Abstract
Background/Aim: A prospective non-randomized study was performed on 68 women who had recently undergone curative treatment (surgery +/− adjuvant radio/chemotherapy) for breast cancer. Patients and Methods: Patients were distributed into 2 subgroups, control (C) group (n=21) and experimental (E) group (n=47). The last group participated in a 12-week rehabilitation program associating physical activity and psychoeducational workshops, including management of stress, diet, and sleep disorders. Results: Despite the initial imbalance between the groups (patients from C group were older and had received less chemotherapy than those from the E group), at the end of the rehabilitation program, we observed a significant improvement in global health feeling and in objective physical tests (distance covered in 6 min and objective measures of ergospirometry), and a decrease in pathological fatigue, while these different items remained quite stable over time in the control group. Conclusion: It is suggested to recommend structured rehabilitation to any patient who does not have a contraindication to it. In addition, the scientific literature encourages us to extend the spectrum of oncological rehabilitation to pathologies other than breast cancer.
The benefits of physical activity on health, in general, are well recognized and do not have to be proved anymore (1-9). The interest in incorporating physical activity in the field of Medical Oncology is more recent. According to multiple studies, this practice would be beneficial for cancer patients if generalized and integrated before, during or even after the therapeutic process (1-9).
Outcome of hormone-sensitive breast and prostate cancers has been especially investigated (1-9). In 2003, under the umbrella of Ghent University, a program for oncological multidisciplinary rehabilitation (OR) was initiated in 5 centers of Belgian Flemish region. Afterwards, a Belgian work group for OR was launched with the support of the Ministry of Health and the National Health Insurance (10).
A multicenter study entitled “Improvement of the quality of life and reintegration of breast cancer patients after adjuvant treatment through physical training and lifestyle supervision” was developed in 3 phases: preparation, execution and information processing. Phase I was completed in 2008. Our hospital group was selected among 14 other Belgian centers to take part in the execution phase.
We present here the quintessence of our observations and conclusions integrated in a literature overview on the subject (10).
Patients and Methods
Ethics. The study was approved by the independent Ethics Committee of Ghent University and by the Ethics Committees of each participating center, i.e. our hospital group, CHC - Liège (B). The trial was held according to Good Clinical Practice recommendations and the Declaration of Helsinki, ethical frame for human experimentation. All patients received detailed information about the proposed program and had to sign an informed consent.
Inclusion criteria. Inclusion and exclusion criteria were applied to both control and experimental groups. The study was not randomized, according to Ghent University Ethics Committee and Health National Insurance recommendations.
Patients aged over 18 years, recently operated for primary breast carcinoma and having completed adjuvant treatment (radio- and/or chemotherapy) between 3 and 52 weeks before inclusion were eligible for the study. They had to be autonomous and with a performance status over 60 on the Karnofsky scale (11). Hormonotherapy or trastuzumab adjuvant treatments were allowed during the study. All patients had to be able to participate in a group program and to develop physical training activity. Signed informed consent was required.
Intervention. A rehabilitation program, which could be qualified as mixed, was proposed on a 12-week schedule for a total of 72 h: 48 h of physical training (4 h a week) and 24 h of psychoeducational sessions divided into 8 sessions.
Physical exercises were performed in organized group classes on specific fitness material (e.g. classical or elliptic bikes, treadmills, exercise machines). In psychoeducational sessions, the following topics were addressed: interest in regular physical activity, feeding, psychosocial aspects, stress management, sleep disorders, sexuality. These workshops were coordinated by various stakeholders: oncology nurse, physiotherapist, dietician, psychologist, sexologist and others (10).
Measures. Various tests were performed in both groups at 2 distinct moments: M0, the time of inclusion, and M3, about 3 months after inclusion, that is after the end of rehabilitation.
At M0, outside of a general biology, the general characteristics as well as the Karnofsky index, actual disease status and the medications received by all patients were reported.
At M0 and M3, the following evaluations were performed:
Administration of various questionnaires: EORTC QLQ-C30 (quality of life) (12), FACIT (fatigue) (13), HADS (“Hospital Anxiety and Depression Scale” (14), which evaluate separately anxious and depressive affects.
Physical capacity and biometric measurements: blood pressure, 6-minute walk test (6MWT) (15), BMI (body mass index: weight[kg]/size[m2]), cycle ergometry with electrocardiogram at rest and after effort, determination of maximal oxygen consumption and maximal developed power (16).
