Effects of supervised exercise intervention on cardiorespiratory fitness and health-related quality of life in breast cancer patients during treatment

I Effects of supervised exercise intervention on cardiorespiratory fitness and health-related quality of life in breast cancer patients during treatment Dissertação apresentada às Provas de Doutoramento em Ciências do Desporto (Decreto-Lei no 74/2006, de 24 de Março), com vista ao grau de Doutor em Ciências do Desporto, sob a orientação do Professor José Manuel da Costa Soares. Dissertation presented to the PhD test in Sports Sciences (Decree-Law nº 74/2006 of 24 March), in order to obtaing the PhD degree in Sports Science under the orientation of Prof. Doutor José Manuel da Costa Soares. Eduardo Nuno Marques da Silva Moitas de Oliveira - 2012 - II Bibliographic Register Oliveira, E. (2012) Effects of supervised exercise intervention on cardiorespiratory fitness and health-related quality of life in breast cancer patients during treatment. Faculdade de Desporto da Universidade do Porto KEY WORDS: Quality of Life, Exercise, Breast Cancer, Fatigue. III Acknowledgements I would like to extend my deepest thanks to: Prof. Doutor José Soares, mentor and counsellor of this thesis, for the motivation during all my academic way, an example of professionalism, persistence and ambition. For his friendship, understanding and trust on me, which were the basics for leading me to this task. Prof. Doutora Maria João Cardoso, determinative during the experimental stage of this thesis. For her character, dynamism, pragmatism, exigency and generosity, which had a deep mark on me during this process. For being always available to help and improve my academic and professional competencies. Prof. Doutor André Seabra, for his enthusiasm in the statistic handling and for all his availability to help in this work. For all the motivation and incentives during this thesis’s work out. Dr. Rui Faria, for his help in getting the apropriate equiqment in order to make this work practicable. Prof. Doutor Carlos Lopes, for his advices at the beginning of this project. Drª. Sofia Magalhães and Drª. Sara Oliveira, Mama Help’s physiotherapists, for their availability in the experimental stage of this thesis. For clarifying all doubts in the intervention periods and for transmitting their professional experience in working with breast cancer women. Drª. Diana Carvalho, for the friendship and incentive in dynamizing and organizing the physical exercise at Mama Help. Manuela Gonçalves, for the organization and professionalism devoted to make the community aware of the physical exercise at Mama Help, whose cooperation was vital for the elaboration of the physical exercise and its practicability. IV Drª. Sofia Pinto, for the availability and cooperation in the early stages of the physical exercise’s programme. Sameiro Braga and Elisa Duval, for helping in my integration and for the joy they daily bring into Mama Help. Cristina Lopes, for the friendship and incentive to materialize the project of physical exercise at the Mama Help. Lovely ladies of the physical exercise at Mama Help, for their example of determination, overcoming and hope. For accepting the programme enthusiastically and for all joys and anxieties we shared all the time. Their attitude was a vivid encouragement during this thesis’s elaboration. Pedro Fraga and Nuno Mendes, for the friendship over the last years and for the constant incentives during the thesis’s elaboration Rowers of RCFP, for being a harmonious group and for transmitting human values to the professional life. For their competitiveness, overcoming and continuous efforts to overtake adversity, as a team. Prof. Doutor José Augusto Rodrigues dos Santos, for inculcate a competitive spirit on me, on sports as well as on professional extent. For his friendship and comprehension and for being a reference in surpassable principles. Prof. Doutor José Magalhães, Prof. Doutor António Ascensão and Prof. Doutor Paulo Santos, for the friendship and unconditional support during all my academic way and for being always available to clarify my doubts. My family, for allowing me the access to education since my infancy, basing it in the human values of the truth, respect, integrity, honesty and on going knowledge. For the their love and incentive through to my personal and professional upbringing. V Index Pag Acknowledgements III Index V List of figures VI List of tables VII List of Abbreviations VIII Abstract IX Resumo XI 1. Introduction 13 2. Review 19 2.1. Cancer Related Fafigue 21 2.1.1.Treatments and toxicity 22 2.1.2. Peripheral and central fatigue 30 2.1.3. Exercise and cancer related fatigue 31 2.2. Cancer, exercise and quality of life 35 3. Objectives 41 4. Material and Methods 45 5. Results 57 6. Discussion 71 7. Conclusions 89 8. References 93 9. Attachments 113 VI List of figures Pag Figure 1. Effect of treatment, disease and detraining in Cancer Related Fatigue. 