Role of physical activity in cancer prevention: An update

Abstract

Cancer prevention via regular physical activity has been studied across the world. This minireview aimed to present the latest updates in research in the context of the role of physical activity in the cancer prevention. The various mechanisms at the molecular level were studied in depth. The essential processes at play involving hormonal balance, weight reduction, adiposity, inflammation, immunity, sunlight exposure and vitamin D levels and insulin resistance were critically analyzed here. The dose response of exercise with respect to cancer prevention was appraised. Strong evidence supports an inverse relationship between physical activity and cancer risk, particularly for breast, liver, lung and colorectal cancers. There is limited evidence for hematologic, head and neck, ovarian, pancreas, prostate, brain, thyroid and rectal cancer. Prehabilitation plays a key role in tertiary prevention of cancer and patient symptom alleviation. The role of physical activity was studied under the entire cancer continuum, from primary to tertiary prevention. The minireview highlights the need for interventional trials involving holistic methods combing modern and traditional medicine/therapies in cancer prevention.

Key Words: Physical activity; Chronic inflammation; Health related quality of life; Yoga; Prehabilitation; Cancer

Core Tip: Physical activity and cancer are inversely related. Prehabilitation involving of cancer patients is beneficial in improving their health-related quality of life and patient symptoms. There is a need for structured physical activity guidelines for cancer prevention focusing on the entire continuum of cancer. The current literature focusses only on improved patient outcomes and not oncologic outcomes like reduction in cancer incidence. There is a dearth in literature of the role of resistance and balance exercises in cancer prevention. Tailor made protocols involving integrative approach (Yoga, Tai chi) need to be established for different stages of various cancers.

INTRODUCTION

Globally, cancer is a public health concern. The Global Cancer Observatory reports estimate for overall cancer incidence, prevalence and mortality for the World Health Organization-South-East Asia Region as about 2.3 million, 5.4 million and 1.5 million[1]. The prime modalities in conventional treatment for cancer remain anti-cancer drugs, surgery and radiotherapy either utilized solo or in conjunction with each other, on a case-to-case basis[2]. In cancer treatment as well as prevention, the role of traditional and complimentary medicine (TCM) along with physical activity is gaining traction worldwide[3]. Physical activity is an essential lifestyle measure for maintaining optimum health. The World Health Organization (WHO) has defined physical activity as any bodily movement produced by muscles requiring energy expenditure. WHO recommends adults to do at least 150-300 minutes of moderate-intensity aerobic activity, or an equivalent mix of moderate and vigorous intensity activity throughout the week[4]. Regular exercise if incorporated in daily routine can provide the necessary boost to immunity, maintain optimum weight and regulate the hormonal balance in the body. Oncogenesis can be mitigated by choosing a healthy lifestyle that incorporates regular exercise, a balanced diet, avoiding smoking and alcohol consumption. Cancer prevention via regular physical activity has been studied across the world. Exercise downregulates inflammation in the body[5]. This reduces the reactive oxidative stress produced due to various processes like alcohol consumption, stress levels and pollutants. Also aiding in peristalsis, clearing the bowels more frequently thus removing harmful toxins from the body. This minireview aims to present the latest updates in research in the context of the role of physical activity in the cancer prevention.

MECHANISMS

The various mechanisms describe how physical activity preventing cancer (Figure 1).

Figure 1  Mechanisms of action of physical activity in prevention of cancer.

Hormonal balance

It has been studied that prolonged hormonal stimulation of target organs contributes to neoplasia. Joshi et al[6] highlighted the normal growth and function of this organ is controlled by one or more polypeptide or steroid hormones. This includes cancers of the endometrium, breast, prostrate, thyroid, ovary, bone and testis. Estrogen and progesterone are crucial in maintaining the hormonal balance in the female reproductive cycle. Raised levels of these hormones increase the risk of breast cancer[7]. A study from United Kingdom demonstrated that the risk of breast cancer reduced significantly by 9% (P < 0.001) with physical activity[8]. A meta-analysis of prospective cohort studies demonstrated raised levels of these hormones are associated with increased risk of endometrial cancer[9]. Studies have revealed significant reduction in prostate cancer risk associated with vigorous physical activity[10].

