THE TAI CHI ROLES IN REDUCING FATIGUE, PAIN, AND TNF-a PLASMA LEVEL ON BREAST CANCER PATIENTS: A SYSTEMATIC REVIEW

Written by Putri Yekti Budi Asih, I Putu Edra Putra Indrawan, Andhika Putri Perdana, Putu Ratna Candra Puspita, Vera Pravitasari Susila, Nila Wahyuni, I Putu Gede Adiatmika
on May 24, 2022

Sport and Fitness Journal

Volume 10, No.2, May 2022: 124-137

E-ISSN: 2654-9182

TAI CHI ROLES IN REDUCING FATIGUE, PAIN, AND TNF-α PLASMA

LEVEL ON BREAST CANCER PATIENTS: A SYSTEMATIC REVIEW

Putri Yekti Budi Asih^1*, I Putu Edra Putra Indrawan¹, Vera Pravitasari Susila¹, Putu Ratna Candra Puspita¹, Andhika Putri Perdana¹, Nila Wahyuni², I Putu Gede Adiatmika²

¹ Magister Program of Biomedical Science Anti Aging Medicine Medical Faculty Universitas Udayana, 80234, Denpasar, Indonesia

²Physiology Department Medical Faculty Universitas Udayana, 80234, Denpasar, Indonesia Email : [email protected]

ABSTRACT

Tai Chi (TC) has been very popular over the last few decades as useful tools for reducing stress and improving health. Survivors of breast cancer (BC) often experience symptoms that reduce their quality of life during and after treatment, such as cognitive dysfunction, fatigue, sleep disturbances, depression, pain, and weight gain. The proinflammatory biomarkers like TNF-α, IL-1, and IL-6 which are activated through the central nervous system were believed to induce fatigue, pain, and other complications that caused hindrance on life activity. The aim of this study is to identify and evaluate the effect of TC training on inflammatory biomarkers, especially TNF-α, pain, and cancer-related fatigue (CRF) in BC patients. Journal searching processes were performed through five electronic databases (ProQuest, Sciencedirect, PubMed, Google Scholar, and Sage Publications) and restricted from 2012 to 2022. The search strategy on the electronic databases was using terms like 'tai ji', 'tai chi', 'tumor necrosis factor-alpha', 'Interleukin-6', 'fatigue', 'pain', 'breast cancer', ‘biomarker’, 'TNF', 'TNF-α', and 'TNF-alpha'. Nine journals were chosen to be reviewed and discussed the intervention of Tai Chi, research methodology, and study results using pain, fatigue, and TNF-α biomarker. Tai Chi seems to be effective to reduce pain, cancer-related fatigue, and improves quality of life for breast cancer patients.

Keywords: Tai Chi; breast cancer; TNF-α; Fatigue; Pain

INTRODUCTION

The most frequently diagnosed cancer worldwide according to the International Agency for Research on Cancer (IARC) GLOBOCAN cancer statistics for 2020, especially those found in women, is breast cancer (BC), which is around 2.26 million cases ¹. Careful evaluation and long-term management of side effects is a major challenge from a clinical point of view which is of great importance for BC patients who have undergone chemotherapy and require long-term adjuvant treatment ².

With early detection and accompanied by advances in the treatment of BC, patients with BC can achieve an increasing percentage of survival and are able to survive longer. With an increase in overall life expectancy, BC survivors who suffer from this disease for a long time are subsequently at risk of accelerated aging, which causes the signs, symptoms of aging and cancer development to overlap. Cancer is also strongly linked with aging ³. Related to this problem, there have been many epidemiological studies that highlight long-term complications that are closely related, especially with BC treatment. But on the other hand, the underlying molecular mechanisms have not been well elucidated.

Treatment for BC includes surgery, chemotherapy, radiation therapy, and hormone therapy, which can be done alone or in combination. Although survival of patients with BC for at least 5 years after diagnosis ranges from over 90% in high-income countries, to 66% in India and 40% in South Africa, side effects after diagnosis and treatment can be persistently debilitating ⁴. It is important to pay attention to other things, not

only from a clinical perspective after cancer treatment, but also the possibility of recurrence and viability, and treatment effect or cancer itself on physical and mental function as well as the welfare of breast cancer patients. Side effects of breast cancer and its treatment include cancer-related fatigue ^5,6, sleep disturbances

⁷, depression, anxiety ^8,9, chronic pain ^10,11, decreased functional capacity, decreased muscle strength and endurance, and weight gain, which in the end will positively change the quality of life (QOL) ¹².

