Effectiveness of physical activity on immunity markers and quality of life in cancer patient: a systematic review

Introduction

Cancer is a vast group of diseases that can affect any part of the human body (Perez-Tejada et al., 2021). Other terms that can describe cancer are neoplasms and malignant tumours. A specific hallmark of cancer is the rapid development of anomalous cells that expand beyond their normal bounds, permitting them to infiltrate other body regions and expand to other tissues and organs; this is known as metastasis (Lanser et al., 2020). Cancer is a significant cause of death worldwide in 2020; and the most common cancers were lung, colon and rectum, liver, stomach, and breast cancers  (Ferlay et al., 2020; Hasham, Ahmed & Zeshan, 2020).

Physical activities can be explained as skeletal, muscular ambulation, or work that leads to energy consumption (Condello et al., 2016). Occupational, sports, conditioning, domestic and other types of physical activity can be seen throughout daily life. At the same time, exercise is a type of physical activity that is scheduled, structured, and done with the intention of improving or sustaining physical fitness as a final or intermediate aim. Physical exercise has been shown to enhance patients’ physical capacity and minimize illness and treatment-related adverse effects such as lower body strength, fatigue, QOL, and functional performance in patients with advanced-stage cancer (Albrecht & Taylor, 2012). Moreover, regular exercise helps to slow the progression of illness and decrease inflammation in people with chronic inflammatory disorders, and improve immunity markers (Shephard, 2017). Exercise regimens for breast cancer patients have been shown to impact the survival rates positively (Higgins et al., 2014). Increased physical exercise has been suggested a potential to significantly lower prostate cancer-specific and total death rates (Shephard, 2017). In addition to increased survival, many studies have shown an association between physical activity and improvement in QOL after a cancer diagnosis, including physical, functional, psychological, and emotional well-being  (Courneya & Friedenreich, 1999; Pinto, Dunsiger & Waldemore, 2013; Voskuil et al., 2010).

The World Health Organization states that exercise improves QOL, and moderate intensity exercise decreases the risk of cardiovascular disease, diabetes, and cancer. Exercise may positively impact cancer outcomes by lowering obesity and adipokine levels, lowering insulin, glucose, and sex hormone levels, increasing intestinal motility, lowering inflammation, and stimulating the immune system (Gleeson et al., 2011; McTiernan, 2008; Prieto-Hontoria et al., 2011). Cancer incidence and immune system dysfunction can also be as a result of age-related changes that can be mitigated to some extent by exercise  (Jones et al., 2009). The immune reaction can be reduced by partial inactivation of antigen-specific B and T cells, dendritic cells, neutrophils, macrophages, and NK cells (Senchina & Kohut, 2007; Bukhari et al., 2021). Therefore, pro- and anti-inflammatory cytokines are engaged in immune system regulation and play a critical role in cancer inflammatory processes (Loprinzi & Cardinal, 2013; Al-Hatamleh et al., 2022). Nevertheless, the molecular mechanisms that explain exercise multi-level effects in cancer patients are mainly unknown. Moreover, in rodents and cell culture research, many putative underlying mechanisms have been explored. However, human evidence is insufficient, and the clinically relevant cut-off points of the exercise-induced immuno-inflammatory response still require more investigation in cancer patients (Pedersen et al., 2016; Hojman et al., 2018). In addition, although it has been established that physical activity has anti-inflammatory benefits in healthy individuals, its anti-inflammatory effects in cancer patients suffering from CRF have not yet been identified (Hojan et al., 2016). Currently, it is unclear what kind of exercise is required to provide the best outcomes related to QOL and immune function (Brown et al., 2012b; Kruijsen-Jaarsma et al., 2013). The study aimed to determine the effect of physical activity on immune markers and QOL in cancer patients, and to evaluate CRF in cancer patients and its association with physical activity.

Materials and Methods

Results

Study selection results

A total of 13,931 studies were retrieved from PubMed, Scopus, Cochrane, and ScienceDirect using all MeSH keywords. After identifying duplicate articles (384), a total of 13,547 studies have proceeded for further selection. After reading the title and abstract of the articles, a total of 12,440 articles were excluded according as per general inclusion and exclusion criteria. The remaining 1,107 articles were proceeded for further selection by reading the full texts, out of which 1,053 were excluded. Data extraction was done from the nine studies that purely met the whole eligibility criteria (Fig. 1).