Statistics. All variables were recorded in an ad hoc Excel file after eventual normalization and transformation in percentages. In general, the higher the values of variables expressed as percentages (from 0 to 100), the more favorable the results for the patients, except for fatigue where lower percentages indicated favorable results.
The general characteristics of patients were compared between control (C) and experimental (E) groups. Only paired values were retained for statistical analysis. All analyses were performed using classical SAS 9.2 software. Continuous data were compared using non-parametric Student's t, Wilcoxon and Kuskall-Wallis tests. Categorical data were compared using exact Chi-square and Fisher tests.
Results
Patients. Between January 2014 and May 2015, 68 patients aged 32 to 80 were invited to participate in the study. Among them, 21 were included in the control group for various reasons: good well-being or have returned to work [7], retired or live too far from the hospital [4], negative medical advice [3], live abroad [2] or others [5]. Forty-seven patients were eventually included in the experimental group.
Patients characteristics at time 0 (M0).
Their characteristics are described in Table I.
Some differences were observed between the groups. The median age of the control group was about 13 years higher than that of the experimental group (59.6 vs. 47.8; p<0.0001). This group had also received less chemotherapy than the experimental group (87.2 vs. 61.9%; p<0.05). Furthermore, the delay between completion of oncological treatments and inclusion in the protocol was longer in the control group (195 +/− 106 days vs. 95 +/− 74 days; p<0.0001). For all other criteria, groups were comparable (e.g. histology, stage, surgery type, radiotherapy, hormonotherapy, trastuzumab). BMI was also similar: 27.3 +/− 5.3 kg/m2 in group C vs. 26.3 +/− 6.1 kg/m2 in group E (NS).
Variables. Although a significant difference was noted regarding the delay before inclusion in both groups, there were no differences in the delay between M0 and M3 (102 +/− 12 days for the control group and 111 +/− 11 days for the experimental group; NS).
EORTC QLQ-C30 Questionnaires (except «Fatigue» and «Emotional Functions»).
A significant improvement in global health was observed between M0 and M3 in the experimental group through the EORTC QLQ-C30 questionnaire, increasing from 57% to 69% (Table II; p<0.02). The control group presented a more favorable global health index at the beginning of the observation, but the stability of this variable along time was recorded (Table II).
Fatigue was also evaluated based on 2 questionnaires (EORTC-QLQ C30 and FACIT) (Table III). At the beginning (M0), patients of the experimental group had more fatigue than those of the control group; however, this feeling did not vary during the study period in the control group, while a significant improvement in this variable was seen in the experimental group (Table III).
Functional role and physical activity (EORTC questionnaire) were similar in both groups at inclusion time (Table II). However, while a significant improvement at M3 time of both parameters was assessed in the experimental group, no change was recorded in the control group (Table II). The same kinetics were retrieved in social activities (EORTC questionnaire), but a difference in favor of the control group at the beginning was noted (Table II).
The influence of the rehabilitation program on mind and mood was assessed by application of EORTC and HADS questionnaires. An improvement in general mind and depression was recorded by both subjective evaluations, but no improvement in anxiety could be shown in the HAD scale (Table IV).
Fatigue (EORTC QLQ-C30 and FACIT questionnaires).
Also, no impact of rehabilitation could be detected on cognitive capacities (Table II).
No difference in biometric measures (BMI) could be observed between both groups, regardless of the times of investigation (data not presented).
About objective physical evaluations (Table V), if both groups were similar at inclusion regarding traveled distance (6-min walk test) and VO2 maximal consumption, patients of the control group had better performance in terms of relative maximal power (Table V). However, upon completion of the assessment, subjects in the control group did not progress at all, while rehabilitated women experienced a significant improvement in their physical performances, with an increase in traveled distance, VO2 maximal consumption and relative maximal power (Table V).
Discussion
General considerations. This retrospective study details results observed in one of the 14 selected Belgian centers for recruitment of women recently treated (and considered as “cured”) for early breast cancer, who were eligible for a multidisciplinary rehabilitation program. To the best of our knowledge, this is the most complete analysis in terms of detailed variable evaluation in our country. This is also the first study procuring precise cardiorespiratory assessment of cancer patients by cycle ergometry before and after rehabilitation (8, 17).
Emotional functions/anxiety/depression (EORTC QLQ-C30 and HADS questionnaires).
