Physical Training Influences the Immune System of Breast Cancer Patients
Der Einfluss von körperlichem Training auf das Immunsystem von Brustkrebspatienten
It has been suggestedthat physical activity in breast cancer patients can improve not only quality of life, but also other parameters. Influences on physical and psychological levels have been evaluated, but effects on the immune system of breast cancer patients are hardly known. Generally an evaluated dose-response relationship for exercise in oncology barely exists.
The effects of physical activity on the immune system can be formulated only with reservations, but an immunomodulatory effect is expected to occur. Increased immunological anti cancer activity due to physical activity is probably mediated via an increase in number and cytotoxicity of monocytes, natural killer cells and cytokines.
A PubMed search identified relevant trials and meta analyses from 1970 to 2016.
This reviewsummarizes 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. 13 original articles and 15 reviews are included in this review. Three original and 13 review articles include other tumor entities besides breast cancer.
KEY WORDS: Breast Cancer, Immune System, Immune Response, Physical Activity, Physical Intervention
Körperliche Aktivität beeinflusst neben der Lebensqualität von Brustkrebspatienten weitere Parameter auf psychischer und physischer Ebene. Die möglichen Effekte auf das Immunsystem sind hingegen nicht vollständig bekannt, sodass eine Dosis-Wirkung-Beziehung für Sport in der Onkologie bisher kaum existiert.
Die immunmodulierenden Auswirkungeneiner körperlichen Aktivität auf das Immunsystem lassen sich nur unter Vorbehalt formulieren. Die veränderten immunologischen Reaktionen werden unter anderem durch die erhöhte Anzahl der Monozyten, als auch durch deren verbesserte Zytotoxität erreicht. Zusätzlich spielt eine erhöhte Zytotoxität der natürlichen Killerzellen und der Zytokine eine Rolle.
Dieses Reviewfasst die relevanten Studien und Meta-Analysen einer PubMed-Recherche von 1970 bis 2016 zusammen.
Dargestellt werden die Ergebnisseinternationaler Studien und die aktuelle Diskussion der Auswirkungen von körperlicher Aktivität auf das Immunsystem von Brustkrebspatienten. 13 Originalarbeiten sowie 15 Übersichtsarbeiten werden in diesem Review aufgenommen. Drei der 13 Originalartikel und 13 Übersichtsartikel befassen sich neben Brustkrebs auch mit weiteren Krebsentitäten.
SCHLÜSSELWÖRTER: Brustkrebs, Immunsystem, Immunantwort, körperliche Aktivität, Sportintervention
Breast cancer is the most frequent cancer disease in women and the incidence is rising (36). Physical exercise is recommended as part of primary prevention in parallel to all medical interventions and to recurrence prophylaxis, as well as for the reduction of side effects. Various studies confirm the positive effects of physical activity in the various therapy phases, and also on the physical, emotional and social level (26, 45, 46).
The influence of physical training on the immune system of healthy athletes has been examined in many studies (9, 31). The effects on the immune system or on the disease prognosis of cancer patients, by contrast, must still be further examined (16). The first results of the effect of physical exercise on the immune system of cancer patients were reported in the 1990s (49). Some authors report that an improved immune function and lower susceptibility for cancer are elicited by moderate exercise, and that by contrast a lack of exercise and too-great stress can reduce the immune function and increase the susceptibility to infections (3, 7, 18, 20, 25, 26, 50).
The function of the human immune system is limited by advancing age and by exogenic factors. This appears to be very important in the increased incidence of malignant diseases in elderly people. The immunoreaction may be reduced in part by inactive antigen-specific B- and T-cells, dendritic cells, macrophages, natural killer cells (NK) and neutrophils. Moreover, increased release of cytokines has been reported (3, 42, 43).
