Intern Emerg Med DOI 10.1007/s11739-015-1259-8
IM - ORIGINAL
Exercise training improves cardiopulmonary and endothelial function in women with breast cancer: findings from the Diana-5 dietary intervention study Francesco Giallauria1 • Alessandra Vitelli1 • Luigi Maresca1 • Maria Santucci De Magistris2 • Paolo Chiodini3 • Amalia Mattiello2 • Marco Gentile2 • Maria Mancini1 • Alessandra Grieco1 • Angelo Russo1 Rosa Lucci1 • Giorgio Torella1 • Franco Berrino4 • Salvatore Panico2 • Carlo Vigorito1
•
Received: 1 December 2014 / Accepted: 12 May 2015 Ó SIMI 2015
Abstract To investigate whether exercise training (ET) improves cardiopulmonary and endothelial function in women with breast cancer (BC). Fifty-one female patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (diet and androgens)-5 Trial were subdivided into 2 groups: an ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60–70 % VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and at 1-year follow-up, all patients underwent cardiopulmonary exercise stress test (CPET) and measurements of vascular endothelial function by peripheral artery tonometry (Reactive Hyperemia Index, RHI). There were no significant differences between the groups in baseline anthropometrical, BC characteristics, and metabolic profile. No differences in baseline CPET and RHI parameters were found. Peak oxygen consumption (VO2peak) significantly increased in ET group (from
& Francesco Giallauria [email protected]; [email protected] 1
Division of Internal Medicine and Cardiac Rehabilitation, Department of Translational Medical Sciences, University of Naples ‘‘Federico II’’, Via S. Pansini 5, 80131 Naples, NA, Italy
2
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
3
Medical Statistics Unit, Second University of Naples, Naples, Italy
4
Department of Preventive and Predictive Medicine, National Cancer Institute, Milan, Italy
12.4 ± 2.9 to 14.3 ± 3.3 mL/kg/min, p \ 0.001) compared to the control group (from 12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p \ 0.001 between groups). Compared to the control group (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62), the ET group showed a significant improvement of RHI after 1 year (from 2.1 ± 0.7 to 2.5 ± 0.8, p \ 0.001). Changes in VO2peak were correlated with changes in RHI (DVO2peak vs. DRHI: r = 0.47, p = 0.017). In BC survivors, ET program improves cardiopulmonary functional capacity and vascular endothelial function after 12 months. Whether these changes may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution should be investigated. Keywords Cancer Breast cancer Exercise training Cardiopulmonary exercise testing Endothelial function
Introduction Breast cancer (BC) is the most common cancer in women worldwide, and it is also the principal cause of death from cancer among women globally. Different studies suggest a key role for diet and physical activity on occurrence of BC [1–5]. Epidemiological studies suggest a possible effect of physical activity on the incidence of primary BC [6–9]; and in secondary prevention after BC diagnosis, observational studies consistently show that the level of physical activity of BC women is correlated to an improvement in several cancer-related outcomes. Moreover several studies focused on physical intervention suggest that a structured program of exercise training is also able to improve several cancerrelated outcomes in BC survivors [10–14].
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Patients with breast cancer are obviously exposed to the normal aging decline, age- and disease-related comorbidity, and deconditioning that adversely affect cardiopulmonary function. However, compared to women from the general population, BC women are also subjected to the use of prolonged and aggressive multimodal anticancer therapy [15], which together is suspected of causing further impairments in cardiopulmonary function predisposing to cardiovascular disease [16]. Incremental cardiopulmonary exercise test (CPET) with gas exchange measurement provides the gold standard assessment of aerobic capacity as expressed by peak oxygen consumption (VO2peak) [17]. VO2peak is inversely correlated with cardiovascular and all-cause mortality in a broad range of adult populations [18, 19]. Accordingly, CPET is widely used in numerous clinical settings, and provides a wealth of diagnostic, prognostic, and decisionmaking information [20–24]. In addition, endothelial activation and dysfunction may play a significant role in the progression of BC [25] and recent evidence suggests that it might be on the basis of drug cardiotoxicity [26]. Therefore, this study tested the hypothesis that exercise training might improve cardiopulmonary and endothelial function in BC women.
Methods Study population The DIANA (diet and androgens)-5 study is a multicentre randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer (BC) events in women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu [27]. The overall design of the study has been described elsewhere [27]. We analyzed monocentric data (University of Naples ‘‘Federico II’’) consisting of 51 patients subdivided into two groups: 25 patients (51.8 ± 7.7 years, training group) underwent structured exercise training intervention (3 times/week for the first 3 months, and once/week for the following 9 months); whereas 26 patients (53.9 ± 8.5 years, control group) received recommendations to adhere to the lifestyle intervention suggestions of the DIANA protocol. The protocol was approved by the institutional ethics committee. The purpose of the protocol was explained to the patients and written informed consent was obtained from each patient before inclusion.