Fatigue, particularly, has a negative effect on quality of life, in breast cancer patients and survivors can last 10 years or more ⁶. CRF is described as prolonged discomfort with a feeling exhausted and tired that could interfere with daily activities as the symptoms. Control and monitoring on it is required ^13,14. Even though the CRF pathophysiology is still not well-understood, some mechanisms are proposed to explain the CRF development mechanism, such as dysfunction of inflammation and mitochondria, activation of the immune peripheral, and central mechanism ^14,15. BC patients who sense CRF complaints will find elevated levels of pro-inflammatory cytokines, especially Tumor Necrosis Factor-α (TNF-α), interleukin-1 (IL-1), as well as interleukin-6 (IL-6) ¹⁶. CNS (central nervous system) pathways activated by proinflammatory cytokines, such as interleukin-1beta (IL-1β), IL-6 and TNF-α due to cell stress, cell death, chemotherapy, and tumor microenvironment can induce fatigue, pain and other disturbances ^12,16,17. Due to the limitation on conventional therapies, other methods such as complementary and alternative medicine (CAM) were approached by BC survivors and TC started to gain attention ^18,19.

TC is a traditional Chinese training in the form of movements that are full of ancient Chinese philosophy and Chinese medicine, such as Confucianism and Taoism. TC is a mind-body exercise that combines breathing exercises, meditation and a series of sequential body movements with coordinated, balance-based postures ²⁰. TC is often used to improve physical function, strength, balance, and to prevent falls in breast cancer patients ²¹. In addition, TC also plays a good role in improving the quality of life (QoL) and improving sleep quality in cancer patients ^22–24. Some possible mechanisms that Tai Chi could relieve fatigue are developing relaxation through slow movement and shifting weight, increasing aerobic capacity, enhancing immune system ¹³. The National Comprehensive Cancer Network (NCCN) has proposed a guideline for managing CRF, however the gold standard for CRF has not been decided ¹³. Even though several studies show improvement in fatigue and reducing pain as well as reducing TNF-α plasma level, the contrary studies result still remain ¹³. Some studies also indicated that no significant changes were made _{by TC} 18,25–28_.

Ten randomized controlled trials have investigated the effect of TC on systemic markers inflammation in noncancerous samples. TC reduces circulating TNF-α levels in patients with COVID-19 ²⁹, in patients with ankylosing spondylitis ³⁰, in stroke patients ^31,32, COPD patients ³³, heart failure patients ^34,35. Few of these studies have focused on breast cancer survivors, and almost none have thoroughly reviewed and assessed the effects of TC on inflammation at the cellular level of proinflammatory cytokines (specifically, TNF-α) regarding the mechanisms of their effect on pain and fatigue in breast cancer patients.

METHODS

a. Methodology

Study design

This study is a systematic review which was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ³⁶. Literature search, literature selection, data extraction, and critical assessment were performed by the five reviewers independently, and any inconsistencies were resolved by mutual agreement or in consultation with a third experienced reviewer.

Subjects recruitment

The eligibility criteria for this study were as follows: (a) study design: randomized controlled trials (RCTs), and randomized partially blinded trials; (b) participants: adult patients diagnosed with BC who are receiving active treatment (i.e. surgery, radiation therapy, chemotherapy, or antihormonal

therapy); (c) intervention: TC with or without a combination of other interventions; and (d) The control group: other exercise, class meeting, conventional therapy or no treatment at all.

The primary outcome of this study was TNF-α measured with ELISA-kit, and for the second outcomes were pain and fatigue. Other results such as repeated publications, review comments, magazine articles, and other types of research were excluded.

Literature Research

Five electronic databases (ProQuest, Sciencedirect, PubMed Central NCBI, Google Scholar, and Sage Publications) were searched from 2012 to 2022. Search strategy in English electronic database was compiled using the terms The search strategy on the electronic website used terms from 'tai ji', 'tai chi', 'tumor necrosis factor-alpha', 'interleukin-6', 'fatigue', 'pain', 'breast cancer', ‘biomarker’, 'TNF', 'TNF-α', and 'TNF-alpha'.

b. Material and Procedure

Article searching processes were begun with inserting the keywords to each search engine that was chosen independently by the reviewers to find the literature needed. The next step was excluding the duplications found from the 5 search engines. Title and abstract that qualified the eligibility standard were identified, which next will be assessed by the reviewers. The studies chosen consist of randomized control trials and randomized partially blinded trials with TC exercises that were performed in various times from 20 to 120 minutes per session, with frequency range from once to 5 times a week, over 1-15 months of intervention. These TC practices were under the supervision of experienced TC instructors.

c. Assessment

The reviewers assessed independently by the inclusion criterias and excluded non-representing journals. Then the reviewers analyzed several things from the journal’s contents based on the suitability of topics, indexes or journal ratings through the Scimagojr website with journal criteria that met Q1 and Q2 quality, sample size, results from each journal, and limitations that occurred. The journals that met the criterias would proceed for data extraction.

d. Data analysis

Data extraction was performed by five reviewers from selected studies and independently assessed methodological quality. The extracted information included the authors and the year of publication of the journal, the participants, research purposes, intervention characteristics used in the study (the frequency of exercise and the length of time), the outcome being measured, and study results. If any disagreement arises between the five investigators, the discussion would be organized to propose a solution after reaching an agreement. The third party suggestion would be included if the five reviewers could not reach an agreement.