Before any consideration regarding the outcome of patients in this trial, we first analysed the differences in the characteristics of the control and the experimental groups. These dissimilarities are probably related to the nature of the trial, which was not randomized, according to the wishes of promotors (UZ Gent) and Ethics Committees. Thus, just by chance, the control group was constructed later (mean time between the end of active treatments and study inclusion: 195 vs. 95 days) than the experimental one, and included older subjects (mean age 60 vs. 48 years old) that were less intensively treated with chemotherapy (62 vs. 87%). These differences may probably explain more favorable items at inclusion time in the control group, such as better global health, physical and effort indices, social activities and less fatigue. Nevertheless, all patients complied with the inclusion criteria and were fully comparable regarding other inclusion characteristics (Table I).
Notwithstanding the limited size of our sample, we were able to find significant results favoring the rehabilitated group, even though this group presented worse clinical characteristics at presentation.
Compared to the control group, we clearly observed a significant improvement in global health, quality of life indices, fatigue, mind and mood, depression and also physical capacities as objectively measured by 6MWT and cycle ergospirometry (Tables II, III, IV and V). Perhaps in part due to its limited size, no difference was recorded in the studied population regarding cognitive functions or weight (BMI). Also, subgroups analyses (e.g. age, stage, chemotherapy, radiotherapy) could not be performed.
Objective physical activity (walk test and ergospirometry).
Improvements in variables retrieved from our experimental group vs. the control have already been reported in various international publications (1-9, 18, 19). However, most of these studies were non-randomized and concerned a limited number of patients (1-9). However, in the rehabilitation groups, an improvement in quality of life, fatigue and cardio-respiratory functions has generally been described (1-9, 18, 19). Moreover, a positive impact of physical activity on vitality, general well-being, positive mind, depressive status, cognitive items and quality of sleep are also regularly reported (20, 21). Such considerations have been confirmed in some recent meta-analyses on hundreds of subjects (8, 17).
Observations relating to the physical function in cancer patients are predominantly derived from general health-related quality-of-life tools rather than from more precise functional assessments. Interdisciplinary and clinician-researcher collaborative efforts should be directed toward a unified definition and assessment of physical function, which is precisely what we did here (6, 9).
The cost-effectiveness of exercise and physiotherapy interventions in the management of breast cancer remains sparse and with contrasting conclusions (22). However, Mairiaux et al. have provided encouraging observations regarding the faster return to active work of rehabilitated breast cancer patients (23).
Physical activity and breast cancer. Five-year survival of all stage breast cancer patients is around 89%. It appears indispensable to take quality of life into account for women who will ultimately die from other diseases.
Precisely, it is now recognized that regular physical and/or sportive activities may exert a protective role in the oncological process: prevention, management of side-effects during and after treatments, and outcome in terms of relapse and long-term survival (17).
Twenty-five to 30% of all breast cancers could be avoided by a better lifestyle. For example, 10-12% of all breast cancers may be linked to excessive sedentary or “prolonged sitting” (3, 10, 24). Physically active women would present a 25% risk reduction in developing breast cancer compared to sedentary subjects (3, 10, 24). This phenomenon has also been reported for other solid tumors (kidney, lung, colon, prostate, uterine corpus), but not in proliferative hematology (25-27).
Some authors, as Squires et al., have developed the concept of “pre-habilitation”, suggesting the implementation of a significant physical program before beginning oncological treatments (6) so the patient can optimize his cardiovascular “reserve”. This could have a protective effect against given cardiotoxic systemic treatments (6). Furthermore, physical activity before the initiation of chemotherapy could improve its tolerance and efficiency thanks to the better access of drugs to tumor cells through modification of tumor vascularization (6, 8, 9, 17).
In general, adding sport at a sufficient level (minimum 150 min of moderate intensity exercise per week, or minimum 75 min of vigorous exercise per week, or a combination of both) for achieving the 6 American Heart Association items (BMI <25 kg/m2; blood pressure ≤120/80 mmHg; fasting glycemia <100 mg/dl; cholesterol <200 mg/dl; + diets and tobacco eviction) allows to reduce significantly, not only the cardiovascular risk, but also the oncological risk (9, 17). Some authors also proposed to sustain home-based physical activity interventions. Walking programs may also be applied (28).
Of interest, in early prostate cancer, Galvao et al. (2, 25) showed that adding an active physical program to the “watch and wait” decision will allow to postpone the recourse to ADT (Androgen Deprivation Therapy). Delaying disease progression was related to improvement in the general quality of life, including the sexual and psychological aspects (2, 7, 25, 26).