Various in-vivo studies addressed the relationship between physical activity and the parameters of the immune system. The results of these studies show that physically-trained rats and mice not only had a higher lymphocyte population, but also presented an improved macrophage function. In another study, it was demonstrated that physical activity significantly increases the number of dendritic cells in rats compared to the control group (21, 22). An anti-inflammatory effect resulting from a reduction of the IL-6 plasma concentration in physical activity was found in mice (28). Moreover, regular movement appears to exert an influence on the activity of NK-cells and thus on tumor growth in mice (32).
Physical exercise can reduce the relative risk of dying from breast cancer by 10-50% (8). The study “The Women’s Healthy Eating and Living” reports a survival advantage of up to 50% in women who exercise regularly and maintain a healthy diet (35). Similar positive results were obtained in the “Nurses’ Health Study” (13), the “Collaborative Women’s Longevity Study” (14) and the “Life after Cancer Epidemiology Study” (48). These studies report a 30-40% reduction in the risk of dying in breast cancer patients who are active at least 1h per week at moderate intensity. The positive results make clear that a lack of exercise, overweight and adiposity can not only increase the risk of suffering breast cancer, but are also associated with an elevated risk of recurrence and increased mortality (36).
Whether the immunological effects of sport and exercise therapy are clinically relevant and contribute to improved breast cancer prognosis, can only be presumed on the basis of studies to date; proof is still outstanding.
This review provides a summary of all studies to date which have addressed the immunological reaction to physical exercise in cancer patients, especially breast cancer patients. An immunomodulating effect of physical exercise is assumed and thus improvement of the course of disease in breast cancer patients is expected. This assumption emphasizes the necessity for validated and individualized sport-therapy concepts, primarily for breast cancer patients.
To prepare this review, a thorough literature search with the following search terms was performed by two independent persons (TS and AH): “Cancer and immune and/or physical training/exercise” and “breast cancer and/or immune and physical training/exercise” and “immune system and cancer and/or sports/exercise” and “immune system and breast cancer and/or sports/exercise”. Additional studies were added from references in the identified literature.
All search results were checked with further screening, so that finally 13 original articles and 15 reviews were considered to be relevant.
International original articles and review articles published between 1970 and 2016 were taken into account.
The literature search brought 28 manuscripts, of which 13 were original articles and 15 reviews. These publications are listed and discussed in the present survey article. Three of the original articles and 13 reviews address cancer entities in addition to breast cancer. The study design, the intervention and the effects on the immune cell population are presented (Fig. 1, Tab. 1, 2 and 3).
All reviews confirm the influence of physical activity on the specific cell population of cancer patients. Whereas two review articles do not give any direct information (1, 19), the remaining 13 articles describe a change in the NK cells, monocytes macrophages, lymphocytes or the tumor-associated macrophages, interleukines and the tumor necrosis factor (TNF) (2, 7, 10, 16, 17, 24, 25, 26, 41, 45, 46, 50, 51).
14 overview articles document a positive relationship between physical activity and the cell population, but without providing concrete statements concerning the extent of exercise and the changes in the immune system (1, 3, 10, 16, 17, 19, 24, 25, 26, 41, 45, 46, 50, 51).
The following articles address the influence of physical training on the immune system of breast cancer patients. Three articles include other cancer entities in their studies (4, 37, 47).
Dimeo et al. report a shorter duration of neutropenia through sports activity following high-dosed chemotherapy in various carcinomas. The participants in the intervention group performed daily aerobic endurance training using a bed ergometer. The results show that neutropenia (p=0.01) and thrombocytopenia were shorter in the intervention group. The necessity of a thrombocyte transfusion was also lower in the intervention group than in the control group (p=0.06) (4).