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Study protocol At the study enrollment and after 12 months, all patients underwent anthropometrical and biochemical assessment, cardiovascular clinical examination, and cardiopulmonary exercise stress testing. At the study enrollment, all women received a leaflet illustrating the WCRF/AICR recommendations for cancer prevention [28]. Training group patients were administered both the dietary and exercise training program as detailed below. The intervention group (training group, 25 patients) underwent, in addition to exercise training sessions, a counseling dietary program supported by cooking classes, reinforcing meetings and print materials. The counseling program aimed at increasing leisure-time physical activity level, controlling weight, and promoting a healthy and low calorie diet. Control group (26 patients) received only general recommendations to adhere to the lifestyle intervention suggestions of the DIANA protocol. Anthropometrical and biochemical assessment Body mass index (BMI) was used as a general measure of obesity, and was calculated at the final visit as weight (kilograms) divided by height (meters squared). Waist circumference (WC), an index of abdominal obesity, was measured midway between the bottom of the rib cage and the top of the iliac crest. Blood pressure was measured twice after 5 min rest using a mercury sphygmomanometer. Anthropometric measurements were made with the subjects in indoor clothing and without shoes. Blood specimens were collected after 12- to 14-h fast, from 08:00 to 09:30 h, to reduce the influence of circadian variation. Total cholesterol, triglyceride and high-density lipoprotein (HDL) cholesterol levels were measured using standard enzymatic methods [29]. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula. Fasting glucose levels were enzymatically determined by the peroxidase method. Fasting insulin levels were determined by enzyme immunoassay (Ultrasensitive Insulin Elisa, Mercodia, Sweden). The homeostatic assessment model (HOMA) index was used to estimate insulin resistance, and calculated as fasting serum insulin (mU/L) 9 fasting serum glucose (mM)/22.5, as previously described [30]. Cardiopulmonary exercise training testing Respiratory gas exchange measurements were obtained breath by breath with the use of a computerized metabolic cart (Vmax 29C, Sensormedics, Yorba Linda, CA, USA) as detailed elsewhere [31, 32]. Briefly, after a 1-min warm-up
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period at 0 Watts workload, a ramp protocol of 20 W/min was started and continued until exhaustion. The pedaling was kept constant at 55–65 revolutions/min. A 12-lead electrocardiogram (ECG) was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 min. VO2peak was recorded as the mean value of VO2 during the last 20 s of the test and was expressed in milliliters per kilogram per minute. Predicted VO2peak was determined by use of a sex-, age-, height- and weight-adjusted and protocol-specific formula as previously detailed [17, 31, 32]. The ventilatory anaerobic threshold (VAT) was detected by use of the V-slope method. The VE versus VCO2 relationship was measured by plotting ventilation (VE) against carbon dioxide production (VCO2) obtained every 10 s of exercise (VE/ VCO2slope): both VE and VCO2 were measured in liters per minute. The VE/VCO2slope was calculated as a linear regression function, excluding the non-linear part of the relationship after the onset of acidotic drive to ventilation [17, 31, 32]. Endothelial function assessment Endothelial function was assessed using Endo-PAT device (Itamar Medical Ltd, Caesarea, Israel). During the measurement the subject sat in a chair with the hands at the level of the heart and fingers hanging freely. Fingertip probes were placed on both index fingers and pulse wave amplitudes were detected and recorded during the study. After a five-minute baseline measurement, arterial flow was occluded using a cuff on the non-dominant arm. The cuff was inflated to 40 mmHg above systolic pressure. After 5 min of occlusion, the cuff was rapidly deflated to allow reactive hyperemia. Pulse wave amplitudes were recorded again for at least five minutes. The software provided by the manufacturer was then used to compare the arterial pressure ratio in the two fingers before and after occlusion. It then calculated a reactive hyperemia index (RHI), which was a ratio of the average pulse wave amplitude measured over 60 s, starting 1 min after cuff deflation, to the average pulse wave amplitude measured at the baseline. The other arm served as a control, and the ratio was corrected for changes in the systemic vascular tone. An RHI value of \1.67 was used as a cut-off value to diagnose endothelial dysfunction [33]. Exercise training program and cooking session Training group patients were enrolled in an in-hospital structured exercise training program. The frequency goal of in-hospital exercise training sessions was 3 times/week for the first 3 months, and once/week for the following 9 months. Each session consisted of cycle or treadmill
30 min exercise, preceded by 5 min of warming and followed by 5 min of cooling down, at a work load of 60–70 % of baseline VO2peak. This structured exercise training was on top of the general leisure-time physical activity recommendations or prescription of the general DIANA study (questionnaires, caloric control, etc., see above). From the 4th month to the 12th month, in-hospital exercise training sessions were reduced to one session/ week, integrated with general leisure-time physical activity sessions, according to recommendations and prescription of the general DIANA study [27]. During cooking sessions, patients were invited cooking and eating some dishes prepared according to the WCRF/AICR recommendations and inspired by a macrobiotic Mediterranean diet [28]. Statistical methods Continuous variables were reported as either mean and standard deviation (SD) or median and range according to their distribution. The normality of residuals was tested with the Shapiro–Wilks test, and if residuals were not normally distributed the difference between RHI values was tested using the Wilcoxon test. Categorical variables were reported as percentage. Differences in characteristics of patients among groups were tested by means of one-way ANOVA and Pearson Chi square test for continuous and categorical variables, respectively. Data were analyzed using SAS version 9.2 (SAS Inc, Cary, NC). All statistical tests were twosided and p values\0.05 were considered significant.