What about suggesting a significant physical activity during and after active treatment? If adapted to the capacities of the patient, this initiative could have a positive effect on chemotherapy tolerance (less nausea/vomiting, less pain, less dose reductions) and a beneficial effect on fatigue and general quality of life (7, 8, 25). The higher the intensity of sport activity, the better the outcome (7, 8, 25). Indeed, in terms of physical rehabilitation exercises, it has been recently suggested to alternate high intensity interval training (HIIT) with more classical exercises (29, 30). As an example, a 16-week program of resistance and HIIT was effective in preventing increases in cancer-related fatigue (CRF) and in reducing symptom burden for patients during chemotherapy for breast cancer. These findings, added to a growing body of evidence supporting the prescription of structured exercise, allowed to include HIIT as a component of cancer rehabilitation (29, 30). The same conclusions about HIIT applies also to prostate cancer (25, 31). By now, our group has no experience on that subject (10).
In patients under aromatase adjuvant hormonotherapy, a randomized trial entitled “HOPE” has shown lessened osteoarticular pain in the “exercise” group vs. the “control” one (3% vs. 29%) (32).
Similarly, in patients suffering from prostate cancer and receiving ADT, regular exercise improved muscular power, cardio-respiratory function, sexual function and iatrogenic, sometimes severe, treatment-induced hypogonadism, and pathological fatigue (2, 25, 26, 31).
Finally, some meta-analyses have revealed that patients treated for breast carcinoma and practicing a regular physical activity had a significant reduced risk of relapse (-24%), death from cancer (-34%) and global mortality (-41%), compared to inactive patients (5, 17). A similar observation was made for colorectal cancer (mortality was reduced by 50%) (5, 27). Also, a BMI inferior to 30 kg/m2 could be related to fewer relapses in hormone-sensitive breast cancer patients (8, 24).
Physiopathology
Hormonal system. It is well known that estrogen exposure increases the risk to develop breast cancer (33, 34). A prospective study has shown that pre-menopausal women with elevated estradiol and androgen levels at the follicular phase of menstrual cycle could have two to three-fold higher risk to develop breast carcinoma (33, 34). Precisely, physical activity allows the regulation of stress hormones, and regulation of estrogen production through FSH lowering, which could be important in case of hormone-sensitive breast carcinoma (35). Similarly, reduction of fat mass, where the aromatase enzymes convert androgens into estrogens, exerts a protective effect against the development of such tumors (36). Precisely, the prospective SHAPE-2 trial published in 2015 showed the efficiency of physical exercise for reducing sexual hormones levels (estradiol, free estradiol, SHBG, free testosterone) with a concomitant reduction in breast cancer risk in overweighed post-menopausal patients with low activity (36).
Physical activity could also reduce breast cancer lethality through a decrease of insulinemia and an increase of sensitivity to insulin (27, 35, 36). However, activating mutations of PI3K and/or loss of PTEN signal may decrease sensitivity of tumor cells to insulin and insulin-like growth factor (IGF-1), thus reducing the potential protective effect of exercise on tumorigenesis.
Rundqvist et al. have found a link between growth hormone (GH) levels, IGF-1 levels and physical training (29, 30). Prolonged exercise (endurance) was beneficial by lowering GH and IGF-1, while acute exercise (resistance) had the contrary effect, which could raise fears of an unfavorable effect in terms of tumor growth and progression (29, 30). The question about the possible decrease of stress hormones in post-menopausal breast cancer women thanks to one-year moderate or high intensity exercise was asked in a large randomized trial in Alberta (35). Unfortunately, between baseline and 12 and 24 months, there were no significant differences in the levels of all stress hormones between the two intervention groups (35). In the same trial, a comparison of biomarker concentrations (C-reactive protein, insulin, glucose, HOMA-IR, estrone, sex hormone binding globulin, total estradiol, and free estradiol) over time (0, 12, and 24 months) by group [“MODERATE” or “HIGH” volume of exercise (150 vs. 300 min per week)] was performed (35). Exercise led to larger improvements in breast cancer biomarkers after intervention only among women who also experienced fat loss with exercise (35).
Inflammation and immunity. Carcinogenesis and tumor progression are regulated by complex interactions between tumor cells, their microenvironment and host systemic milieu (37-43).
A chronic inflammatory state, linked to chronic infections, dysimmune diseases or obesity, may be the source of prolonged cell stress, which can result in malignant transformation. Elevated circulating levels of inflammatory cytokines, pro-angiogenic factors and growth hormones are associated with an increased risk of relapse and cancer death in various solid tumors (37-39, 41).