33 Figure 2. Flow of breast cancer patients through the study. 48 Figure 3. Percentage of change from baseline to 12 week in VO2max, power output, ventilation, anaerobic threshold, handgrip, sit-stand test and leg extension in breast cancer patients. 63 Figure 4. Score change from baseline to 12 week in quality of life, physical function, role function, emotional function cognitive function, fatigue and pain in breast cancer patients. 64 Figure 5. Percent of patients that increased, decreased, or did not change in VO2max, power output, sit-stand and leg extension, from baseline to 12 weeks of supervised exercise. 64 Figure 6. Percent of patients that increased, decreased, or did not change in global QOL, physical function, emotional function, fatigue and pain, from baseline to 12 weeks of supervised exercise. 64 Figure 7. Percentage of change from baseline to 12 week in VO2max, watts, sitstand test and leg extension from exercise program and control group of breast cancer patients. 67 Figure 8. Score change from baseline to 12 week in quality of life, physical function, role function, emotion function, cognitive function, social function, fatigue and pain in breast cancer patients intervention group and control group. 68 Figure 9. Comparison of percent of change decrease in VO2max, Watts, sit stand test and leg extension from baseline to week 12, between healthy group and breast cancer patients in intervention exercise program. 70 VII List of Tables Pag Table 1. Baseline demographic characteristics, diagnosis and treatment according to group. 60 Table 2. Baseline and follow-up muscle strength and cardiorespiratory fitness components of breast cancer patients in supervised exercise program. 61 Table 3. Baseline and follow-up health-related quality of life subscales (EORTC QLQ-C30/BR23) of breast cancer patients in the control group. 62 Table 4. Baseline and 12-week muscle strength and cardiorespiratory fitness components in intervention group and control group. 65 Table 5. Baseline and 12-week health-related quality of life subscales (EORTC QLQ-C30/BR23) in intervention group and control group. 66 Table 6. Baseline and 12-week muscle strength and cardiorespiratory fitness components in intervention group and healthy group. 69 V II I List of Abbreviations VO2max Maximal Aerobic Power EORTC European Organization Research Treatment of Cancer HRQOL Health Related Quality of Life QOL Quality of Life ACSM American College Sports Medicine VO2VE Oxygen Consumption at Ventilatory Anaerobic Threshold FACT Functional Assessement of Cancer Therapy CRF Cancer Related Fatigue QL General Quality of Life PF Physical Functioning RF Role Functioning CF Cognitive Functioning SF Social Functioning FA Fatigue PA Pain BRBI Body Imagem BRAS Arm Symptoms IX Abstract BACKGROUND. With 1.3 million new breast cancer cases reported every year and improved survival, it is important to develop interventions to maintain health related quality of life (HRQOL) during and after cancer treatment. Aerobic and strength training is an intervention that can enhance HRQOL and physical components during treatment. OBJECTIVES. To examine the effect of 12 weeks of supervised exercise in physical capacity measurement and HRQOL in breast cancer patients during treatment. METHODS. Breast cancer patients were allocated into an exercise intervention program (EI, n=40) and to a control group (CG, n= 8) that received standard care. The intervention comprised cardiovascular training at 70-85% of VO2max in cycle ergometer, resistance training and specific rehabilitation arm exercises. Patients were trained during 60 minutes, two times per week, during 12 weeks, with progression in time and intensity during the intervention period, with the main goal to achieve, at week 12, thirty minutes at 85%VO2max. Physical capacity and health related quality of life EORTC QLQ-C30 were assessed pre and post intervention. General linear model for repeated measures was used to compare (baseline and 12-week follow-up) with group assignment and time x group interaction included as fixed effects (p.05 for significance). RESULTS. Highly significant increases were achieved with an increase of 17.0% vs. 7.7% in VO2max, and 