RESULTS

Reviewers have found 1.557 journals (including duplicates) from five databases. The selection process on several journals were performed according to the relevancy to the title and the article’s abstract. In order to check the journals’ index, investigations through Scimagojr website were conducted.

Figure 1. Flowchart of the study selection and identification

Forty-nine journals were selected for this systematic review. At the end, nine journals were chosen to be explored and discussed in more depth because of the appropriateness of the intervention, research methodology and study results using pain, fatigue and TNF-α biomarker. The data extraction of the nine journals is presented in Table 1.

Table 1. Data Extraction of Literature Review Results

No Author,

Year of Research

Participant/ Outcomes Intervention and Duration Frequency Research Research Result

Research Research Purpose (weeks or Methods

Groups months)

1. Robins

et al., 2013 ²⁵

A total of 109 Psychosocial Spiritual growth group 10 weeks 90 minutes Randomized Psychosocial interventions such as TC

participants instruments and and TC per session control trial or spiritual growth groups may not

immunological by each week have a significant enough effect to

proinflammatory Research purpose: to overcome the physiological or

cytokines in the evaluate quality of life, psychosocial stress experienced by BC

acute phase psychosocial functioning, patients during the treatment period

(TNF-α, IL-1, and biological markers who generally experience side effects

and IL-6) thought to reflect cancer- such as gastrointestinal disturbances,

specific mechanisms and and fatigue.

treatment

There was a better recovery in the production of proinflammatory cytokines (TNF-α, IL-1, and IL-6) as indicated by an elevation in IFN- □ levels

2. Cheng et

al., 2021 ³⁷

120 cancer patients CRF Resistance training and 12 weeks Duration 40 Randomized The study showed a significant

aged 55 years or TC minutes per controlled trial improvement on CRF of cancer

older; diagnosed day patients in both groups (RT and TC) in

with lung, stomach Research purpose: 3 times per 12 weeks after intervention, better than

and breast cancer Learning impact of TC week. pre-treatment (P<0.05).

histopathologically and RT on CRF and QoL

; had received 2-4 in patients diagnosed

courses of with BC, lung, and

chemotherapy stomach cancer.

and/or with additional radiation therapy and with a Brief Fatigue Inventory (BFI) examination showed complaints of CRF.

3.	Tsang	105 breast cancer	white blood cell	Tai Chi Chuan	12 weeks	90 minutes	Randomized-	No significant changes on cytokines
	et al., 2015 ²⁸	patients aged 32– 42 years that underwent mastectomy for invasive ductal carcinoma and completed 4 cycles of FEC 50 healthy female participants, aged 26–36 years.	(WBC), red blood cell (RBC) count and cytokine levels (IL-2, IL-4, IL-6, IFN-c and TNF-α)	Research Purpose : explore Tai Chi chuan effects on biological marker and psychological aspect of patients diagnosed with advanced invasive ductal carcinoma		3 times per week	controlled trial	(IL-2, IL4, IL6, IFN-c and TNF-α) level between patients and healthy groups after 12 months of Tai Chi Chuan.
4.	Larkey et al., 2016 ³⁸	250 fatigued, post-menopausal women aged 45 -75 years, diagnosed with breast cancer (stage 0-III), between 6 months and 5 years past primary treatment. postmenopausal status; and 5) current	Anxiety, fatigue, depression, cognitive function, sleep quality, physical activity Biomarker of HPA axis dysregulation (diurnal cortisol) Inflammation biomarkers (IL-1 Ra, IL-6, TNF-α and INFᵧ)	Qigong/Tai Chi Easy (QG/TCE), educational support (ES) group, and Qigong group (SQG) Research purpose : Finding Qigong/Tai Chi Easy effects on reducing CRF in BC patients and the following biochemical mechanism	12 weeks	Weekly for 1 hour	Three-armed randomized controlled trial Pre - post intervention	No significant differences pre and post intervention on cortisol and inflammation biomarkers.
5.	Irwin	123 breast cancer	Systemic (CRP	Cognitive-Behavioral	4 months	20 minutes	Randomized	This study declared that CBT-I
	et al., 2015 ³⁹	adult older than 55 years who met the criteria for primary insomnia in the DSM-IV	values), Cellular (TNF-α, TLR-4 activation, and IL-6), Genomic (gene expression)	Therapy for Insomnia (CBT-I), Tai Chi Chih intervention (TCC), and Sleep seminar education active control condition.	and followed up in the 7th and 16th month	class time done every week	control trial	improved sleep behavior and reduced CBT-I-induced systemic inflammation. Tai Chi Chih, induced reduction of cellular inflammation, suggesting that this change was independent of sleep quality improvement.

6. Irwin et 145 BC survivors

al., 2017 ⁴⁰

Improve Tai Chi Chih and CBT-I 3-15 months 120 minutes Randomized The study conducted with this non^{insomnia, boost} per sessions ^partially inferiority test showed that TCC was

good quality of Research purpose: blinded trial _{not lower than CBT-I at 3 months,}

sleep, reduce Sleep Quality Index to

One times which was indicated by the absence of

fatigue, and evaluate insomnia

_{depression. treatment response and} per week significant differences between the two

fatigue ^groups.

