|Year : 2017 | Volume
| Issue : 3 | Page : 392-398
Physical activity influences the immune system of breast cancer patients
Thorsten Schmidt1, Marion van Mackelenbergh2, Daniela Wesch3, Christoph Mundhenke2
1 University of Kiel, Comprehensive Cancer Center, Kiel, Germany
2 Department of Obstetrics and Gynecology, University of Kiel, OB/GYN, Breast Unit, Kiel, Germany
3 Institute of Immunology, University of Kiel, Institute of Immunology, Kiel, Germany
|Date of Web Publication||31-Aug-2017|
University of Kiel, OB/GYN, Breast Unit, Arnold-Heller-Str. 3, 24105, Kiel
Source of Support: None, Conflict of Interest: None
It has been suggested that physical activity in breast cancer patients can not only improve quality of life. Influences on physical and psychological levels have been evaluated, but effects on the immune system of breast cancer patients are hardly known. A PubMed search identified relevant trials and meta-analyses from 1970 to 2013. This review summarizes the results of international studies and the current discussion of effects of physical activity on the immune system of breast cancer patients. Highlighted are effects of physical activity on the immune system. Seven original articles and 14 reviews included in this review. Two original and the review articles includes other tumor entities besides breast cancer.Evaluated methods such as dose-response relationships for exercise in oncology, hardly exist. Increased immunological anti-cancer activity due to physical activity is probably mediated via an increase in number and cytotoxicity of monocytes and natural killer cells and cytokines.
Keywords: Breast cancer, immune response, immune system, physical intervention
|How to cite this article:|
Schmidt T, van Mackelenbergh M, Wesch D, Mundhenke C. Physical activity influences the immune system of breast cancer patients. J Can Res Ther 2017;13:392-8
| > Introduction|| |
Breast cancer incidence continues to rise. For primary prevention and the prevention of breast cancer recurrence it is important to assess the potential of new approaches to supportive care. Nowadays physical activity is often used as adjunctive therapy during chemo- and radiotherapy to relieve disease and therapy related symptoms. Besides the known improvement of quality of life and side effects such as fatigue, further positive effects of physical activity on the mental, social and physical status of cancer patients have previously been described.,,,,,,,,,,,,
While the influence of physical activity on the immune system in healthy athletes has already been studied well, the impact on the immune system of cancer patients and on disease prognosis has not been investigated.,,,, Initial findings on the immunological impact of physical activity in cancer patients have been made in the 1990 s. Some authors describe an enhanced immune function and low susceptibility to cancer occur with regular moderate exercise, whereas sedentariness and exhaustive exercise suppress immune function, and elevate susceptibility to infections.,,,,,,
The effector function of the human immune system is reduced with advanced age and by exogenous agents. This appears to be important for the increased incidence of malignant diseases in the elderly. The immunological reaction can be decreased by partially inactivating antigen-specific B and T cells, dendritic cells, macrophages, natural killer (NK) cells and neutrophils. Furthermore, an increased release of cytokines such as interleukins 1 (IL-1), IL-4, IL-6 and IL-10 has been detected., Pro- and anti-inflammatory cytokines are involved in regulating the immune system and play a major role in the inflammatory processes in cancer.
Experimental in vivo studies to investigate the interplay of physical movement and parameters of the immune system in cancer demonstrated that physically trained rats and mice have a higher lymphocyte population and an enhanced macrophage function. In a study with rats a significant increase in dendritic cells was detectable in the exercise group compared to the control group., An anti-inflammatory effect of physical activity by reducing IL-6 plasma concentrations has been described in mice.
The relative risk reduction of dying from breast cancer through physical activity is estimated between 10% and 50%.,, The Womens' Healthy Eating and Living Studyreported a relative survival advantage of 50% in women who were engaged in the metabolic equivalent of walking for 30 min 6 days a week as well as consuming five or more portions of fruit and vegetables. Similar protective effects on women after primary breast cancer diagnosis have been described by the Nurses' Health Study, the Collaborative Women's Longevity Study and the Life After Cancer Epidemiology study. These studies reported a 30-40% decrease in the risk of overall mortality among breast cancer survivors who performed moderate intensity activity of at least 1 h/week. The results of the success study suggested that a lack of physical activity, overweight and obesity are not only associated with an increased risk of suffering from breast cancer, but are also associated with an increased rate of recurrence and mortality.