The influence of physical activity on the sleep-promoting cytokines IL-6, TNF-alpha (TNF-α) and on the soluble TNF-alpha receptors (sTNF-R) is described in the study by Sprod et al. In this (two-arm) study, the influence of home-training is compared to the standard treatment with sleep-promoting cytokines. 38 breast and prostate cancer patients were randomized at the start of radiation therapy to a control and an intervention group. The intervention group performed a 4-week exercise program, the control group, by contrast, no additional intervention. IL-6, TNF-αand sTNF-R were measured before and after the intervention. The results of this study emphasize the positive effects of walking and strength training during radiation therapy for breast and prostate cancer patients. The quality of sleep may possibly be positively influenced via regulation of the inflammation mediators (47).
The effect of physical activity on the activity of lymphocytes in breast cancer patients after chemotherapy was investigated by Hutnick et al. 49 breast cancer patients were enrolled in the 6-month intervention study. The intervention group (n=28) performed three supervised training sessions per week, while the control group (n=21) had no sports program. The participants in the intervention group showed a significant percent increase in CD4+- and CD69+-cells. However, if the comparison focuses on the total count, there are no significant differences between the two groups at any time. The plasma- and the mitogen-stimulated IL-6 and the IFγ-production were similar in both groups (15).
The change brought by physical exercise in the immune system of breast cancer patients was the goal of the study by Fairey et al. 52 breast cancer patients were enrolled in the study after the operation and adjuvant therapy. Over a period of 15 weeks, the intervention group (n=25) performed ergometer training three times per week, while the control group (n=28) had no additional intervention. The intensity was defined by the ventilatory equivalent for carbon dioxide. The supervised training started with a 15-minute program from the first to the third weeks. In the subsequent weeks, the training was increased every three weeks by 5 minutes, so that the ergometer training in weeks 12 to 15 lasted 35 minutes. The primary endpoint of the study was the change in NK-cells in peripheral blood. Moreover, other hematological changes were determined. The results show a significant increase in NK-cells (p=0.035) and improvement in the proliferation capacity of the lymphocytes (p=0.007) in the intervention group compared to the control group. Monocytes and neutrophils do not differ significantly (6).
Mohamady et al. examined the influence of a sport intervention on the immune system of 40 breast cancer patients following mastectomy. The 3-month training consisted of 30-minute mobilization training twice daily. In the final month, moderate endurance training was performed on an upper-body or cycle ergometer. The results show improvement in NK-cell activity compared to the control group (27).
Evans et al. also reported an increase in NK-cells in both breast cancer patients and participants without an oncological background. The study included 18 subjects, nine breast cancer patients and nine comparable subjects without carcinoma. Unlike other studies, Evans et al. performed single interval training on the cycle ergometer with all subjects. The interval training consisted of 10 exercise phases for three minutes at 60% of the VO2maxwith 90-second pauses between phases. Blood samples were drawn at four times, prior to the intervention, immediately after the intervention, two hours after the intervention and 24 hours after the intervention. The results show an increase in NK-cells in all subjects. It is noteworthy that the NK-count directly after the intervention is lower in breast cancer patients than in participants without cancer (5).
The study by Peters et al. could demonstrate physical exercise-induced changes, especially in the monocytes and the NKcells (CD56+). A group of 24 breast cancer patients completed a 7-month training program on a cycle ergometer. The training program was initially conducted in a rehabilitation clinic 5-times per week for 5 weeks with increasing length. Subsequently, it was continued for another 6 months 2-3 times per week in an outpatient group. The blood samples to determine the cell counts of monocytes and NK-cells were examined at three time points: at the start of the study, after 5 weeks and at the end of the study. The results showed 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). In addition, a constant NK-cell count with elevated cytotoxic activity was determined. At the start of the study, the basal activity of the NK-cells in cancer patients (18.9% lysis) showed lower performance capacity than in healthy persons (30-35% lysis). After the 7-month intervention program, the NK-cells of the cancer patients showed a cytotoxic activity of 28.3% lysis capacity and thus attain the range of the healthy subjects (p>0.05) (33, 34).