7. Sprod et 35 BC survivors

al., 2012

41

Cortisol, insulin, Standard support therapy 12 weeks 60 minutes, Randomized No significant differences in IL-6,

glucose, IL-6, (SST) and Tai Chi Chuan 3 times per controlled trial IGF-1, and Body Mass Index.

IGF-1, IL-8, week

insulin-like Research purpose: Physical capacity limitations, social

growth factor- To examine the impact of well-being, mental health, energy,

binding protein TCC based on health- significantly better in the TCC group.

(IGFBP)-1, and related QoL,

IGFBP-3. Inflammatory biomarkers No significant change in pain,

and other biomarkers emotional limitations, and general

Quality of life associated with health responses in both groups, SST

(includes physical aftereffects of disease and TCC.

and emotional and treatment in BC.

capacity limitations, mental health, social and physical wellbeing, pain, energy, and general health responses).

8. Campo 63 women with

et al., cancer (aged 55 –

2015 ⁴² 84 years) who

have limited physical function (physical role 72 or SF-12 physical function 80)

Salivary cortisol, Intervention: Tai Chi and 5 to 12 weeks 45 minutes - Randomized The results showed no significant

BP, anti- Health Education. 2 hours per controlled trial difference between post-intervention

inflammatory session pro-inflammatory and anticytokines Research purpose: to 2 - 5 times a inflammatory cytokines.

(IL-12, IL-4, examine TC as a mental week No interventional effect was seen on

IL-6, IL-10, and and physical exercise that the levels of inflammatory cytokines,

TNF-α) is associated with this is consistent with the results

reduced risk factors for reported in a previous TC study

chronic illness. conducted in a group of healthy elderly

and elderly with breast cancer.

9.

Irwin

90 insomnia -

IL-6 and TNF-α

Intervention: Tai Chi

3 months

2-hour

Randomized

This study highlights Tai Chi and other

et al.,

breast cancer

sessions

controlled trial

mind-body therapy may play a role in

2014 ⁴³

survivors.

Research purpose: This study assumed that Tai Chi (TCC) reduced systemic, cellular, and genomic markers of inflammation compared to cognitive-behavioral therapy (CBT-I) for insomnia in breast cancer survivors.

weekly.

the regulation of the immune system, consistent with other findings that psychosomatic therapy and CBSM (cognitive behavioral stress management, help reduce inflammation, including in cancer patients

Post-treatment assessments showed reduced TLR4-activated monocyte

production of IL6 and TNF-α in cancer survivors treated with TCC.

DISCUSSION

This systematic review describes the procedures and methodology of a ten-year randomized controlled trial, housed in various locations, which will investigate the effectiveness of TC exercise on fatigue, pain and its effect on TNF-α biomarkers in breast cancer patients.

Several trials were included in this review, and there was a high risk of bias in the blinding. This literature review analysis was carried out according to the types of TC exercises with different intensities, consisting of 12 weeks with a frequency of 1-3 times per week with a duration of 40 minutes ³⁷, 60 minutes ^38,41, 90 minutes ²⁸, 10 weeks with a duration of 90 minutes per session each week ²⁵, 4 months with a duration of 20 minutes class time done every week ³⁹, 3 months for 120 minutes per session each week ⁴³, 3-15 months ⁴⁰, 5-12 weeks with a duration of 45 minutes - 2 hours per session and frequency 2 - 5 times a week ⁴², 120 minutes per session each week for 3 until 15 months ⁴⁰.

From existing studies, TC intensity has been shown to have an effect on IL-6 and TNF-α, which results show that high-intensity TC significantly reduces TNF-α ²⁹.

TC has steadily grown in recent decades. It has been shown that this intervention approach to reduce aging symptoms and improve quality is valid. And several recent studies have begun to look for evidence of the influence of TC on biological processes of the body (including the inflammatory response including cellular, circulatory, and genomic marker responses of inflammation), that quantitatively assess the effect of TC on inflammatory markers such as IL-6, TNF-α, CRP, and stimulated cytokine production ²⁷.

Irwin et al emphasizes that TC and other mind-body therapy may play a role in the regulation of the immune system. This is consistent with other findings that psychosomatic therapy and CBSM (cognitive behavioral stress management, help reduce inflammation, including in cancer patients ⁴³.

Figure 2. Hypothesis Of Tai Chi Roles In Reducing Fatigue, Pain, And TNF-α Plasma Level On Breast Cancer Patients

a. Tai Chi And Fatigue In Breast Cancer

Cancer-related fatigue (CRF) is defined as the most common side effect experienced by cancer patients in the form of persistent emotional, physical, and/or cognitive fatigue associated with cancer itself or cancer treatment that can interfere with function and quality of life. Guidelines on fatigue screening and

recommendations for intervention based on treatment stage can be studied further in the NCCN Guidelines for Clinical Practice in Oncology. Interventions include counseling and education, common strategies for fatigue management, specific pharmacological and non-pharmacological interventions. Thus, routine screening for identifying CRF is important to ameliorate the quality of life of cancer patients ^6,44,45.