Weight reduction

Physical activity is a medium for weight reduction. Obesity is linked to many comorbidities like diabetes, hypertension and cancer risk[11]. According to global predictions, by 2030 about 20% of the world’s population will be obese with a remarkable increase in the developing nations[12]. The International Agency for Research on Cancer[13] has found ample evidence to indicate a relation between excess adiposity and cancer in the following anatomical sites: (1) Esophageal; (2) Gastric cardia; (3) Colorectal; (4) Pancreas; (5) Liver; (6) Gallbladder; (7) Endometrium; (8) Breast (in post-menopausal patients); (9) Thyroid; (10) Ovaries; (11) Kidneys; (12) Meningioma; and (13) The bone marrow (multiple myeloma). There is additional data showing the relationship between advanced prostate cancer and adiposity[14]. One of the hormones, leptin is known to foster breast cancer via advancing angiogenesis and cell proliferation, indirectly via hormones like estrogen and insulin signalling pathways. Hence the link between leptin, adiposity and higher risk of breast and ovarian cancers[15]. Another hormone, adiponectin is inversely correlated with adiposity and breast cancer risk, apparently as a result of their anti-inflammatory properties[16].

Adiposity and inflammation

The adipose tissue releases adipokines that regulate energy homeostasis and inflammation. Elevated leptin and visfatin levels, coupled with low adiponectin, are implicated in carcinogenesis[17]. For instance, in case of colorectal cancer, leptin induces the growth of neoplastic colorectal cancer cells. Ahechu et al[18] reported chronic inflammation is another mechanism of cancer development. In case of reproductive organs, leptin stimulates endometrial, breast, and ovarian cancer cell growth and impairs apoptosis through activation of multiple signalling pathways. In addition, it induces hyperestrogenism via increasing the expression of aromatase[19].

Immunity

Tumor cells evade immune destruction through mechanisms such as elevated lactate levels, impairing cytotoxic T-cell function. This mechanism promotes tumor growth. They accomplish this task via various methods. elevation of lactate levels within cancer cells is one such method[20]. This affects the functioning of cytotoxic T cells thus escaping elimination. Muscles secrete muscle cytokines or myokines on physical activity. These mediate beneficial functions on the immune system. The notable myokines are interleukins, namely interleukin (IL)-4, IL-6, IL-7, IL-8 and IL-15. IL-6 has both prominent proinflammatory and anti-inflammatory properties. In the context of exercise, IL-7 and IL-15 play a crucial role in the promotion of cell survival through upregulating antiapoptotic mechanisms and telomerase activity to preserve telomere length. IL-15 is vital in the proliferation and differentiation of natural killer (NK) cells, which then recognise and kill cancer cells[21]. Subsequent to dynamic exercise (rowing, cycling, swimming), there is an acute mobilization of leucocytes to the blood compartment. These include the NK cells, gamma delta (γδ) T-cells, CD8+ T cells, CD4+ T cells and B-cells. These then identify cancer cells and are capable of terminating them[22].

Sunlight exposure and vitamin D levels

Exercising in open air has the benefit of increasing vitamin D levels via increased sunlight exposure[23]. Vitamin D has a role in the modulation of cell differentiation, proliferation, and apoptosis of neoplastic cells, as well as the antineoplastic action of the immune system[24]. The beneficial effects of physical activity in the sun in preventing cancer are indirect. Chakraborty et al[25] reports a deficiency of serum vitamin D increasing the risk of breast cancer. Vitamin D has an effect on cell differentiation, proliferation and apoptosis. Yet not direct causal link has been established between the same. These maybe via beneficial effects of sunlight on the immune system and circadian rhythm[26].

Insulin resistance

Regular physical exercise reduces insulin resistance[27]. It has been noted that insulin resistance leads to hyperglycemia and hyperinsulinemia further associated with an increased risk of neoplasia, poorer prognosis and greater risk of relapse after initial treatment[28]. Insulin resistance may lead to altered metabolic (MET) states leading to obesity and type 2 diabetes.