Discussion

The study aimed to determine the effect of physical activity on immune markers and QOL in cancer patients. Also, to evaluate CRF and its association with physical activity. This review observed significant improvements in QOL, fatigue, and immunity markers such as NK cells and other cytokine profiles following exercise. The presence of NK cells in the body confers immunity that helps to fend or kill cancer cells by secreting perforins and granzymes (Zuo & Zhao, 2021). Upon contact with cancerous cells, NK cells form immune synapses to deliver the lethal hit. These findings are consistent with those of other studies involving a well-trained study population (Kruijsen-Jaarsma et al., 2013; Kawada et al., 2010) and asthma patients (McFarlin, Hutchison & Kueht, 2008). These significant findings could be related to the different types of exercise performed by different cancer patients, indicating that immunity of the cancer patients can be increased with many types of exercise.

TNF-α levels are linked to a wide range of diseases and chronic inflammatory processes and have been associated with delayed wound healing (Ashcroft et al., 2012). The outcome of the present study showed that TNF-α, as well as other inflammatory markers such as IL-6 and CRP, were found to be significantly reduced following exercise intervention. This was likely due to the anti-inflammatory effects of the physical activity performed by the exercise group (Petersen & Pedersen, 2005). IL-6 has been associated with fatigue in breast cancer survivors (Schubert et al., 2007; Saligan & Kim, 2012), the most prevalent and debilitating symptom among cancer survivors, and some studies showed that physical activity reduces fatigue in people with breast cancer specifically (Battaglini et al., 2014; Zou et al., 2014), and people with cancer in general (Meneses-Echávez, González-Jiménez & Ramírez-Vélez, 2015; Meneses-Echavez, Gonzalez-Jimenez & Ramirez-Velez, 2015). In addition to being linked to fatigue, IL-6 has been shown to predict survival in patients with breast cancer (Salgado et al., 2003). Therefore, this result can help in understanding the positive trend in survival due to physical activity in various cancer populations. Indeed, since chronic inflammation is well known to play a critical role in cancer progression, development, and survival, the finding of decreases in a variety of cytokines (particularly IL-6, and TNF-α) may have similar implications (Coussens & Werb, 2002; Pierce et al., 2009). Previous studies comparing long-term yoga practitioners to non-yoga practitioners found that long-term practitioners had significantly lower levels of TNF-α, CRP, and IL-6 than non-yoga practitioners (Kiecolt-Glaser, 2010; Vijayaraghava et al., 2015). Huffman et al. (2008) concluded that exercise training reduces the expression of some proinflammatory cytokines, including TNF-α and IL-6, by reducing adipose tissue. These findings suggest that consistent reductions in circulating pro-inflammatory markers can be achieved through regular exercise.

Early integration of palliative care in the course of disease for patients with incurable cancers has gradually drawn interest as a viable and effective strategy not only to enhance QOL and mood, but also to prolong survival (Shephard, 2017; Thornton, Andersen & Carson, 2008). According to Hojan et al. (2016), frequent, moderate-intensity exercise improves functional ability, reduces inflammatory markers and fatigue, and improves QOL in high-risk prostate cancer patients undergoing radiation. Similarly, Kim et al. (2018) found that a home-based exercise-program can help patients receiving thyroid hormone replacement after thyroid surgery reduce fatigue and anxiety, improve QOL, and boost immunological function. Similar previous studies on different cancer subjects also reported that the exercise-programs are safe and helpful in improving QOL and reducing depression in cancer patients who have completed their treatments (Spence, Heesch & Brown, 2010; Pacheco et al., 2019; Battaglini et al., 2009; Daly et al., 2020; Williams et al., 2021).

Ergun et al. (2013) conducted research looking at the effects of exercise on angiogenesis and apoptosis-related markers, QOL, fatigue, and depression in breast cancer survivors. In that study, 63 patients with breast carcinoma were divided into three groups: supervised exercise, home exercise, and education. It was found that IL-8 and neutrophil-activating protein-78 levels in the home and the supervised exercise group were substantially lower after the exercise-program. Monocyte chemoattractant protein-1 levels increased significantly in the education group. Depression and fatigue were significantly lower after the intervention in the supervised exercise group. Both home and supervised exercise groups showed improvement in QOL after the exercise-programs, while no differences were reported in the education group. This might be due to the use of various quality of life scales and the variances in the type, duration, and intensity of exercise  (Demark-Wahnefried et al., 2006; Cadmus et al., 2009).