Fatigue is a complication that is often underreported, but is considered to be majorly responsible for the decline in quality of life. This CRF has been shown to be a consequence of active treatment, and can be felt until after treatment ⁴⁴. Many women with breast cancer report markedly increased fatigue in intensive care patients. Biering et al (2020), conducted a study to describe the process of fatigue in women with breast cancer ⁴⁶. The pathophysiological background of fatigue is unknown and its correlation with various biomarkers is weak and still not consistent ⁴⁷.

The development of CRF is thought to be related to serotonin, adenosine triphosphate and HPA (hypothalamic-pituitary-adrenocortical) axis dysregulation, skeletal muscle shrinkage, desynchronization of circadian rhythms, and cytokines level (especially proinflammatory cytokines). Immune system activation by body injury, trauma, and infection causes proinflammatory cytokine release and other immune factors. These immune factors include soluble receptors, receptor antagonists, and cellular activation products, one of which is TNF-α. These inflammatory cytokines then control local and systemic immune responses. This regulation will mediate neurologic symptoms i.e. fatigue ⁴⁷.

Therefore, the CRF deserves special review, firstly, because of the demographic relevance of the issue. Fatigue has been considered, not only the most common, but also the most damaging, symptom after treatment for breast cancer patients ⁴⁵.

The relationship between TC and fatigue was discussed in several literature reviews. Research conducted by Cheng Duan et al (2021) showed that CRF in BC patients improved better than the control group with a TC exercise intervention of 60 minutes per session for 12 weeks ³⁷. According to Irwin et al (2017) TC exercises provide a significant change in fatigue in breast cancer patients ⁴⁰. The same thing is also shown in research conducted by Lisa Sprod and Linda Larkey ^38,41. Whereas in other literature does not show significant changes ²⁵.

b. Tai Chi And Pain In Breast Cancer

Chronic pain is a common complaint in breast cancer patients and is connected with the release of inflammatory mediators from the tumor, tissue injury, and nerve involvement. This mechanism is the outcome of a network generated by pro-inflammatory cytokines, inflammatory pathway genes and cytokine gene polymorphisms. Breast cancer patients, especially in pre menopausal phase, usually has lower estrogen levels that linked to increased pain as well as impairment of descending pain inhibitory pathways, which may be a risk for developing chronic pain and symptoms such as discomfort and stiffness ⁴⁸. According to Sprod et al (2012) in their study that assessing pain as one of the pathological parameters, showed not much improvement-related to BC ⁴¹.

There is an explorative study that investigates the effect of TC on β-endorphin, describes that pain and stress may have increased basal β-endorphin and by doing TC could reduce the levels, implying that TC and other physical exercise may increase the capacity of endogenous opioid. But this study also found no significant influence of TC or modest physical activity on inflammatory markers, especially on older adults who suffer from chronic pain ²⁶.

c. Tai Chi And TNF-α Plasma Level In Breast Cancer

The study conducted by Campo et al showed that the study group had no significant difference between post-intervention pro-inflammatory and anti-inflammatory cytokines ⁴². No interventional effect on inflammatory cytokine levels was seen consistent with cytokine results reported in previous TC studies conducted in healthy elderly and breast cancer survivors ⁴⁹. The speculation about the finding of nulls is that due to the complex interaction of age-related factors (chronic mild inflammation), the presence of comorbidities, and the late impairment of cancer treatment, TC have older cancer survival. It has a limited effect on a person's inflammatory cytokines. This can lead to immunodeficiency dysregulation ⁵⁰.

The same result also obtained from the Linda et al and William Tsang et al studies showing that no significant differences caused by TC intervention between pre-post intervention to TNF-α and other biomarkers ^28,38. The same thing is also shown in research conducted by Rebecca Campo ⁴². However, a contrary post-treatment assessments by Irwin et al showed reduced TLR4-activated monocyte production of IL-6 and TNF-α in cancer survivors treated with TC Chih ^39,43.

Cancer patients have proinflammatory tendencies which could activate the immune system, including releasing inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α and CRP) but the mechanism of physical exercise in decreasing inflammatory biomarkers is still not clearly understood ⁵¹. Several studies showed inflammatory gene expression was decreased due to MBT (Tai Chi and Yoga) and that statement was supported by the trial results that identified changes in molecular signaling pathway even on trials that showed no significant differences ²⁷. In spite of that, further studies are required to deeply understand the benefit of TC in downregulation of inflammatory biomarkers.

CONCLUSION

Survivors as well as breast cancer patients, during and after treatment, often experience complaints of fatigue, pain, depression, sleep disturbances, and cognitive dysfunction. There is an increased interest among breast cancer patients and survivors to use mental and physical practices, including Tai Chi, Qigong, Yoga, and other practices. TC is still under-researched but seems promising to increase the ability of physical activity, which adds meditative benefits to cancer survivors and thereby improves survival outcomes.