Results Baseline characteristics of the study population are shown in Table 1. There were no significant differences between groups in baseline anthropometrical, BC characteristics and metabolic profile (Table 1). The study period was similar in both groups. In training group, the average exercise intensity was 70 ± 2 % of baseline VO2peak. No adverse events took place during any of training sessions in BC patients undergoing exercise training sessions. Both groups were overweight at baseline (Table 1). At 1-year follow-up, a significant decrease in BMI (from 27.3 ± 5.2 to 26.6 ± 4.9 kg/m2, p = 0.02), in WC (from 94 ± 15 to 90 ± 13 cm, p = 0.005), and in systolic blood pressure (from 121 ± 17 to 115 ± 12 mmHg, p = 0.011), while no changes were observed among controls (Table 2). Baseline plasma lipids, glucose and insulin levels were normal and did not change at 1 year in both groups. No differences in baseline CPET and RHI parameters were found (Table 2). At baseline, VO2peak and O2-pulse were in the lower range (Weber class C) in both groups. In
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Intern Emerg Med Table 1 Anthropometrical and clinical characteristics of the study population
Training group (n = 25)
Control group (n = 26)
p value
Anthropometrics Age (years)
51.8 ± 7.7
53.9 ± 8.5
0.55
Waist circumference (cm)
94 ± 15
94 ± 12
0.66
Body Mass Index (Kg/m2)
27.3 ± 5.2
28.2 ± 4.8
0.20
Breast cancer characteristics Presence of invasive carcinoma (%)
25/25 (100)
26/26 (100)
–
Node positivity (%)
48 (n = 12/25)
54 (n = 14/26)
0.58
Estrogen positivity (%)
80 (n = 20/25)
85 (n = 22/26)
0.78
93.5 ± 12.5
92.2 ± 15.5
0.67
Metabolic and hormonal profile Glycemia (mg/dL) Insulin (ng/mL)
7.8 ± 4.0
8.2 ± 2.2
0.29
HOMA index
1.739 ± 1.403
1.925 ± 0.908
0.54
Total cholesterol (mg/dL)
205 ± 34
203 ± 32
0.85
LDL-cholesterol (mg/dL)
126 ± 35
123 ± 29
0.24
HDL-cholesterol (mg/dL) Triglycerides (mg/dL)
54.3 ± 11.6 100 ± 43
54.8 ± 12.7 109 ± 52
0.63 0.13
Testosterone (nmol/L)
0.36 ± 0.36
0.38 ± 0.26
0.79
HOMA homeostatic assessment model, LDL low-density lipoprotein, HDL high-density lipoprotein
ET group VO2peak (from 12.6 ± 3.0 to 14.5 ± 3.3 ml/kg/ min, p \ 0.001) and O2-pulse (from 6.2 ± 1.2 to 6.9 ± 1.2 ml/kg/min/beat-1, p \ 0.001) improved at 1-year follow-up, respectively. No significant changes in VO2peak (12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p \ 0.001 between groups), and in O2-pulse (from 6.0 ± 1.4 to 6.2 ± 1.2 ml/kg/min/beat-1, p = 0.39; p \ 0.001 between groups) were observed at 1-year follow-up among controls. ET group showed a significant improvement of RHI (from 2.1 ± 0.7 to 2.5 ± 0.8, p \ 0.001); whereas no significant changes were observed among controls (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62; p \ 0.001 between groups). At 1-year follow-up, the level of physical fitness achieved in ET group as expressed by VO2peak was inversely correlated with the 1-year value of BMI (r = -0.426, p = 0.001) and WC (r = -0.47, p \ 0.001). In ET group, a significant negative correlation between 1-year BMI and WC and 1-year RHI was observed (r = -0.460, p = 0.001 and r = -0.425, p = 0.002, respectively). In addition, in ET group, changes in VO2peak were correlated with changes in RHI (DVO2peak vs. DRHI: r = 0.47, p = 0.017).
Discussion The main finding of this study is that structured exercise training improves cardiopulmonary and endothelial function in women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu.
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Epidemiological studies have shown that the level of physical exercise is associated with improved outcome in BC patients, included cancer related and total mortality [8–10]. Notably, despite normal cardiac function, BC women have significant and marked impairments in cardiopulmonary function [34]. Jones et al. [34] find that, on average, in BC women VO2peak is 27 % less than that of age-matched sedentary but otherwise healthy women without a history of breast cancer. Remarkably, patients with breast cancer reach a predicted VO2peak for a particular age group (e.g., 40 years) approximately 20 to 30 years earlier than healthy women without a history of breast cancer. Sweeney et al. [35] report that elderly cancer survivors (of mixed diagnoses) are less likely to be able to do heavy household tasks, walk half a mile, or walk up and down stairs, compared with women without a history of cancer. Our findings indicate that patients with breast cancer, at baseline, are in the lower range for VO2peak and O2-pulse (Weber class C), less than the functional independence threshold and, by definition, unlikely to be able to perform such tasks. Several studies show that moderate intensity exercise interventions in postmenopausal breast cancer (i.e. 60 % VO2peak) are associated with several favorable effects in several cancer-related outcomes, such as physical and psychological function and quality of life [36, 37]. The individual characteristics, type and intensity of exercise, as well as the timing of cancer diagnosis and stage may have an interplay role. In our study population, we observe a significant exercise-induced improvement of cardiopulmonary functional capacity at 1-year follow-up. Aerobic
Intern Emerg Med Table 2 Anthropometrics, metabolic and hormonal, cardiopulmonary and endothelial parameters at baseline and at 1-year follow-up Trained group (n = 25) Baseline
p value
1-year
Control group (n = 26) Baseline
p-value
1-year
Differences in changes between groups
Anthropometrics Waist circumference (cm) Body Mass Index (Kg/m2) Metabolic and hormonal profile Glycemia (mg/dL) Insulin (ng/mL) HOMA index
94 ± 15
90 ± 13
0.005
94 ± 12
95 ± 12
0.88
\0.001
27.3 ± 5.2
26.6 ± 4.9
0.02
28.2 ± 4.8
28.3 ± 5.4
0.67
\0.001
93.5 ± 12.5
92.8 ± 13
0.61
92.2 ± 15.5
90.6 ± 18.1
0.63
0.44
7.8 ± 4.0
8.0 ± 5.0
0.74
8.2 ± 2.2
7.9 ± 3.1
0.71
0.88
1.739 ± 1.403
1.822 ± 0.629
0.51
1.925 ± 0.908
1.825 ± 0.477
0.61
0.77
