancer mortality for men in the highest physical activity category compared with the lowest^{(Reference McTiernan, Friedenreich and Katzmarzyk7)}. One limitation of cohort studies which investigate links between physical activity and survival is the possibility of reverse causation. This is where patients with a higher disease burden who have a lower expected survival time are unable to engage in physical activity due to the more severe symptoms they are experiencing. To reduce the risk of reverse causation, it has been recommended to use disease progression rather than mortality as an outcome measure^{(Reference Richman, Kenfield and Stampfer11)}.

The importance of regular physical activity for prostate cancer patients is highlighted in current recommendations for cancer patients published by the American College of Sports Medicine^{(Reference Campbell, Winters-Stone and Wiskemann13)}. Their review of previously published evidence concluded that participation in structured exercise was safe for prostate cancer patients, and details the amount and type of exercise that should be completed to improve specific health outcomes. Their overall recommendation is that cancer patients should complete moderate-intensity aerobic activity for ≥30 min at least three times per week, along with at least two resistance exercise sessions per week, using at least two sets of 8–15 repetitions at 60 % of one repetition maximum or above, for at least 8–12 weeks. This recommendation is for all cancer patients, although it recognises that potential adaptions may be required for specific subgroups. For example, patients with bone metastases will require modifications to their exercise programmes to reduce fracture risk. Despite these recommendations, and the link between a physically active lifestyle and survival, a survey of prostate cancer patients found that 47⋅5 % were completing no moderate or vigorous physical activity^{(Reference Galvão, Newton and Gardiner14)}. This highlights the need for interventions that promote and provide support for long-term physical activity behaviour change.

Studies investigating the relationship between dietary behaviours and prostate cancer survival have also reported some interesting associations. For example, prostate cancer patients in the highest quintile of vegetable fat consumption had a 29 % lower risk of lethal prostate cancer and a 26 % reduced risk of all-cause mortality, while adherence to a Mediterranean diet after diagnosis reduced overall mortality risk by 22 %^{(Reference Richman, Kenfield and Chavarro15)}. Moreover, a review suggested several dietary factors, including coffee, cruciferous vegetables and vegetable fats, may reduce the risk of prostate cancer progression by up to 59 %^{(Reference Peisch, Van Blarigan and Chan16)}. However, further research is required to corroborate these findings and determine the optimal diet for improving prostate cancer survival outcomes.

As for primary prevention, a potential mediator of reported associations between habitual physical activity, diet and prostate cancer survival is the effect of exercise and healthy dietary behaviours on body weight. A recent review found that a postdiagnosis weight gain of >5 % body weight was associated with a 65 % increased risk of prostate cancer mortality, and 27 % increased risk of all-cause mortality, when compared with stable weight patients postdiagnosis (<3 % increase)^{(Reference Troeschel, Hartman and Jacobs17)}. Therefore, physical activity and dietary behaviours, which help to promote a healthy body weight (i.e. reduce the amount of excess body fat), after diagnosis may be important for improving patient survival outcomes.

Physical activity and dietary considerations for the quality of prostate cancer survivorship

Due to the high survival rates for prostate cancer, it is important to consider long-term health and wellbeing. One of the most common treatments is androgen deprivation therapy (ADT), which is given to 38⋅4 % of non-metastatic prostate cancer patients globally, but with the UK rate at 54⋅6 %^{(Reference Liede, Hallett and Hope18)}. The aim of ADT is to inhibit the effect of hormones such as testosterone on prostate cancer cell growth^{(Reference Ridgway and Aning19)}. Current guidelines published by the National Institute for Health and Care Excellence recommend that ADT may be used as an individual treatment to control prostate cancer growth, or in combination with other treatments such as radiotherapy with a curative intent⁽²⁰⁾.

While ADT is an important treatment for controlling prostate cancer progression, it has side-effects which may reduce a patient's lifespan and health-related quality of life (HR-QoL). There is evidence of elevated cardiovascular risk for men receiving ADT, with a review of over 22 000 ADT patients finding a 20 % higher risk of cardiovascular morbidity than prostate cancer patients who did not receive ADT^{(Reference Saigal, Gore and Krupski21)}. However, this elevated risk has not been found in all studies^{(Reference Nguyen, Je and Schutz22)} and may depend on the type of ADT received^{(Reference Perrone, Degli Esposti and Giacomini23)} or confounding influences, including lifestyle behaviours. Men receiving ADT also frequently report increased feelings of fatigue unrelated to recent activity levels and hot flashes^{(Reference Langston, Armes and Levy24,Reference Nguyen, Alibhai and Basaria25)} . An elevated risk of sexual dysfunction, diabetes, bone fractures and dementia have also been reported v. men who receive active surveillance, with the risk of sexual dysfunction increasing further when ADT is combined with radiotherapy and surgery^{(Reference Nguyen, Lairson and Swartz26)}.