In this systematic review, there are three studies showing that TC had no significant impact on TNF-α plasma levels in breast cancer patients. However, two other studies showed significant impact in reducing TNF-α plasma levels in BC patients. One study showed that TC had no significant impact on pain in breast cancer patients. Two studies showed that TC had a significant impact on fatigue in breast cancer patients, yet one study stated otherwise.

These contrary results might be caused by age-related multifactorial condition interactions that impaired inflammatory cytokines function. These conditions possibly lead to no improvement on fatigue and pain. Based on published research, it is still difficult to determine inflammatory biomarkers that are influenced by the frequency, duration and intensity of TC exercise. A clearer comprehension is required of the biological pathways through which TC design was capable of developing a powerful TC intervention to decrease the symptom of breast cancer survivors.

This conclusion should be interpreted with more caution because the included journal is limited. Additional randomized controlled trials with more rigorous and precise methodologies accompanied by a lower risk of bias in each study, are needed to provide more accurate evidence. Furthermore, more research is needed in all areas of cancer survival and TC.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENT

Author would like to thank for the advice, tutoring and consulting guidance from Prof. Dr. dr. I Putu Gede Adiatmika, M.Kes and dr. Nila Wahyuni, M. Fis. And for collaboration of dr. I Putu Edra Putra Indrawan, dr. Andhika Putri Perdana, dr. Putu Ratna Candra, dr. Vera Pravitasari Susila, and dr. Putri Yekti Budi Asih are gratefully acknowledged.

REFERENCES

1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year

2020: An overview. Int J Cancer. 2021;149(4):778–89.

2. Moo T, Sanford R, Dang C, Morrow M, Sloan M, Cancer K, et al. Overview of Breast Cancer Therapy. PET

Clin. 2018;13(3):339–54.

3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31–46.
4. WHO. Breast Cancer [Internet]. 2021 [cited 2022 Mar 23]. Available from: https://www.who.int/news-

room/fact-sheets/detail/breast-cancer

5. Nail L, Portenoy R, Weiss MC. Side Effect: Fatigue [Internet]. Breastcancer.org. 2022 [cited 2022 Mar 23].

Available from: https://www.breastcancer.org/treatment-side-effects/fatigue

6. Bower JE. Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat Rev Clin Oncol [Internet].

2014;11(10):597–609. Available from: http://dx.doi.org/10.1038/nrclinonc.2014.127

7. Palesh O, Aldridge-Gerry A, Ulusakarya A, Ortiz-Tudela E, Capuron L, Innominato PF. Sleep disruption in

breast cancer patients and survivors. JNCCN J Natl Compr Cancer Netw. 2013;11(12):1523–5930.

8. Tsaras K, Papathanasiou I V., Mitsi D, Veneti A, Kelesi M, Zyga S, et al. Assessment of depression and

anxiety in breast cancer patients: Prevalence and associated factors. Asian Pacific J Cancer Prev. 2018;19(6):1661–1669.

9. Naser AY, Hameed AN, Mustafa N, Alwafi H, Dahmash EZ, Alyami HS, et al. Depression and Anxiety in

Patients With Cancer: A Cross-Sectional Study. Front Psychol. 2021;12:1–12.

10. Peretti-Watel P, Bendiane MK, Spica L, Rey D. Pain narratives in breast cancer survivors. Pain Res Treat.

2012;2012:1–8.

11. Costa WA, Monteiro MN, Queiroz JF, Gonçalves AK. Pain and quality of life in breast cancer patients.

Clinics. 2017;72(12):758–63.

12. Perez-Tejada J, Aizpurua-Perez I, Labaka A, Vegas O, Ugartemendia G, Arregi A. Distress, proinflammatory

cytokines and self-esteem as predictors of quality of life in breast cancer survivors. Physiol Behav [Internet]. 2021;230(2021):113297. Available from: https://doi.org/10.1016/j.physbeh.2020.113297

13. Xiang Y, Lu L, Chen X, Wen Z. Does Tai Chi relieve fatigue? A systematic review and meta-analysis of

randomized controlled trials. PLoS One. 2017;12(4):1–22.

14. Puigpinós-Riera R, Serral G, Sala M, Bargalló X, Quintana MJ, Espinosa M, et al. Cancer-related fatigue and

its determinants in a cohort of women with breast cancer: the DAMA Cohort. Support Care Cancer. 2020;28(11):5213–21.

15. Fu HJ, Zhou H, Tang Y, Li J, Zhang D, Ding SY, et al. Tai Chi and other mind-body interventions for cancer-

related fatigue: An updated systematic review and network meta-analyses protocol. BMJ Open. 2022;12(1):8– 13.