Whether immunological effects of sport intervention are clinically relevant resulting in an improved prognosis of breast cancer (disease-free + overall survival) can only be suggested and has remained unconfirmed so far.
This review gives an overview of recent studies, which have examined immunological effects of physical activity in cancer patients and specifically in women with breast cancer. Immune-modulatory effects of physical activity could occur and could likely be correlated with an improved course of breast cancer. This would further underline the need for validated and individualized sports therapy concepts in primary breast cancer patients.
| > Methods|| |
In this review an extensive literature search was conducted. The search terms were: “Cancer and immune and physical training” and “immune system and cancer and sports.” Further studies on the subjects “physical activity and immune and breast cancer prognosis/survival were found on the reference lists of the identified literature.” International original and review articles from 1970 to 2013 were included.
| > Results|| |
The literature search revealed 21 manuscripts including seven original articles and 14 review articles. These publications are further discussed in this paper. Two original and the review-articles include other tumor entities besides breast cancer. Trial designs described in the original articles and review articles, as well as intervention methods and the effects on immune cell populations are presented [Table 1] and [Table 2].
|Table 1: Summary of original articles: Effects of physical activity on the immune system of breast cancer patients|
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|Table 2: Summary of original and review articles: Effects of physical activity on the immune system of breast cancer patients and other entities|
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Five original articles are specifically related to physical intervention in breast cancer patients,,,,, two original articles, and seven review articles also include patients with other cancer entities (colon, prostate etc.).,,,,,, Two reviews are focused on breast cancer, and five reviews also include patients with other entities.,,,,
Description of the intervention
Regarding the timing of therapeutic exercises in relation to cancer treatment 10 reviews do not present sufficient information.,,,,,,,,, However, Fairey et al. refer to the physical intervention during and after completion of therapy, De Backer et al. describe it after completion of chemotherapy and radiation therapy, Kruijsen-Jaarsma et al. report about an intervention during and after the therapy and Lee focus on primary prevention.
Regarding the type of intervention, three reviews present a specific movement description,,, while McTiernan only refer to “endurance training” and Kruijsen-Jaarsma et al. refer to aerobic and resistance training, Shephard and Shek designate “physical activity” as indicating movement.
Eight reviews do not mention details regarding movement extent and type.,,,,,,,
In all reviews the impact of physical activity of cancer patients on specific cell populations is described. While two reviews give no precise values of cell populations,, the additional 12 reviews present changes in NK cells, monocytes, macrophages, lymphocytes, tumor associated macrophages and in IL and tumor necrosis factor (TNF).,,,,,,,,,,,
Thirteen reviews describe a positive correlation without mentioning the exact significance level of physical activity and changes in the immune system.,,,,,,,,,,,, Kruk and Aboul-Enein suspect an immunological impact of physical activity in breast cancer patients. Six reviews only provide general information about immunological effects of physical activity in cancer patients. A positive relationship between physical activity and the functional state of the immune system is described, without relating to a specific cancer entity.,,,,,
Two original articles examine the impact of physical activity on the immune system in breast cancer patients and other entities.,
Dimeo et al. report a decreased duration of neutropenia by sports after high-dose-chemotherapy. Patients in the training group performed a daily program of aerobic exercise, consisting of “biking” with a bed ergometer. The patients “bike” for 1 min with an intensity sufficient to reach a heart rate equivalent to at least 50% of cardiac reserve. The procedure was repeated 15 times with pauses of 1 min between bouts. The supervised training was carried out for a total of 30 min each day. The training group has a shorter duration of neutropenia (P - 0.01) and of thrombocytopenia. The requirement for platelet transfusion is also lower in the training group (P - 0.06).
The influence of physical activity on sleep-mediating cytokines IL-6, TNF-alpha (TNF-a) and soluble TNF-alpha-receptor (sTNF-R) is described in the study of Sprod et al. In a two-arm study the influence of a home-based-exercise intervention is compared with a standard care on sleep-mediating cytokines. Thirty eight breast and prostate cancer patients were randomized to a 4 weeks exercise program or no exercise arm at the beginning of their radiation therapy. IL-6, TNF-a and sTNF-R were measured before and after intervention. The home-based-exercise intervention consisted of progressive resistance and a walking training. The resistance training portion was designed to be performed at a low moderate intensity, 7 days/week, for 4 weeks. The aim of the resistance training was maintaining upper body muscular strength. The progressive walking component of the home based intervention was designed to be performed at a moderate intensity. The patients wore a pedometer during the initial 1-week assessment period and recorded their daily number of steps. The patients in the exercise arm were instructed to increase the number of steps attained each day by 5-20%. The result from the study support the use of a home-based-walking and resistance training during radiation therapy for breast and prostate cancer to positively influence sleep quality, possibly by regulating mediators of inflammation.