Total cholesterol (mg/dL)
205 ± 34
200 ± 29
0.66
203 ± 32
210 ± 26
0.42
0.62
LDL-cholesterol (mg/dL)
126 ± 35
122 ± 30
0.36
123 ± 29
126 ± 35
0.22
0.29
HDL-cholesterol (mg/dL)
54.3 ± 11.6
55.5 ± 9.7
0.78
54.8 ± 12.7
50.1 ± 8.7
0.19
0.52
Triglycerides (mg/dL)
100 ± 43
108 ± 42
0.53
109 ± 52
119 ± 46
0.60
0.41
Testosterone (nmol/L)
0.36 ± 0.36
0.40 ± 0.16
0.21
0.38 ± 0.26
0.33 ± 0.19
0.49
0.42
12.6 ± 3.0
14.5 ± 3.3
\0.001
12.8 ± 2.5
12.6 ± 2.8
0.55
\0.001
Cardiopulmonary parameters VO2peak (ml/kg/min) O2-pulse (ml/kg/min/beat-1) VE/VCO2slope
6.2 ± 1.2
6.9 ± 1.2
\0.001
6.0 ± 1.4
6.2 ± 1.2
0.39
\0.001
29.7 ± 4.4
30.9 ± 3.9
0.12
30.1 ± 3.8
31.3 ± 4.9
0.46
0.44
2.1 ± 0.7
2.5 ± 0.8
\0.001
2.0 ± 0.4
1.9 ± 0.4
0.62
\0.001
Endothelial function Reactive Hyperemia Index
HOMA homeostatic assessment model, LDL low-density lipoprotein, HDL high-density lipoprotein, VE/VCO2slope the minute ventilation–carbon dioxide production, VO2peak peak oxygen consumption
exercise training is the most effective therapy to improve VO2peak in healthy individuals given that it improves the reserve capacity of all O2 transport organs, which together lead to favorable improvements in VO2peak [38]. Data from meta-analysis show that exercise training in patients with cancer causes d a significant improvement in VO2peak (weighted mean difference ?2.90 mL/kg/min; 95 % CI, 1.16–4.64 mL/kg/min), compared to sedentary control [39]. Our findings are in line with these data, considering that in the ET group, VO2peak improves on average of about 2 ml/kg/min compared to controls. Investigation of the most effective type and intensity of exercise training to increase VO2peak and other outcomes, as well as the physiologic mechanisms underlying the exercise training– VO2peak relationship in breast cancer populations should be further investigated. Breast cancer–endothelium interactions provide regulatory signals facilitating tumor progression [25]. Conventional models of carcinogenesis suggest that endothelial cells are closely related with tumor perfusion. In this view, the endothelium acts not only as a passive strong barrier against cancer cells [40] but also as a stromal regulator during tumor progression [41]. A recent study also suggests that endothelial dysfunction might be at the basis of drug cardiotoxicity [26]. In this study, a significant improvement of vascular endothelial function as expressed by the
increase of RHI is observed among exercising BC women. However, the impact of endothelium on cancer cells and vice versa is still to a great degree undefined. Whether exercise training might favorably modulate endothelial function or might interfere with the mechanisms by which cancer cells can transmigrate through the endothelial lining remains to be investigated. It is largely possible that the macrobiotic Mediterranean diet may have a predominant contribution to the increased bioavailability of NO, thus improving endothelial and cardiopulmonary function. Further studies are encouraged in order to evaluate whether exercise/diet-induced improvement of endothelial function might interfere with drug cardiotoxicity. Along with the improvement of cardiopulmonary functional capacity and endothelial function, weight loss, reduced levels of insulin, glucose, and sex hormones, decreased inflammation and immunostimulation might also explain the beneficial effects of exercise on cancer outcomes [11, 42, 43]. Of note, all BC patients were overweight at study entry. Recent studies showed that obese BC patients have a poorer prognosis than non-obese patients of all ages [44, 45]. The underlying reason for this association is not clear. Patients with a high BMI tend to present with larger tumors, and some studies report more biologically adverse features including grade 3 tumors and nodal involvement in obese patients [46, 47]. Patients with a high BMI may also
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receive less effective treatment for early breast cancer [48]. Finally, obesity can be viewed as a sub-clinical inflammatory state, and activated macrophages in adipose tissue producing proinflammatory mediators may potentially affect the tumor micro-environment [49]. Interestingly, in our study, a significant decrease of BMI and WC is observed among exercising BC women at 1-year follow-up; while no changes is observed among controls. Studies exploring whether the improvement of BMI and WC has beneficial prognostic effect are encouraged. A number of limitations of the present study should be considered. Training patients underwent a moderate intensity exercise program: whether an exercise program of higher intensity might have additional clinical and prognostic value should be clarified. Despite the aforementioned limitations, this study has several unique strengths. This is the first study enrolling high-risk BC survivors (women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu) to 1-year structured exercise intervention showing significant improvement of both cardiopulmonary and endothelial function. In conclusion, moderate intensity exercise training combined with diet in breast cancer survivors improves cardiopulmonary functional capacity and vascular endothelial function. Whether the improvement of both cardiopulmonary and endothelial function may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution needs further investigation. Acknowledgments The DIANA-5 Project was financed by the Italian Association for Cancer Research (AIRC, Grant no. 11942) and by the Italian Department of Health (PIO program). This study was also financed by the FARO (Fondo per l’Avvio di Ricerche Originali). Conflict of interest of interest.
The authors declare that they have no conflict
Statement of human and animal rights The institutional ethical committee approved the protocol. The purpose of the protocol was explained to the patients. Informed consent Written informed consent was obtained from each patient before inclusion.