Hagstrom et al. could also determine a positive effect of physical training on the immune system. 39 breast cancer patients were randomized to an intervention and a control group. The 20 participants in the intervention group completed equipment training over 16 weeks at 80% of the “one repetition maximum”. The NK-cells, the “natural killer T-cells” (NKT) and the inflammation markers, TNF-α, IL-6, IL-10 and CRP (C reactive protein) were measured before and after the intervention. The results showed a change in NK and in the NKT-function. Compared to the control group, the intervention group had a lower expression of TNF-αon the NK-cells (p=0.005) and on the NKT-cells (p=0.04) at the end of the study. There were no other significant differences (11).
Zimmer et al. investigated the short-term effect of a half-marathon on the immune system of breast cancer patients. Blood samples were drawn from nine breast cancer patients in follow-up care and nine healthy athletes before, 15 minutes after and 24h after a half-marathon. The focus of this investigation is on the leukocytes (granulocytes, monocytes, lymphocytes), the T-cells and the anti-inflammatory cytokines. No significant difference was observed at any time between breast cancer patients and healthy athletes (52).
Nieman et al. found no influence of physical activity on the immune system in their study. 16 breast cancer patients were randomized in this study to an intervention and a control group, of whom only 12 completed the study. Nieman et al. focus the study on the physical performance capacity, the cell count of lymphocytes and the activity of the NK-cells. The intervention group completed a 60-miniute supervised strength and endurance training over 8 weeks, 3-times per week. The results showed an improvement in physical performance capacity and a significant improvement in the 6m-walking test (p=0.02) in the intervention group. No increase in lymphocytes and NKcells was observed. The T-lymphocyte count and the activity of the NK cells also remained stable (29).
Saxton et al. were also unable to confirm the expected influence of their intervention on the NK-cells. 85 breast cancer patients were randomized to an intervention and a control group. The intervention consisted of a 6-month progressive aerobic and strength training at 65-85 % of maximal heart rate, and a nutritional program. The results showed a change in neither the count nor the activity of the NK-cells compared to the control group. However, the leukocyte, lymphocyte and neutrophil counts in the control group increased compared to the intervention group. But no unequivocal conclusions can be drawn, since it is not apparent whether the sports and/or the nutritional program were responsible for the results (38).
Six studies report changes in lymphocyte subpopulations (5, 6, 15, 33, 34, 38). There is evidence that regular exercise has no influence on the CD3+T-lymphocyte (6, 15) and the CD56+-cell counts (6, 33, 34). Two of these studies also point out that regular exercise apparently brings no changes in the CD4+-/ CD8+- and CD20+-B-lymphocytes (6, 15). Five studies describe a change in cell function, for example the cytotoxic activity of NK-cells (6, 11, 15, 27, 33).
Ten studies address especially the effects of physical training on the immune system of breast cancer patients (5, 6, 11, 15, 27, 30, 33, 34, 38, 52). The results of these studies show that the NK cell populations increase or their function improves due to different sports interventions. Fairey et al. and Peters et al. report in addition a change in the lymphocyte population (5, 33). Both the NK-cells and also the lymphocytes play an important role in the immune system and the immunoreaction. Improvement in the function or the number of cells can work against a recurrence.
The studies and reviews described present the influence of physical exercise on the immune system, the effect on the cellular level and the changes in cytotoxins in various cancer forms. The focus of this review is on breast cancer.
Despite different intervention programs, all of the studies included expect physical exercise to bring improvement in the immunostatus of breast cancer patients, as well as in the other types of carcinoma considered. The possible effects of movement and physical exercise are, on the one hand, an increase in cells, on the other hand, improvement of the function of monocytes, macrophages, NK-cells and increased release of cytokines. The relevant exercise-induced immunomodifications in cancer still remain unclear (22, 45).
Various clinical studies show that physical exercise supports the activity of the cellular immune function and exerts a positive influence on the immune system with respect to tumor formation (42, 43, 45, 46). The intensity and duration play an important role in influencing the immune system.