Cancer rehabilitation is a procedure that helps people work within their physical, social, psychological, and vocational limitations  (Basen-Engquist et al., 2006; Cho, Yoo & Kim, 2006). Physical symptoms (fatigue and physical endurance), nutritional symptoms (poor appetite, unintentional weight loss, and nutritional deterioration), psychological symptoms (anxiety, depression, and nervousness), and overall QOL have been shown to improve with post-rehabilitation (Pedersen et al., 2016; Hojan et al., 2016; Guinan, Connolly & Hussey, 2013). In a previous study, patients who had undergone a cancer rehabilitation program qualitatively said that rehabilitation was a significant stepping stone in their recovery and that physical and psychological treatment was an important mix (Cho, Yoo & Kim, 2006). Apart from the advantages mentioned above, the physical activity results differ depending on the stage of the disease or the research patients with incurable advanced disease (palliative care patients) (Lanser et al., 2020; Mustian et al., 2009). In patients with prostate cancer undergoing radiation, long-term supervised exercise training is more beneficial than educational materials on physical activity to lower cardiovascular risk and improve functional status (Hojman et al., 2018; Hojan et al., 2017).

According to the systematic studies, exercise enhanced QOL in cancer patients with significant evidence, particularly in breast cancer  (Perez-Tejada et al., 2021; Boivin et al., 2020; Inglis et al., 2021). The QOL scores in exercising cancer patients were shown to be higher when compared to controls or baseline values (Husson et al., 2013; Sadeghi et al., 2020). Some studies demonstrate exercise does not affect QOL in breast cancer patients who have completed the treatment (Basen-Engquist et al., 2006; Benoy et al., 2002; Brown et al., 2012a; Burnham & Wilcox, 2002). This might be due to the use of various QOL scales/inventory in studies, the multifactorial nature of QOL, variances in the type, length, and intensity of the exercise, a scarcity of high-quality research, or discrepancies in study populations. After the exercise program, the functional and general health scores of the EORTC QOL-C30 in the supervised exercise group and the functional score of the EORTC QOL-C30 in the home-exercise group were significantly improved (Cramp & Byron-Daniel, 2012). In similar observational research, individuals with a lengthy period following diagnosis had better baseline function and QOL scores (Daly et al., 2020).

Fatigue is a common early symptom of cancer that can develop before therapy and worsen throughout treatment (Jones et al., 2009). Fatigue affects almost all patients, with a reported frequency of 99% (DeSantis et al., 2015). While some studies have shown that walking, AE, and resistive exercise-programs can reduce CRF (Williams et al., 2021; Inglis et al., 2021; Husson et al., 2013). Physical activity may help to lower CRF by activating neuromuscular function and causing hemodynamic changes, as well as by decreasing social isolation (Schubert et al., 2007; Bower et al., 2000). However, results from Ji et al., exhibited that there was no significant effect of the exercise programs on CRF (Lee et al., 2010). According to  Parent-Roberge et al. (2020), exercise may have had a beneficial effect on CRF that was not mediated by changes in the pro-inflammatory cytokine profile.

To examine the process of changes in QOL, fatigue, and depression in cancer patients in response to different exercise programs, requires a larger scale survey. The beneficial effect of physical activity on cancer therapy can improve systemic immunity and cancer prognosis through adequately structured physical activity; thus, this would be an excellent public-health intervention for reducing the impact of cancer at relatively low cost and risk. Psychosocial support can also be another relevant topic to be investigated in future studies. Finally, the longitudinal follow-up should be planned to determine whether better QOL would help to improve the severity of diseases in patients or not.

Study Limitations

Only those studies included in the present systematic review that published in the English language which may result in the leftover of some studies. Furthermore, the case reports, short communications, and conference papers were also excluded. Another limitation of the current study was the heterogeneity of included studies, because of which it is difficult to say anything about one specific type of cancer. Apart from this, there was no such limitation for the review process.

Conclusions

From the outcome of the present study, it was found that physical exercise can reduce cancer incidence by improving immunity markers such as TNF-α, IL-6, IL-10, and NK cells. However, only through an indebted understanding of the impact of physical activity on the growth and mechanisms of tumour cells, metabolic pathways, and systemic immune functions might help to fully understand the correlation between exercise, cancer prevention, and treatment. In the future, this may also enable adequate administration of personalized exercise treatment plans for patients with cancer. However, no single study can solely identify a particular form of exercise as the most prudent or futile approach to improving the QOL, fatigue, and immunity markers in cancer patients. Hence, investigations on the effects of various forms of exercise on QOL and immunity in cancer patients are required.

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