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IM - ORIGINAL
Exercise training improves cardiopulmonary and endothelial function in women with breast cancer: findings from the Diana-5 dietary intervention study Francesco Giallauria1 • Alessandra Vitelli1 • Luigi Maresca1 • Maria Santucci De Magistris2 • Paolo Chiodini3 • Amalia Mattiello2 • Marco Gentile2 • Maria Mancini1 • Alessandra Grieco1 • Angelo Russo1 Rosa Lucci1 • Giorgio Torella1 • Franco Berrino4 • Salvatore Panico2 • Carlo Vigorito1
•
Received: 1 December 2014 / Accepted: 12 May 2015 Ó SIMI 2015
Abstract To investigate whether exercise training (ET) improves cardiopulmonary and endothelial function in women with breast cancer (BC). Fifty-one female patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (diet and androgens)-5 Trial were subdivided into 2 groups: an ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60–70 % VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and at 1-year follow-up, all patients underwent cardiopulmonary exercise stress test (CPET) and measurements of vascular endothelial function by peripheral artery tonometry (Reactive Hyperemia Index, RHI). There were no significant differences between the groups in baseline anthropometrical, BC characteristics, and metabolic profile. No differences in baseline CPET and RHI parameters were found. Peak oxygen consumption (VO2peak) significantly increased in ET group (from
& Francesco Giallauria [email protected]; [email protected] 1
Division of Internal Medicine and Cardiac Rehabilitation, Department of Translational Medical Sciences, University of Naples ‘‘Federico II’’, Via S. Pansini 5, 80131 Naples, NA, Italy
2
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
3
Medical Statistics Unit, Second University of Naples, Naples, Italy
4
Department of Preventive and Predictive Medicine, National Cancer Institute, Milan, Italy
12.4 ± 2.9 to 14.3 ± 3.3 mL/kg/min, p \ 0.001) compared to the control group (from 12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p \ 0.001 between groups). Compared to the control group (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62), the ET group showed a significant improvement of RHI after 1 year (from 2.1 ± 0.7 to 2.5 ± 0.8, p \ 0.001). Changes in VO2peak were correlated with changes in RHI (DVO2peak vs. DRHI: r = 0.47, p = 0.017). In BC survivors, ET program improves cardiopulmonary functional capacity and vascular endothelial function after 12 months. Whether these changes may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution should be investigated. Keywords Cancer Breast cancer Exercise training Cardiopulmonary exercise testing Endothelial function
Introduction Breast cancer (BC) is the most common cancer in women worldwide, and it is also the principal cause of death from cancer among women globally. Different studies suggest a key role for diet and physical activity on occurrence of BC [1–5]. Epidemiological studies suggest a possible effect of physical activity on the incidence of primary BC [6–9]; and in secondary prevention after BC diagnosis, observational studies consistently show that the level of physical activity of BC women is correlated to an improvement in several cancer-related outcomes. Moreover several studies focused on physical intervention suggest that a structured program of exercise training is also able to improve several cancerrelated outcomes in BC survivors [10–14].
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Patients with breast cancer are obviously exposed to the normal aging decline, age- and disease-related comorbidity, and deconditioning that adversely affect cardiopulmonary function. However, compared to women from the general population, BC women are also subjected to the use of prolonged and aggressive multimodal anticancer therapy [15], which together is suspected of causing further impairments in cardiopulmonary function predisposing to cardiovascular disease [16]. Incremental cardiopulmonary exercise test (CPET) with gas exchange measurement provides the gold standard assessment of aerobic capacity as expressed by peak oxygen consumption (VO2peak) [17]. VO2peak is inversely correlated with cardiovascular and all-cause mortality in a broad range of adult populations [18, 19]. Accordingly, CPET is widely used in numerous clinical settings, and provides a wealth of diagnostic, prognostic, and decisionmaking information [20–24]. In addition, endothelial activation and dysfunction may play a significant role in the progression of BC [25] and recent evidence suggests that it might be on the basis of drug cardiotoxicity [26]. Therefore, this study tested the hypothesis that exercise training might improve cardiopulmonary and endothelial function in BC women.
Methods Study population The DIANA (diet and androgens)-5 study is a multicentre randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer (BC) events in women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu [27]. The overall design of the study has been described elsewhere [27]. We analyzed monocentric data (University of Naples ‘‘Federico II’’) consisting of 51 patients subdivided into two groups: 25 patients (51.8 ± 7.7 years, training group) underwent structured exercise training intervention (3 times/week for the first 3 months, and once/week for the following 9 months); whereas 26 patients (53.9 ± 8.5 years, control group) received recommendations to adhere to the lifestyle intervention suggestions of the DIANA protocol. The protocol was approved by the institutional ethics committee. The purpose of the protocol was explained to the patients and written informed consent was obtained from each patient before inclusion.