To date, only a few scientific results are available on which to evaluate the dosage or a suitable sport and exercise intervention. An intensive and long-lasting intervention program leads to improved activity in various areas of the immune system (2, 25). A program which is too intensive and too long, on the other hand, can also have negative effects at the immune-system level.
Training at moderate intensity appears to exert a stimulating and activating effect (12). It is still not known whether endurance training or strength training is the more important for immunostimulation.
The influence of physical exercise on the change in the immune system takes place at the cellular level. An increase in cells or improved cell function can be demonstrated in various studies (5, 6, 11, 15, 27, 33, 34). In addition to adaptation of the immune system, the cytokines have an additional positive secondary effect on the well-being of cancer patients (reduction of fatigue, reduction of cancer cachexia) (39, 46). The immune function and reaction can be improved by an increase in cells and improvement in the function of monocytes, macrophages and NK-cells (3, 23, 42, 43, 45, 46).
The different results of the available studies can be attributed to the various study designs. This review concentrates on the phase after operation, chemotherapy or radiation therapy. The sport and exercise programs in the studies cited differ in several points, so that comparability is limited (6, 45). The intervention programs differ with respect to their intensity, duration of the individual training sessions, their frequency and the overall extent of physical activity. While Peters et al. set the intensity of endurance training at 60-85% of maximal heart rate, Nieman et al. choose an intensity of 75% of maximal heart rate. Other differences can be observed with respect to the length of the individual training sessions (30-60 minutes), the frequency (three times per week – five times per week) and the overall duration (between 8 weeks and 7 months).
A further common limitation of all cited studies is the lack of attention to additional activity on the job, in everyday life and leisure. Endurance training was selected as the intervention in most cases (4, 5, 6, 15, 27, 29, 33, 34, 47, 52). This was conducted in six studies on an ergometer (4, 5, 6, 27, 33, 34), in one study as an aerobic program (15) and in two other studies as walking sessions (47) or on a treadmill (29). Two studies combined cardio-training with a strengthening program (29, 38). One study supplemented endurance training with mobilization and mobility training (27). Strength training was selected as intervention only in the study by Hagstrom et al. (11), and Zimmer et al. chose a single half-marathon as intervention (52). The terms “physical training” and “physical exercise” do not allow deduction of which specific training methods and what intensity are involved (17, 26, 45).
The original articles and reviews do not adequately state the times at which blood samples were drawn (directly after training, 24h after training or at some other time). The changes in the immune system are short-lived and are often determined by the type and duration of activity. Here, again, determination of the optimal “training dosage” appears to be decisive.
The cited reviews focus on the effect of physical exercise on the immune system of breast cancer patients. Although the quality of the studies has improved with time, further investigations and studies are necessary to optimize and broaden the possibilities of sport and exercise therapy on the quality of life, chance of survival and risk of recurrence. In addition to breast cancer, other types of cancer (such as prostate and colon carcinoma) are taken into account. The data in the additionally-named carcinomas on the topic “Effects of physical activity on the immune system” are similarly as heterogeneous as for breast cancer.
The discussion in all publications on this topic is found to be difficult and complicated, since each article has its own methodical limitations, which makes the discussion and interpretation of the results more difficult. The results of the various study designs point to possibilities and tendencies. The individual lifestyle of the individual subject, along with other secondary diseases, cannot be ruled out as possible disruptive factors.
This review demonstrates the complexity of the topic. The authors reach different results due to various study designs and the limitations of the various individual studies. Future studies should address more homogeneous subject groups so that specific exercise recommendations can be made. Scientific and more specific statements about the effect of targeted sports intervention after a breast cancer diagnosis are possible only after further prospective, standardized and controlled clinical studies confirming the assumption of an immunomodulating effect of physical activity. Investigation of the dose/effect relationship of sports in breast cancer or various carcinoma entities in general should additionally be the focus of future studies to enable more precise statements on the intensity, duration and extent of sport activities.
Conflict of Interest
The authors have no conflict of interest.
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