Five original articles investigate the effects of physical activity on the immune system in breast cancer patients.,,,,
The effects of physical activity on the immune system have been examined in a randomized study by Fairey et al. in postmenopausal breast cancer patients who had completed surgery and adjuvant therapy. While the intervention group (n = 25) received an ergometer training for 3 times/week over 15 weeks, the control group (n = 28) had no training. The intensity of the exercise was set on the power output that elicited ventilator equivalent for carbon dioxide. The supervised exercise duration started with 15 min for weeks 1-3. In the following weeks the exercise duration systematically increased by 5 min every 3 weeks thereafter to 35 min for week 12-15. The primary end point of this study was the change of NK cells in peripheral blood. Furthermore, other haematological changes were monitored. The results showed a significant increase of NK cells (P = 0.035) and all lymphocytes (P = 0.007) in the exercise group compared to the control group. Monocytes and neutrophils did not differ significantly.
The aim of the study from Hutnick et al. was to determine whether exercise training would increase lymphocyte activation in patients with breast cancer following chemotherapy. In a 6 months exercise – program 3 times a week with a personal trainer 28 breast-cancer patients were compared with 21 patients who did no exercise. The exercise program consisted of resistance training and aerobic activity at 60-75% functional capacity. The primary endpoints was the change in the number of CD4 and CD69 blood lymphocytes, the concentration of interferon gamma and IL-6 in the culture medium of mitogen-stimulated lymphocytes as well as the plasma concentration of IL-6 an IFγ. The exercise patients showed a significantly elevated percentage of CD4 and CD69 cells. Plasma and mitogen stimulated IL-6 and IFγ production were similar in both groups.
A physical activity-induced change especially of monocytes and NK cells (CD56) has been examined in studies conducted by Peters et al. A small cohort of 24 breast cancer patients completed cycle training for more than 7 months. The intensity of training was determined on the basis of a grades bicycle ergometer test, which began at 25 watts and was elevates every 2 min for 25 watts until exhaustion. With regard to their age and resting heart frequency, the intensity of training was determined moderately according to the formula of Lagerström. The bicycle ergometer training started in a rehabilitation hospital. The women cycled 5 times a week for 5 weeks with an increasing duration of training. After the 5 weeks they cycled 2-3 times a week in an ambulant group for further 6 months. The blood samples to determine the cell numbers of monocytes and NK cells were taken at the beginning, after 5 weeks and at the end of the study. The results reveal an increase in granulocytes (initial: 61.3 ± 7.9%, after 5 weeks: 60.0 ± 9.7%, and after 7 months 65.4 ± 6.8%) (P < 0.05) and a decrease in lymphocytes and monocytes (P < 0.05). A consistent NK cell number with a higher cytotoxic activity was observed after physical intervention. At the beginning of the study, the basal activity of the NK cells in cancer patients (18.9% lysis) shows a lower level than in healthy individuals (30-35% lysis). After 7 months of moderate aerobic exercise the NK cells show a cytotoxic activity of 28.3% lysis and achieve the range of healthy subjects (P < 0.05).,
No influence of physical activity on the immune system is described in the study of Nieman et al. Only 16 breast cancer patients are randomized into the control and intervention group, of which 12 patients completed the study. The focus of the investigation is on physical performance, the cell number of lymphocytes and the activity of NK cells. The 60 min workout of the intervention group consists of a supervised strength and endurance training 3 times a week for 8 weeks. In the aerobic phase, the patients maintained a maximal heart rate about 75% by walking on indoor track for 30 min a session. In the resistance component of the program, subjects completed two sets of 12 repetitions of seven different exercises, with the weight progressively increase throughout the study. As one end point of the study, a significant improvement in the 6 min walking test was detected (P = 0.02) in the intervention group compared to the control group. An increase in cell numbers of lymphocytes and NK cells compared to healthy persons could not be found, while an improvement in physical performance in the intervention group could be observed. The number of T-lymphocytes and the activity of NK cells remains stable.