Yoga as a form of prevention

Yoga, an ancient practice originating in India, is now studied for its health benefits, including cancer prevention[29]. One of the mechanisms is reduction in pro tumorigenic cytokines. A study in Texas examined how a 16 weeks therapeutic Yoga program modulated the cytokine levels in cancer survivors. Cytokines are released as a response to chronic inflammation in the body[30]. These are remarkably raised as a response to cancer therapies leading to chronic non-resolving inflammation. In a metanalysis performed to determine the effect of exercise training on pro and anti-inflammation markers, a decrease in pro inflammatory biomarkers were was noted (P < 0.001)[31]. Structured exercise interventions (aerobic, resistance or combined training or Tai chi/Yoga) were compared to usual care control group. Further it was found that that prostate (P = 0.004) and breast cancer populations were most responsive (P = 0.001), combined aerobic and resistance training had the greatest effect (P < 0.001), and that C-reactive protein (P = 0.025) and tumour necrosis factor (P = 0.004) were the most sensitive to change. Yoga has been incorporated into primary health care in India and is being implemented from the village level[32]. Health and wellness centres in villages have a designated Yoga room and teacher for Yoga classes. This helps improve lifestyle and reduce the overall burden of all non-communicable diseases including cancer[24]. Glaser et al[33] in an integrative approach to cancer care in Buffalo reported, cancer survivors, their caregivers and hospital staff were included in an adaptive Yoga program at the comprehensive cancer centre. In patients of breast cancer, much research has been conducted to find the effect of Yoga on the health-related quality of life. This has a positive effect as noted by preventing and/or managing chemotherapy-related adverse effects and increasing the quality of life among breast cancer patients[34].

EXERCISE DOSE RESPONSE ON THE PREVENTION OF CANCER

A significant negative relationship between total physical activity and the risk of gastric, liver, colon, breast and lung cancers has been demonstrated by the Global Burden of Disease Study[35]. Compared to individuals with insufficient activity, measured as MET equivalents, (total activity level < 600 MET-minutes/week), individuals with high levels of activity (≥ 8000 MET-minutes/week) experienced a 10.3% risk reduction for breast cancer; 5.9% for lung cancer; 7.1% for colon cancer; 5.1% for gastric cancer; 17.1% for liver cancer. A systematic review was conducted to assess the associations between physical activity and risk for cancer, and mortality in cancer patients[36]. This review found out that there is strong overall evidence linking physical activity and the risk of developing breast, colon, endometrium, esophageal (adenocarcinoma), renal, bladder and gastric cancer. Lung cancer has moderate overall evidence whereas there is limited evidence for hematologic, ovarian, pancreas, prostate, brain, thyroid, head and neck and rectal cancer. Table 1 summarizes the evidence linking physical activity and cancer risk reduction[6,7,9,11,18,35,36].

Table 1 Summary of evidence linking physical activity and cancer risk reduction.

Cancer type	Evidence strength	Type of physical activity	Risk reduction (%)	Ref.
Breast	Strong	Aerobic, resistance	9%	Drummond et al[7], Poorolajal et al[9]
Liver	Strong	Aerobic	17.1%	Diao et al[35]
Lung	Strong	Aerobic, walking	5.9%	Diao et al[35]
Colorectal	Strong	Aerobic, walking, resistance	7.1%	Ahechu et al[18]
Endometrial	Strong	Aerobic, resistance	10%	Joshi et al[6]
Esophageal (adenocarcinoma)	Moderate	Aerobic, resistance	6%	McTiernan et al[36]
Renal	Moderate	Aerobic	8%	Friedenreich et al[11]
Bladder	Moderate	Walking, aerobic	4%	McTiernan et al[36]
Gastric	Moderate	Aerobic	5.1%	Diao et al[35]
Hematologic	Limited	Resistance, walking	Not specified	McTiernan et al[36]
Head and neck	Limited	Aerobic, walking	Not specified	McTiernan et al[36]
Ovarian	Limited	Aerobic, walking	Not specified	McTiernan et al[36]
Pancreas	Limited	Aerobic	Not specified	McTiernan et al[36]
Prostate	Limited	Vigorous, resistance	5%-10%	Shephard (2017)
Brain	Limited	Aerobic, resistance	Not specified	McTiernan et al[36]
Thyroid	Limited	Aerobic	Not specified	McTiernan et al[36]
Rectal	Limited	Aerobic, resistance	3%	McTiernan et al[36]

Physical activity as a form of prehabilitation

Prehabilitation, as stated by Stout et al[37], is a program that prepares individuals for cancer treatment by focusing on physical and mental well-being before treatment begins, aiming to improve outcomes and recovery. Cancer drugs related cardiovascular fitness, neurotoxicity and fatigue have shown improvement with exercise[38]. Improvement in cancer related psychological wellbeing and quality of life has been associated with exercise as a prehabilitation therapy, as reported by Michael et al[39].