16. Rogers LQ, M.P.H. AF, Trammell R, Hopkins-Price P, Vicari S, Rao K, et al. Effects of a physical activity

behavior change intervention on inflammation and related health outcomes in breast cancer survivors: pilot randomized trial. Integr Cancer Ther. 2006;12(4):323–35.

17. Kwekkeboom KL, Tostrud L, Costanzo E, Coe CL, Serlin RC, Ward SE, et al. The Role of Inflammation in

the Pain, Fatigue, and Sleep Disturbance Symptom Cluster in Advanced Cancer. J Pain Symptom Manage [Internet]. 2018;55(5):1286–1295. Available from: https://doi.org/10.1016/j.jpainsymman.2018.01.008

18. Pan Y, Yang K, Shi X, Liang H, Zhang F, Lv Q. Tai Chi Chuan exercise for patients with breast cancer: A

systematic review and meta-analysis. Evidence-based Complement Altern Med. 2015;2015.

19. Lo-Fo-Wong DNN, Ranchor A V., de Haes HCJM, Sprangers MAG, Henselmans I. Complementary and

alternative medicine use of women with breast cancer: Self-help CAM attracts other women than guided CAM therapies. Patient Educ Couns [Internet]. 2012;89(3):529–536. Available from:

http://dx.doi.org/10.1016/j.pec.2012.02.019

20. Cheng D, Wang B, Li Q, Guo Y, Wang L. Research on Function and Mechanism of Tai Chi on Cardiac

Rehabilitation. Chin J Integr Med. 2020;26(5):393–400.

21. Winters-Stone KM, Li F, Horak F, Luoh SW, Bennett JA, Nail L, et al. Comparison of tai chi vs. strength

training for fall prevention among female cancer survivors: Study protocol for the GET FIT trial. BMC Cancer. 2012;12(577):1–12.

22. Chen YW, Hunt MA, Campbell KL, Peill K, Reid WD. The effect of Tai Chi on four chronic conditions -

cancer, osteoarthritis, heart failure and chronic obstructive pulmonary disease: A systematic review and metaanalyses. Br J Sports Med. 2016;50(7):397–407.

23. Yan JH, Pan L, Zhang XM, Sun CX, Cui GH. Lack of efficacy of tai chi in improving quality of life in breast

cancer survivors: A systematic review and meta-analysis. Asian Pacific J Cancer Prev. 2014;15(8):3715–3720.

24. Yang L, Winters-Stone K, Rana B, Cao C, Carlson LE, Courneya KS, et al. Tai Chi for cancer survivors: A

systematic review toward consensus-based guidelines. Cancer Med. 2021;10(21):7447–7456.

25. Robins JLW, McCain NL, Elswick RK, Walter JM, Gray DP, Tuck I. Psychoneuroimmunology-based stress

management during adjuvant chemotherapy for early breast cancer. Evidence-based Complement Altern Med. 2013:1–7.

26. You T, Ogawa EF. Effects of T’ai Chi on Chronic Systemic Inflammation. J Altern Complement Med.

2019;25(6):656–658.

27. Bower JE, Irwin MR. Mind-Body Therapies and Control of Inflammatory Biology: A Descriptive Review.

Brain, Behav Immunit [Internet]. 2016;51:1–11. Available from: file:///C:/Users/Carla

Carolina/Desktop/Artigos para acrescentar na qualificação/The impact of birth weight on cardiovascular disease risk in the.pdf

28. Tsang WWN, Gao KL, Chan KM, Purves S, Macfarlane DJ, Fong SSM. Sitting Tai Chi improves the balance

control and muscle strength of community-dwelling persons with spinal cord injuries: A pilot study. Evidencebased Complement Altern Med. 2015:1–9.

29. Shu C, Feng S, Cui Q, Cheng S, Wang Y. Impact Of Tai Chi On CRP, TNF-Alpha And IL-6 In Inflammation:

A Systematic Review And Meta-Analysis. Ann Palliat Med. 2021;10(7):7468–7478.

30. Cetin SY, Calik BB, Ayan A, Kabul EG. The Effectiveness Of 10-Tai Chi Movements In Patients With

Ankylosing Spondylitis Receiving Anti-Tumor Necrosis Factor Therapy: A Randomized Controlled Trial. Eur J Integr Med [Internet]. 2020;39:101208. Available from: https://doi.org/10.1016/j.eujim.2020.101208

31. Morawin B, Tylutka A, Chmielowiec J, Zembron-Lacny A. Circulating Mediators Of Apoptosis And

Inflammation In Aging; Physical Exercise Intervention. Int J Environ Res Public Health. 2021;18(6):1–18.

32. Taylor-Piliae RE, Morrison HW, Hsu CH, Whitman S, Grandner M. The Feasibility of Tai Chi Exercise as a

Beneficial Mind-Body Intervention in a Group of Community-Dwelling Stroke Survivors with Symptoms of Depression. Evidence-based Complement Altern Med. 2021;2021.