Four trials report about changes in the lymphocyte subsets.,,, There is evidence that chronic exercise does not alter CD3+ T lymphocyte, and CD56+ cell numbers.,,, Two studies show, that CD4+/CD8+ and CD20+ B-lymphocyte numbers are not altered by chronic exercise., Three trials describe a change in cell function, like in NK cytotoxic activity.,,
| > Discussion|| |
The presented trials and reviews describe physical activity-induced effects on the immune system in terms of cell number changes and cytotoxic activity in breast cancer patients. The studies suggest an improved immunological status of breast cancer patients after physical activity, however the statements of the included studies about the impact of physical activity are different.
The possible effects of physical activity on cancer outcomes are the increased number and effector function of monocytes, macrophages, NK cells and the increasing release of cytokines, but the relevant cut-off points of the exercise-induced immune-inflammatory response are still unknown within cancer.,,,
The different results of the studies may be related to their different designs. The trial reports relate to the phase after surgery and after the completion of radiotherapy and chemotherapy. The designs of the movement therapy trials are partially different and lead to limited comparability of these studies.,,,,,, The intervention programs differ in intensity, duration of each training session, frequency and the total amount of physical activity. While the intensity of the endurance training is specified with a range of 60-86% HRmax by Peters et al., it is at 75% HRmax by Nieman et al. There are also differences in the durations of each training session (30-60 min), in the frequencies (3 times a week/5 days a week) as well as in the total amount (8 weeks to 7 months).
A major problem of all studies is to determine the additional physical activity at work, in everyday life and at leisure time. The most common training intervention is endurance training.,,,,,, This was performed in five studies on an ergometer,,,, in one as aerobic workout, in one as a walking training and in one study on a treadmill. Three studies combined cardio and strength training.,, Other sport interventions such as strength training are underrepresented. From the description “physical exercise” or “physical activity” it cannot be concluded which specific methods of training and which intensities have been performed.,,,
Various clinical studies show that physical activity maintains and supports the cellular immune function and has a positive influence on the immune system in terms of tumor development.,,,,,, The intensity and duration of exercise have an important influence on the immune system. A more intense and prolonged exposure leads to an enhanced activation of different parts of the immune system.,,, In contrast, a too hard and too long period of physical exertion can have negative effects on the immune system. Exercise in the middle range of intensities seems to have a stimulating and activating effect.
Only few scientific results are available regarding the dosage and appropriate method of exercise intervention. It is still unknown whether endurance training or strength training is more meaningful for immune stimulation.
The influences of physical activity on acute and chronic changes of the immune system of cancer patients are not in line with the results of studies with healthy athletes. The increase in the number of NK-cells and the NK cytotoxicity in healthy athletes was seen after acute exercise, while studies with cancer patients reported about changes after chronic exercise interventions.,,, The differences between the results may be due to the different types of exercise performed in the studies. Beside modulation of the immune system, the cytokines have additional positive effects (reduction fatigue, decrease in cancer cachexia) on the wellbeing of cancer patients.,
In the included original articles and reviews it is not sufficiently described at which time points blood samples were taken (immediately after training/24 h after exercise or at any other time). The alterations in immune function are short lived and the changes are accumulated over the time and will often depend on the type of exercise and the duration. Once more the identification of the optimal “exercise dose” appears to be crucial.
This review discusses literature with a focus on the impact of physical activity on the immune system of breast cancer patients. The quality of studies has improved over time, however optimized concepts and strategies to prevent tumor recurrence and to improve quality of life and survival of cancer patients are necessary. The studies discussed also include other tumor entities than breast cancer. Overall the discussion of these papers is difficult as the performed trials come along with inherent methodological limitations. This also restricts the interpretation of the results discussed. The results of the intervention trials can only show associations. Elements of individual lifestyles could possibly be disruptive. Incidental findings cannot be excluded.
| > Conclusion|| |
In this review we found an increase of the lymphocytes subsets after physical activity in breast cancer patients. Future studies should involve more homogeneous populations. Only a prospective, standardized procedure in controlled clinical studies can provide scientifically more specific statements about effects of a targeted sport intervention after breast cancer diagnosis. For understanding the mechanism linking exercise and immune function in breast cancer patients further research is needed. For physical activity recommendations for breast cancer patients further research is needed.
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[Table 1], [Table 2]