Another important side-effect of ADT is the adverse impact it has on body composition, including an increase in body weight associated with accumulation of body fat, often accompanied by a reduction in lean body mass (i.e. bone mineral density and skeletal muscle mass)^{(Reference Galvão, Spry and Taaffe27)}. A loss of lean body mass in older men may increase their risk of falls and fractures, impairing their ability to perform daily activities and resulting in a loss of functional independence^{(Reference Wong, Wong and Zhang28)}. Furthermore, older age might augment the effect of ADT on skeletal muscle mass. A longitudinal study showed that men on ADT aged >70 years lost 2⋅8 % of their lean body mass over a 3-year period, compared with a 0⋅9 % loss for men <70 years of age^{(Reference Smith, Saad and Egerdie29)}. Importantly, men who were within their first 6 months of ADT at the start of the study also lost significantly more lean body mass than men who had already been on ADT for longer than 6 months (3⋅7 v. 2⋅0 %, respectively). These data suggest that men over 70 years, who are starting ADT could be particularly vulnerable to losing lean body mass. Strategies aimed at preserving lean mass in newly diagnosed men >70 years starting on ADT could therefore be particularly important for preserving functional independence and HR-QoL.

Studies have found that exercise programmes (aerobic, resistance, combined) can attenuate the effects of ADT on body composition in prostate cancer patients when compared with usual care^{(Reference Cormie, Galvão and Spry30,Reference Wall, Galvao and Fatehee31)} . A meta-analysis of 11 randomised control trials found that participating in an exercise training programme increased whole-body lean mass by a mean difference of 0⋅7 kg, reduced whole-body fat mass by 0⋅67 % and improved aerobic fitness compared with usual care^{(Reference Bigaran, Zopf and Gardner32)}. Similar results have been reported by other systematic reviews^{(Reference Cormie and Zopf33,Reference Edmunds, Tuffaha and Scuffham34)} along with reductions in fatigue^{(Reference Edmunds, Tuffaha and Scuffham34,Reference Bourke, Smith and Steed35)} , and improvements in HR-QoL^{(Reference Cormie and Zopf33,Reference Bourke, Smith and Steed35)} . Collectively, these data highlight the potential benefits of exercise programmes for prostate cancer patients on ADT, in terms of attenuating the adverse effects of treatment on body composition and improvements in HR-QoL. It is important to note that patients are recommended to complete both aerobic and resistance exercise as these may have separate complementary benefits, as well as a combined effect^{(Reference Campbell, Winters-Stone and Wiskemann13)}.

One particularly effective strategy for helping to preserve lean body mass is resistance exercise, which promotes muscle protein synthesis^{(Reference Yarasheski, Zachwieja and Bier36)}. However, this effect may be blunted in older men^{(Reference Fry, Drummond and Glynn37)} and this may explain why previous studies investigating lean body mass using dual-energy x-ray absorptiometry, found no significant benefit of resistance exercise on lean body mass^{(Reference Galvao, Nosaka and Taaffe38,Reference Nilsen, Raastad and Skovlund39)} . For this reason, nutritional strategies such as concurrent protein supplementation alongside exercise may provide an additional anabolic stimulus to enhance muscle synthesis in older individuals^{(Reference Tang and Phillips40)}. Of relevance to prostate cancer patients, a study which investigated the effect of resistance exercise and daily protein supplementation using milk protein concentrate in healthy older men found that this combination led to a 1⋅6 kg improvement in lean mass compared with resistance training alone^{(Reference Tieland, Dirks and van der Zwaluw41)}. Similarly, in prostate cancer patients, an intervention combining resistance and impact exercise with protein supplementation improved total lean body mass by 1⋅0 kg compared with usual care, although only in participants with high adherence to the intervention^{(Reference Via, Owen and Daly42)}. A recent review concluded that protein supplementation is likely to be beneficial for men with prostate cancer, but highlighted the need for future studies to investigate the combination of resistance exercise with protein supplementation^{(Reference Umlauff, Weber and Freitag43)}. While future research is required, the use of protein supplementation alongside exercise provides an example of how exercise and nutrition may be used concurrently as a strategy for reducing the adverse side-effects of ADT, and subsequently preserving a patient's musculoskeletal health, HR-QoL and independence.