Modulation of the immune system by physical exercise has been studied in a limited series, bearing in mind that it could be an adjuvant strategy to inhibit oncogenesis or tumor cell proliferation. Some authors, have observed a reduction in the levels of cytokines such as IL-1β, IL-2, IL-4, MIP-1β and TNFα in rehabilitated patients (38). Schmidt et al. suggested that increased immunological anti-cancer activity due to physical activity was probably mediated via an increase in the number and cytotoxicity of monocytes and natural killer cells and cytokines (40). Exercise-dependent mobilization and activation of NK cells provides a mechanistic explanation for the protective effect of exercise against cancer (42).
Reduced levels of physical activity in people's daily lives results in the development of metabolic syndrome or age-related disorders. Chronic inflammation is now understood to be an underlying pathological condition in which inflammatory cells such as neutrophils and monocytes/macrophages infiltrate into fat and other tissues and accumulate when people become obese due to overeating and/or sedentary lifestyle (39). Metabolic syndrome can create a climate of immune tolerance towards tumor development. Indeed, the obesity-induced pro-inflammatory and pro-thrombotic climate induces platelet activation (41, 43). Platelets by covering circulating lymphoid blood cells, will induce a down-regulation of NK (natural killer) cells and thus immune surveillance towards tumor cells (42). Continuous update and meta-analyses of observational cohorts have systematically confirmed the relation between physical inactivity, sedentary behavior, adiposity and weight gain on breast cancer risk (24).
Chronic systemic inflammation is also associated with increased catabolism, inducing muscular wasting, thus being a negative factor regarding survival chances (24, 38, 39). Physical exercise will fight against it and will allow reduction of circulating inflammatory markers (cytokines) and modification of pro-inflammatory harmful effects linked to obesity (39). This was also the conclusion in the Alberta trial mentioned above (35).
Age-related immune deficiency and chronic inflammation may contribute to cancer development (43). Some data confirm the emerging role of exercise in immunology and in preventing and treating cancer in older adults (43). Myokines (muscle-derived cytokines), such as oncostatin M and osteonectin, could mediate anti-cancer effects by promoting immune surveillance or inhibiting cancer cell viability. Previous studies have suggested that exercise-induced release of myokines and other endocrine factors into the blood and increase in the capacity of blood serum to inhibit cancer cell growth in vitro (43). In fact, in a recent study, Hwang et al. have observed that, in older men, increased serum myokine levels after exercise can inhibit tumor expression in androgen responsive prostatic cancer cell lines (43).
Tumor microvascularization. Concerning the microenvironment, it is known that in hypoxic regions, immune system effectors acquire an immunosuppressive phenotype (37-43). Through microvascular remodeling, exercise could modify tumor vasculature and reduce this effect. Aerobic exercise increases tumor blood flow, recruits previously non-perfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes of several types of cancers (41).
This assumption is supported by studies in prostate cancer patients: those well active physically retained more frequently a regular tumor vasculature (44).
Epigenetics. The ability of epigenetic processes to regulate oncogene or tumor-suppressor gene expression without modifying the DNA sequence of genes has been recently investigated (44, 45).
Inflammation and cancer expression, immune system, central nervous system as well as aging processes could benefit from physical activity thanks to epigenetic mechanisms. Modulation of epigenetic processes by physical exercise positively influence prevention, development and course of inflammatory and cancer diseases, as well as neurodegenerative illnesses (46). Consequently, epigenetic regulation of tumor suppressor genes in physically active people could have a beneficial impact on breast cancer patients' survival (45). It is also known that athletes present longer telomeres compared to the normal population (45, 46).
Conclusion
Our study recruited females recently operated and in remission from early breast cancer. We compared a group benefiting from a 12-week rehabilitation program associating physical activity and psychoeducational structured workshops to an observational group. At the end of the rehabilitation program, we observed an improvement in global health feeling, in the results of quantified physical tests (distance covered in 6-minute walk and objective cardiorespiratory measures by ergospirometry), as well as a decrease in pathological fatigue. All these variables remained quite stable over time in the control group. For the first time, we have provided objective measurements of cardio-vascular performances for all included cases.
Therefore, we recommend this type of management early in the course of any breast cancer woman who does not have a contraindication to it. In addition, the scientific literature encourages us to extend the concept of oncological rehabilitation to pathologies other than breast cancer.
Footnotes
Authors' Contributions
SM, MPG contributed to recruitment of patients; SM, MC, LC, CF contributed to follow-up of patients, recording, normalization and encoding of variables at MO and M3; VR, GB contributed to physical training; PE performed all cardiological evaluations; JPL, CF performed statistical analysis; CF, SM wrote the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received May 28, 2020.
- Revision received July 5, 2020.
- Accepted July 6, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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