33. Gilliam EA, Cheung T, Kraemer K, Litrownik D, Wayne PM, Moy ML, et al. The impact of Tai Chi and

mind-body breathing in COPD: Insights from a qualitative sub-study of a randomized controlled trial. PLoS One [Internet]. 2021;16(4 April):1–17. Available from: http://dx.doi.org/10.1371/journal.pone.0249263

34. Luberto CM, Coey CA, Davis RB, Wayne PM, Crute S, Yeh GY. Exploring correlates of improved depression

symptoms and quality of life following tai chi exercise for patients with heart failure. ESC Hear Fail. 2020;7(6):4206–12.

35. Redwine LS, Pung MA, Wilson K, Bangen KJ, Delano-Wood L, Hurwitz B. An exploratory randomized sub

study of light-to-moderate intensity exercise on cognitive function, depression symptoms and inflammation in older adults with heart failure. J Psychosom Res [Internet]. 2020;128(November 2019):109883. Available from: https://doi.org/10.1016/j.jpsychores.2019.109883

36. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020

statement: An updated guideline for reporting systematic reviews. Int J Surg. 2021;88:1–11.

37. Cheng D, Wang X, Hu J, Dai L li, Lv Y, Feng H, et al. Effect of Tai Chi and Resistance Training on Cancer-

Related Fatigue and Quality of Life in Middle-Aged and Elderly Cancer Patients. Chin J Integr Med. 2021;27(4):265–72.

38. Larkey L, Huberty J, Pedersen M, Weihs K. Qigong/Tai Chi Easy for fatigue in breast cancer survivors:

Rationale and design of a randomized clinical trial. Contemp Clin Trials [Internet]. 2016;50:222–8. Available from: http://dx.doi.org/10.1016/j.cct.2016.08.002

39. Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Cognitive Behavioral Therapy

and Tai Chi Reverse Cellular and Genomic Markers of Inflammation in Late-Life Insomnia: A Randomized Controlled Trial. Biol Psychiatry [Internet]. 2015;78(10):721–9. Available from: http://dx.doi.org/10.1016/j.biopsych.2015.01.010

40. Irwin MR, Olmstead R, Carrillo C, Sadeghi N, Nicassio P, Ganz PA, et al. Tai Chi Chih compared with

cognitive behavioral therapy for the Treatment of Insomnia in Survivors of Breast Cancer: A randomized, partially blinded, noninferiority trial. J Clin Oncol. 2017;35(23):2656–65.

41. Sprod LK, Janelsins MC, Palesh OG, Carroll JK, Heckler CE, Peppone LJ, et al. Health-related quality of life

and biomarkers in breast cancer survivors participating in tai chi chuan. J Cancer Surviv. 2012;6(2):146–54.

42. Campo RA, Light KC, O’Connor K, Nakamura Y, Lipschitz D, LaStayo PC, et al. Blood pressure, salivary

cortisol, and inflammatory cytokine outcomes in senior female cancer survivors enrolled in a tai chi chih randomized controlled trial. J Cancer Surviv. 2015;9(1):115–25.

43. Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Tai Chi, cellular inflammation,

and transcriptome dynamics in breast cancer survivors with insomnia: A randomized controlled trial. J Natl Cancer Inst - Monogr. 2014;(50):295–301.

44. Berger AM, Mooney K, Alvarez-Perez A, Breitbart WS, Carpenter KM, Cella D, et al. Cancer-Related

Fatigue. Version 2.2015: Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2013;65(2):75–8.

45. Ruiz-Casado A, Álvarez-Bustos A, de Pedro CG, Méndez-Otero M, Romero-Elías M. Cancer-Related Fatigue

in Breast Cancer Survivors: A Review. Clin Breast Cancer [Internet]. 2021;21(1):10–25. Available from: https://doi.org/10.1016/j.clbc.2020.07.011

46. Biering K, Frydenberg M, Pappot H, Hjollund NH. The long-term course of fatigue following breast cancer

diagnosis. J Patient-Reported Outcomes. 2020;4(1).

47. Savina S, Zaydiner B. Cancer-Related Fatigue: Some Clinical Aspects. Asia-Pacific J Oncol Nurs.

2019;6(1):7–9.

48. Panis C, Pavanelli WR. Cytokines as mediators of pain-related process in breast cancer. Mediators Inflamm.

2015;2015.

49. Irwin MR, Olmstead R. Mitigating cellular inflammation in older adults: A randomized controlled trial of Tai

Chi Chih. Am J Geriatr Psychiatry [Internet]. 2012;20(9):764–72. Available from: http://dx.doi.org/10.1097/JGP.0b013e3182330fd3

50. Woods JA, Wilund KR, Martin SA, Kistler BM. Exercise, inflammation and aging. Aging Dis. 2012;3(1):130–

40.

51. de Jesus Leite MAF, Puga GM, Arantes FJ, Oliveira CJF, Cunha LM, Bortolini MJS, et al. Effects of combined

and resistance training on the inflammatory profile in breast cancer survivors: A systematic review. Complement Ther Med. 2018;36(December 2017):73–81.

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