Physical activity and mortality reduction in cancer

Evidence suggests an improved survival outcome for cancer with pre and post diagnosis physical activity. In case of breast and colorectal cancers, greater reduction was noted for post diagnosis physical activity [hazard ratio (HR) = 0.58-0.63] compared with prediagnosis physical activity (HR = 0.80-0.86) for all-cause and cancer-specific mortality[40]. In a meta-analysis of prospective cohort studies, the inverse association between prediagnosis physical activity and cancer mortality was more definite for colon cancer than that for rectal cancer (P = 0.08). A meta-analysis of prospective cohort studies for breast cancer inverse dose-response relationships between physical activity and breast cancer-specific and all-cause mortality were observed, with significant decrease in hazards to 10-15 MET equivalent hours per week[40].

ROLE OF TCM ALONG WITH PHYSICAL ACTIVITY IN CANCER PREVENTION

TCM has been in wide usage across the world in cancer prevention and treatment[3]. Natural herbs combined with movement practices like Tai chi and Yoga have gained traction[41]. These practices involve controlled breathing and gentle movements emphasizing the connection between the mind, body, and spirit. Specific protocols for various cancers in its entire continuum are required to be established. There is limited evidence in this regard yet. Literature synthesis can be done with high political will and strong scientific vigour backing age old practices into cancer prevention. Randomized controlled trials involving holistic exercise regimens are essential in establishing scientific credibility of these practices in preventing cancer. Combining these physical activities with complimentary and alternative medicine along with the current modern medicine protocols is crucial in establishing integrative oncology as a remedy. This is in line with the current WHO Traditional Medicine Strategy 2014-2023, integrative oncology is an upcoming field in this regard exploring the role of TCM practices in cancer prevention[42].

RECOMMENDATIONS

Future research should explore the optimal duration and intensity of physical activity for specific cancer types, as well as the mechanisms underlying Yoga's benefits. Integrative oncology needs extensive research with both conventional and TCM exploring the role of physical activity in cancer prevention. Tailor made protocols involving integrative approach need to be established for different stages of various cancers.

For primary prevention, study subjects need to be followed over long durations and systematically monitored for any development of new cases (incidence). This is time consuming, cost intensive and resource intensive. This is why most researchers have conducted observational study designs. Due to limited interventional research availability, the current evidence is restricted in a sense that it focusses on secondary and tertiary prevention but not primary prevention. Hence there is a need for high-quality prospective cohorts or mechanistic trials as more feasible alternatives.

CONCLUSION

Strong evidence supports an inverse relationship between physical activity and cancer risk, particularly for breast, liver, lung and colorectal cancers. There is limited evidence for hematologic, head and neck, ovarian, pancreas, prostate, brain, thyroid and rectal cancer. Dose response for exercise and cancer demonstrates a relation of greater risk reduction with higher MET equivalents per time period. Physical activity has a demonstrated role under prehabilitation or tertiary prevention of cancer. Along with regular cancer treatments, physical activity improves the overall wellbeing of the patient. The minireview highlights the need for interventional trials involving holistic methods combing modern and traditional medicine/therapies in cancer prevention. These can be applied at any stage of cancer continuum. Physical activities rooted in tradition like Yoga and Tai chi are slow, controlled movements that improve balance and coordination. There is also a need for structured physical activity guidelines for cancer prevention focusing on the entire continuum of cancer. The current literature focusses only on improved patient outcomes and not oncologic outcomes like reduction in cancer incidence. The current minireview brings forth the dearth in literature of resistance and balance exercises. The systematic reviews and trials mainly focus on aerobic exercise with minimal focus on the latter.

ACKNOWLEDGEMENTS

We would like to thank Department of Community Medicine, ABVIMS and Dr. Ram Manohar Lohia Hospital, New Delhi for their support.