46,6% vs. 4.9% in power output, respectively, in the intervention group compared to the control group (p.05). Gains in strength occurred only in the intervention group with and increase in leg extension by 13.4% (p.05). Intervention and control groups improved global health status (10.2 vs. 9.3 points) but emotional status (16.6 vs. 11.0 points) and role function (14.9 vs. -0.1 points) were significantly higher in the intervention group (p.05). The fatigue decreased by 16.4 points in the intervention group compared with only 2.7 points in the control group (p<.001). A significant decrease in pain was obtained for the intervention group with a reduction by 20.4 points vs. 2.6 points for the control group (p<.001). CONCLUSIONS. A supervised and individualized prescriptive exercise program, results in an improvement in functional ability and HRQOL functions in women with breast cancer. KEY WORDS: Quality of Life, Exercise, Breast Cancer, Fatigue. 16 treatment (Campbell et al., 2011). Some of these include decrease aerobic capacity and strength, weight gain, fatigue and reduced quality of life. Treatment is focused on curing the disease and preventing relapse due to metastic disease (Hoving et al., 2009). This fact accentuates the importance of investigation regarding the development of strategies to improve patients’ quality of life, reduce the recurrence risk, the probability of contracting other diseases and prolonging the population’s survival (Courneya, 2003). The quality of life in oncological patients is often affected by the fatigue that they feel. In fact, approximately 70% of the cancerous population reports sensations of fatigue and asthenia during radiotherapy, chemotherapy or after surgery. Furthermore, approximately 30% of the population that survives cancer continues to manifest signs of persistent fatigue (Dimeo, 2001). Therefore, in all the types of cancer, the cancer related fatigue (CRF) severely influences several components of the quality of life since in aggravating symptoms like pain, nausea and dyspnoea, it causes physical, economic and social consequences that are devastating to the patients (Winningham, 2001). Cancer related fatigue (CRF) as a profound, negative impact on daily activities, social activities and overall quality of life (Cella et al., 2002). Devoogdt et al. (2010) studied the evolution of the total physical activity levels occupational, sport and household activity on breast cancer patients. Physical activity levels are still significantly lower 12 months after treatment for breast cancer than at the pre-operative level. A greater decrease in occupational activities was associated with having a spouse, lymph node stage pN2 or pN3 (versus stage pN0 or pN1) complete axilary dissection (versus sentinel node biopsy), more than 20 lymph nodes dissected (versus less than 10) or undergoing chemotherapy. Moreover, older patients and those smoking before surgery had a higher risk of having a decreased sport activity level 12 months after surgery. In this study, 1 year after the surgery breast cancer patients showed a 85% reduction from baseline in occupational activities (Devoogdt et al., 2010). 17 So, cancer patients, and in particular those at risk for a decreases physical activity level and affected by fatigue, should be identified, and encourage to increase their activities with supervised exercise programs. In fact, CRF and decreased physical activity may leed to difficulties in return to work. Being unable to return to work after cancer treatment, frequent or prolonged work absenteeism, or problems with work performance may impose a significant economic impact on the survivor and her family (Chirikos et al., 2002). Furthermore, it is stated that the longer people are absent from their jobs, the lower the likelihood is that they will ever return to work. Moreover, Whereas loss of occupational identity can be a source of significant anxiety and depression, continuing or returning to the workplace allows many patients to maintain a sense of normalcy or control (Peteet, 2000). Most of the interventions with patients receiving adjuvant treatment show some improvement on quality of life or an other physical and psychological outcomes, such CRF, but do not pay attention to the aspect of work which is considered to be an important contributor to quality of life (Hoving et al., 2009). Some studies investigated return to work following breast cancer surgery. In a systematic review, Hoving et al. (2009) concluded the lack of methodology sound intervention studies on breast cancer survivors with