An alternative dietary supplement of interest is n-3 fatty acids. It has been proposed that dietary n-3 fatty acids could help to reduce sarcopenia due to their anti-inflammatory effects and their anabolic effects via the mammalian target of rapamycin pathway^{(Reference Dupont, Dedeyne and Dalle44)}. A meta-analysis investigating n-3 fatty acid supplementation in older adults found that it led to skeletal muscle mass gain and improved physical function^{(Reference Huang, Chiu and Hsu45)}. However, these results have not yet been replicated in prostate cancer patients, with previous research only focusing on the effect of n-3 fatty acids on disease progression^{(Reference Zuniga, Chan and Ryan46)}. Importantly, previous research has concluded that daily n-3 fatty acid supplementation of 1 g EPA and 1⋅84 g DHA was well-tolerated and safe, with all adverse events considered minor^{(Reference Aronson, Kobayashi and Barnard47)}. Further research aimed at investigating whether the combination of n-3 fatty acid supplementation and exercise could provide a viable strategy for lean mass preservation in prostate cancer patients on ADT is warranted.

It is important to consider several factors when interpreting current evidence. For example, as previously highlighted, the impact of ADT on lean body mass outcomes is dependent on age and the duration of ADT^{(Reference Smith, Saad and Egerdie29)}. It seems that studies aimed at investigating the effect of physical activity and dietary interventions in older men starting on ADT are warranted, as the impact of ADT side-effects could be more pronounced than those reported for younger men, and men of all ages who have been receiving ADT for some time. However, most existing research has not targeted older men, and very few studies have been focused on newly diagnosed patients starting on ADT. Additionally, although supervised exercise interventions have been shown to be effective in terms of wide-ranging health outcomes, there is also a need for effective home-based, remotely supervised interventions, which may reduce the cost of intervention delivery, and allow access to patients who are unable to attend supervised sessions for logistical reasons^{(Reference Lam, Cheema and Hayden48,Reference Hanson, Alzer and Carver49)} . Future research should investigate ways to safely reduce the amount of exercise supervision via the provision of cost-effective support for long-term behaviour change (maintenance).

In contrast to recently published exercise guidelines for prostate cancer patients^{(Reference Campbell, Winters-Stone and Wiskemann13)}, there are no equivalent dietary guidelines. In a review of potential evidence for dietary guidelines relevant for prostate cancer patients on ADT, it was found that of the sixteen included papers only four examined the effect of a dietary intervention alone, with the other twelve also including elements of exercise, medication or counselling^{(Reference Barnes, Ball and Galvao50)}. This combination of diet with other elements is a common research design, which makes it difficult to isolate the effects of dietary changes. Nevertheless, some small-scale studies have suggested health benefits resulting from specific dietary interventions. For example, a pilot study randomised twenty-three prostate cancer patients to either their usual diet or a Mediterranean diet (low saturated fat, 2 fruit + 5 veg/d, no red meat, 3 weekly fish portions, daily portion of nuts/seeds)^{(Reference Baguley, Skinner and Jenkins51)}. Patients on the Mediterranean diet had improved fatigue, quality of life, lean body mass and total body mass compared with the control group. Similarly, a study which recruited fifty-nine patients found that high-dose vitamin D supplementation (50 000 IU per week above the RDA) improved the bioelectrical impedence ‘phase angle’ of prostate cancer patients, which is a non-invasive technique used to assess functionality and frailty, and with lower phase angle values signalling the onset of functional decline^{(Reference Inglis, Fernandez and van Wijngaarden52)}. However, due to the small sample sizes, further research is required before recommending these dietary changes to prostate cancer patients. Indeed, this is a major limitation of existing nutritional intervention studies, consistent with systematic review evidence, that the majority of studies are either underpowered, at high or unknown risk of bias or too short in duration^{(Reference Hackshaw-McGeagh, Perry and Leach53)}.