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Study protocol At the study enrollment and after 12 months, all patients underwent anthropometrical and biochemical assessment, cardiovascular clinical examination, and cardiopulmonary exercise stress testing. At the study enrollment, all women received a leaflet illustrating the WCRF/AICR recommendations for cancer prevention [28]. Training group patients were administered both the dietary and exercise training program as detailed below. The intervention group (training group, 25 patients) underwent, in addition to exercise training sessions, a counseling dietary program supported by cooking classes, reinforcing meetings and print materials. The counseling program aimed at increasing leisure-time physical activity level, controlling weight, and promoting a healthy and low calorie diet. Control group (26 patients) received only general recommendations to adhere to the lifestyle intervention suggestions of the DIANA protocol. Anthropometrical and biochemical assessment Body mass index (BMI) was used as a general measure of obesity, and was calculated at the final visit as weight (kilograms) divided by height (meters squared). Waist circumference (WC), an index of abdominal obesity, was measured midway between the bottom of the rib cage and the top of the iliac crest. Blood pressure was measured twice after 5 min rest using a mercury sphygmomanometer. Anthropometric measurements were made with the subjects in indoor clothing and without shoes. Blood specimens were collected after 12- to 14-h fast, from 08:00 to 09:30 h, to reduce the influence of circadian variation. Total cholesterol, triglyceride and high-density lipoprotein (HDL) cholesterol levels were measured using standard enzymatic methods [29]. Low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula. Fasting glucose levels were enzymatically determined by the peroxidase method. Fasting insulin levels were determined by enzyme immunoassay (Ultrasensitive Insulin Elisa, Mercodia, Sweden). The homeostatic assessment model (HOMA) index was used to estimate insulin resistance, and calculated as fasting serum insulin (mU/L) 9 fasting serum glucose (mM)/22.5, as previously described [30]. Cardiopulmonary exercise training testing Respiratory gas exchange measurements were obtained breath by breath with the use of a computerized metabolic cart (Vmax 29C, Sensormedics, Yorba Linda, CA, USA) as detailed elsewhere [31, 32]. Briefly, after a 1-min warm-up
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period at 0 Watts workload, a ramp protocol of 20 W/min was started and continued until exhaustion. The pedaling was kept constant at 55–65 revolutions/min. A 12-lead electrocardiogram (ECG) was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 min. VO2peak was recorded as the mean value of VO2 during the last 20 s of the test and was expressed in milliliters per kilogram per minute. Predicted VO2peak was determined by use of a sex-, age-, height- and weight-adjusted and protocol-specific formula as previously detailed [17, 31, 32]. The ventilatory anaerobic threshold (VAT) was detected by use of the V-slope method. The VE versus VCO2 relationship was measured by plotting ventilation (VE) against carbon dioxide production (VCO2) obtained every 10 s of exercise (VE/ VCO2slope): both VE and VCO2 were measured in liters per minute. The VE/VCO2slope was calculated as a linear regression function, excluding the non-linear part of the relationship after the onset of acidotic drive to ventilation [17, 31, 32]. Endothelial function assessment Endothelial function was assessed using Endo-PAT device (Itamar Medical Ltd, Caesarea, Israel). During the measurement the subject sat in a chair with the hands at the level of the heart and fingers hanging freely. Fingertip probes were placed on both index fingers and pulse wave amplitudes were detected and recorded during the study. After a five-minute baseline measurement, arterial flow was occluded using a cuff on the non-dominant arm. The cuff was inflated to 40 mmHg above systolic pressure. After 5 min of occlusion, the cuff was rapidly deflated to allow reactive hyperemia. Pulse wave amplitudes were recorded again for at least five minutes. The software provided by the manufacturer was then used to compare the arterial pressure ratio in the two fingers before and after occlusion. It then calculated a reactive hyperemia index (RHI), which was a ratio of the average pulse wave amplitude measured over 60 s, starting 1 min after cuff deflation, to the average pulse wave amplitude measured at the baseline. The other arm served as a control, and the ratio was corrected for changes in the systemic vascular tone. An RHI value of \1.67 was used as a cut-off value to diagnose endothelial dysfunction [33]. Exercise training program and cooking session Training group patients were enrolled in an in-hospital structured exercise training program. The frequency goal of in-hospital exercise training sessions was 3 times/week for the first 3 months, and once/week for the following 9 months. Each session consisted of cycle or treadmill
30 min exercise, preceded by 5 min of warming and followed by 5 min of cooling down, at a work load of 60–70 % of baseline VO2peak. This structured exercise training was on top of the general leisure-time physical activity recommendations or prescription of the general DIANA study (questionnaires, caloric control, etc., see above). From the 4th month to the 12th month, in-hospital exercise training sessions were reduced to one session/ week, integrated with general leisure-time physical activity sessions, according to recommendations and prescription of the general DIANA study [27]. During cooking sessions, patients were invited cooking and eating some dishes prepared according to the WCRF/AICR recommendations and inspired by a macrobiotic Mediterranean diet [28]. Statistical methods Continuous variables were reported as either mean and standard deviation (SD) or median and range according to their distribution. The normality of residuals was tested with the Shapiro–Wilks test, and if residuals were not normally distributed the difference between RHI values was tested using the Wilcoxon test. Categorical variables were reported as percentage. Differences in characteristics of patients among groups were tested by means of one-way ANOVA and Pearson Chi square test for continuous and categorical variables, respectively. Data were analyzed using SAS version 9.2 (SAS Inc, Cary, NC). All statistical tests were twosided and p values\0.05 were considered significant.
Results Baseline characteristics of the study population are shown in Table 1. There were no significant differences between groups in baseline anthropometrical, BC characteristics and metabolic profile (Table 1). The study period was similar in both groups. In training group, the average exercise intensity was 70 ± 2 % of baseline VO2peak. No adverse events took place during any of training sessions in BC patients undergoing exercise training sessions. Both groups were overweight at baseline (Table 1). At 1-year follow-up, a significant decrease in BMI (from 27.3 ± 5.2 to 26.6 ± 4.9 kg/m2, p = 0.02), in WC (from 94 ± 15 to 90 ± 13 cm, p = 0.005), and in systolic blood pressure (from 121 ± 17 to 115 ± 12 mmHg, p = 0.011), while no changes were observed among controls (Table 2). Baseline plasma lipids, glucose and insulin levels were normal and did not change at 1 year in both groups. No differences in baseline CPET and RHI parameters were found (Table 2). At baseline, VO2peak and O2-pulse were in the lower range (Weber class C) in both groups. In
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Intern Emerg Med Table 1 Anthropometrical and clinical characteristics of the study population
Training group (n = 25)
Control group (n = 26)
p value
Anthropometrics Age (years)
51.8 ± 7.7
53.9 ± 8.5
0.55
Waist circumference (cm)
94 ± 15
94 ± 12
0.66
Body Mass Index (Kg/m2)
27.3 ± 5.2
28.2 ± 4.8
0.20
Breast cancer characteristics Presence of invasive carcinoma (%)
25/25 (100)
26/26 (100)
–
Node positivity (%)
48 (n = 12/25)
54 (n = 14/26)
0.58
Estrogen positivity (%)
80 (n = 20/25)
85 (n = 22/26)
0.78
93.5 ± 12.5
92.2 ± 15.5
0.67
Metabolic and hormonal profile Glycemia (mg/dL) Insulin (ng/mL)
7.8 ± 4.0
8.2 ± 2.2
0.29
HOMA index
1.739 ± 1.403
1.925 ± 0.908
0.54
Total cholesterol (mg/dL)
205 ± 34
203 ± 32
0.85
LDL-cholesterol (mg/dL)
126 ± 35
123 ± 29
0.24
HDL-cholesterol (mg/dL) Triglycerides (mg/dL)
54.3 ± 11.6 100 ± 43
54.8 ± 12.7 109 ± 52
0.63 0.13
Testosterone (nmol/L)
0.36 ± 0.36
0.38 ± 0.26
0.79
HOMA homeostatic assessment model, LDL low-density lipoprotein, HDL high-density lipoprotein
ET group VO2peak (from 12.6 ± 3.0 to 14.5 ± 3.3 ml/kg/ min, p \ 0.001) and O2-pulse (from 6.2 ± 1.2 to 6.9 ± 1.2 ml/kg/min/beat-1, p \ 0.001) improved at 1-year follow-up, respectively. No significant changes in VO2peak (12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p \ 0.001 between groups), and in O2-pulse (from 6.0 ± 1.4 to 6.2 ± 1.2 ml/kg/min/beat-1, p = 0.39; p \ 0.001 between groups) were observed at 1-year follow-up among controls. ET group showed a significant improvement of RHI (from 2.1 ± 0.7 to 2.5 ± 0.8, p \ 0.001); whereas no significant changes were observed among controls (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62; p \ 0.001 between groups). At 1-year follow-up, the level of physical fitness achieved in ET group as expressed by VO2peak was inversely correlated with the 1-year value of BMI (r = -0.426, p = 0.001) and WC (r = -0.47, p \ 0.001). In ET group, a significant negative correlation between 1-year BMI and WC and 1-year RHI was observed (r = -0.460, p = 0.001 and r = -0.425, p = 0.002, respectively). In addition, in ET group, changes in VO2peak were correlated with changes in RHI (DVO2peak vs. DRHI: r = 0.47, p = 0.017).
Discussion The main finding of this study is that structured exercise training improves cardiopulmonary and endothelial function in women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu.
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Epidemiological studies have shown that the level of physical exercise is associated with improved outcome in BC patients, included cancer related and total mortality [8–10]. Notably, despite normal cardiac function, BC women have significant and marked impairments in cardiopulmonary function [34]. Jones et al. [34] find that, on average, in BC women VO2peak is 27 % less than that of age-matched sedentary but otherwise healthy women without a history of breast cancer. Remarkably, patients with breast cancer reach a predicted VO2peak for a particular age group (e.g., 40 years) approximately 20 to 30 years earlier than healthy women without a history of breast cancer. Sweeney et al. [35] report that elderly cancer survivors (of mixed diagnoses) are less likely to be able to do heavy household tasks, walk half a mile, or walk up and down stairs, compared with women without a history of cancer. Our findings indicate that patients with breast cancer, at baseline, are in the lower range for VO2peak and O2-pulse (Weber class C), less than the functional independence threshold and, by definition, unlikely to be able to perform such tasks. Several studies show that moderate intensity exercise interventions in postmenopausal breast cancer (i.e. 60 % VO2peak) are associated with several favorable effects in several cancer-related outcomes, such as physical and psychological function and quality of life [36, 37]. The individual characteristics, type and intensity of exercise, as well as the timing of cancer diagnosis and stage may have an interplay role. In our study population, we observe a significant exercise-induced improvement of cardiopulmonary functional capacity at 1-year follow-up. Aerobic
Intern Emerg Med Table 2 Anthropometrics, metabolic and hormonal, cardiopulmonary and endothelial parameters at baseline and at 1-year follow-up Trained group (n = 25) Baseline
p value
1-year
Control group (n = 26) Baseline
p-value
1-year
Differences in changes between groups
Anthropometrics Waist circumference (cm) Body Mass Index (Kg/m2) Metabolic and hormonal profile Glycemia (mg/dL) Insulin (ng/mL) HOMA index
94 ± 15
90 ± 13
0.005
94 ± 12
95 ± 12
0.88
\0.001
27.3 ± 5.2
26.6 ± 4.9
0.02
28.2 ± 4.8
28.3 ± 5.4
0.67
\0.001
93.5 ± 12.5
92.8 ± 13
0.61
92.2 ± 15.5
90.6 ± 18.1
0.63
0.44
7.8 ± 4.0
8.0 ± 5.0
0.74
8.2 ± 2.2
7.9 ± 3.1
0.71
0.88
1.739 ± 1.403
1.822 ± 0.629
0.51
1.925 ± 0.908
1.825 ± 0.477
0.61
0.77
Total cholesterol (mg/dL)
205 ± 34
200 ± 29
0.66
203 ± 32
210 ± 26
0.42
0.62
LDL-cholesterol (mg/dL)
126 ± 35
122 ± 30
0.36
123 ± 29
126 ± 35
0.22
0.29
HDL-cholesterol (mg/dL)
54.3 ± 11.6
55.5 ± 9.7
0.78
54.8 ± 12.7
50.1 ± 8.7
0.19
0.52
Triglycerides (mg/dL)
100 ± 43
108 ± 42
0.53
109 ± 52
119 ± 46
0.60
0.41
Testosterone (nmol/L)
0.36 ± 0.36
0.40 ± 0.16
0.21
0.38 ± 0.26
0.33 ± 0.19
0.49
0.42
12.6 ± 3.0
14.5 ± 3.3
\0.001
12.8 ± 2.5
12.6 ± 2.8
0.55
\0.001
Cardiopulmonary parameters VO2peak (ml/kg/min) O2-pulse (ml/kg/min/beat-1) VE/VCO2slope
6.2 ± 1.2
6.9 ± 1.2
\0.001
6.0 ± 1.4
6.2 ± 1.2
0.39
\0.001
29.7 ± 4.4
30.9 ± 3.9
0.12
30.1 ± 3.8
31.3 ± 4.9
0.46
0.44
2.1 ± 0.7
2.5 ± 0.8
\0.001
2.0 ± 0.4
1.9 ± 0.4
0.62
\0.001
Endothelial function Reactive Hyperemia Index
HOMA homeostatic assessment model, LDL low-density lipoprotein, HDL high-density lipoprotein, VE/VCO2slope the minute ventilation–carbon dioxide production, VO2peak peak oxygen consumption
exercise training is the most effective therapy to improve VO2peak in healthy individuals given that it improves the reserve capacity of all O2 transport organs, which together lead to favorable improvements in VO2peak [38]. Data from meta-analysis show that exercise training in patients with cancer causes d a significant improvement in VO2peak (weighted mean difference ?2.90 mL/kg/min; 95 % CI, 1.16–4.64 mL/kg/min), compared to sedentary control [39]. Our findings are in line with these data, considering that in the ET group, VO2peak improves on average of about 2 ml/kg/min compared to controls. Investigation of the most effective type and intensity of exercise training to increase VO2peak and other outcomes, as well as the physiologic mechanisms underlying the exercise training– VO2peak relationship in breast cancer populations should be further investigated. Breast cancer–endothelium interactions provide regulatory signals facilitating tumor progression [25]. Conventional models of carcinogenesis suggest that endothelial cells are closely related with tumor perfusion. In this view, the endothelium acts not only as a passive strong barrier against cancer cells [40] but also as a stromal regulator during tumor progression [41]. A recent study also suggests that endothelial dysfunction might be at the basis of drug cardiotoxicity [26]. In this study, a significant improvement of vascular endothelial function as expressed by the
increase of RHI is observed among exercising BC women. However, the impact of endothelium on cancer cells and vice versa is still to a great degree undefined. Whether exercise training might favorably modulate endothelial function or might interfere with the mechanisms by which cancer cells can transmigrate through the endothelial lining remains to be investigated. It is largely possible that the macrobiotic Mediterranean diet may have a predominant contribution to the increased bioavailability of NO, thus improving endothelial and cardiopulmonary function. Further studies are encouraged in order to evaluate whether exercise/diet-induced improvement of endothelial function might interfere with drug cardiotoxicity. Along with the improvement of cardiopulmonary functional capacity and endothelial function, weight loss, reduced levels of insulin, glucose, and sex hormones, decreased inflammation and immunostimulation might also explain the beneficial effects of exercise on cancer outcomes [11, 42, 43]. Of note, all BC patients were overweight at study entry. Recent studies showed that obese BC patients have a poorer prognosis than non-obese patients of all ages [44, 45]. The underlying reason for this association is not clear. Patients with a high BMI tend to present with larger tumors, and some studies report more biologically adverse features including grade 3 tumors and nodal involvement in obese patients [46, 47]. Patients with a high BMI may also
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receive less effective treatment for early breast cancer [48]. Finally, obesity can be viewed as a sub-clinical inflammatory state, and activated macrophages in adipose tissue producing proinflammatory mediators may potentially affect the tumor micro-environment [49]. Interestingly, in our study, a significant decrease of BMI and WC is observed among exercising BC women at 1-year follow-up; while no changes is observed among controls. Studies exploring whether the improvement of BMI and WC has beneficial prognostic effect are encouraged. A number of limitations of the present study should be considered. Training patients underwent a moderate intensity exercise program: whether an exercise program of higher intensity might have additional clinical and prognostic value should be clarified. Despite the aforementioned limitations, this study has several unique strengths. This is the first study enrolling high-risk BC survivors (women with early stage invasive BC at high risk of recurrence because of metabolic or endocrine milieu) to 1-year structured exercise intervention showing significant improvement of both cardiopulmonary and endothelial function. In conclusion, moderate intensity exercise training combined with diet in breast cancer survivors improves cardiopulmonary functional capacity and vascular endothelial function. Whether the improvement of both cardiopulmonary and endothelial function may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution needs further investigation. Acknowledgments The DIANA-5 Project was financed by the Italian Association for Cancer Research (AIRC, Grant no. 11942) and by the Italian Department of Health (PIO program). This study was also financed by the FARO (Fondo per l’Avvio di Ricerche Originali). Conflict of interest of interest.
The authors declare that they have no conflict
Statement of human and animal rights The institutional ethical committee approved the protocol. The purpose of the protocol was explained to the patients. Informed consent Written informed consent was obtained from each patient before inclusion.
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