outcome return to work indicating that returning to work programs and vocational rehabilitation for breast cancer survivors should be further developed and evaluated. At 3 months pos-operative surgery, only 19% of patients working preoperatively has returned to work and after 12 months the proportion had increased to 60% with patients working in a part-time employment than before surgery (Devoogdt et al., 2010). In other study elaborated in Canada, showed at 12 months, 88% of the breast cancer patients had returned to work (Drolet et al., 2005). There is a high variability among studies about working rates after breast cancer surgery being a possible explanation the difference in health care systems between US, Canada and European countries. In US, after 3 months, 60% of breast cancer patients were working but assistance with transportation, limitation in upper-body strength, and employment in jobs requiring physical activiy were needed (Satariano & DeLorenze, 1996). 18 In light of this information, it is the general purpose of this study is analyse and describe the advantages of the individualized effect of training and exercise, with a clinic purpose, in the alteration of the aerobic/ muscular functions and quality of life outcomes in breast cancer patients during treatment. 19 2 2. . R Re ev vi ie ew w 20 21 2.1 Cancer Related Fatigue Every day people experience fatigue and this symptom is commonly associated with diseases such as depression, multiple sclerosis, arthritis and renal disease, as well as different medical and pharmacological treatments (Schwartz et al., 2001). Patients treated for cancer disease experience a different and more disruptive fatigue. In fact, cancer related fatigue (CRF) is the most prevalent and disturbing side effect of treatment for the majority of cancer patients. CRF is described as being more intense and overwhelming than fatigue before treatment, and exercise is an intervention proposed to reduce fatigue (Adamsen et al., 2004; Dimeo et al., 1999; Lucia et al., 2003; Oldervoll et al., 2003; Watson & Mock, 2004). Cancer induces an abnormal inflammatory response with a high level of proinflammatory cytokines that are responsible for the progression and clinical deterioration of the disease (Winkelman, 2004). Cancer treatment itself contributes to muscular atrophy, through the use of high doses of immunosuppressant drugs such as cyclosporine, cyclosfosfamide or glucocorticoids that increase the protein catabolism. The muscular atrophy is essentially the result of the production of tumour necrosis factor-alpha (TNFa) that accentuates the inflammatory response in the musculoskeletal structure (Winkelman, 2004). Most investigators consider that the origin of CRF is multifactor and not just a result of a single factor (Lucia et al., 2003; Ryan et al., 2007; Stasi et al., 2003; Watson & Mock, 2004); on top of that, the interaction between the various aetiological mechanisms is complex. In fact, fatigue represents just a part of the problem that is the physical incapacity experienced by cancer patients. Fatigue is usually defined as a sensation of lack of physical strength, weakness or loss of energy. However, fatigue becomes a pathological condition when it persists in ordinary daily activities, perseveres during a long period of time, does not improve with rest, or becomes severe enough so that it reduces daily physical activity (Dimeo, 2000). Although surviving cancer is a growing reality, medical intervention is almost always necessary. 22 2.1.1 Treatments and Toxicity The most common treatments for cancer are surgery, radiotherapy and chemotherapy. Despite these medical interventions, the patients’ quality of life may suffer consequences. Since in 60% of cases of cancer survivors surgery is used, depending on the location and the extent of the operation, a significant morbidity may occur (complications with wounds, infections, loss of function, diminished movement amplitude, diarrhoea, dyspnoea, pain, drowsiness and lymphatic oedema) (Courneya, 2003). Radiotherapy is used at a certain stage of the treatment in approximately 50% of cancer survivors. Generally, radiotherapy is administered in small fractions repeated over a period of 5 to 8 weeks to maximize the cellular death of the cancerous cells and minimize the damage to normal cells (Courneya, 2003). However, it can induce toxicity in normal cells and depends on the location of the radiation (pain, blistering, reduced elasticity, diminished movement amplitude, nausea, fatigue, pulmonary fibrosis, dry mouth, and cardiomyopathy). The tumour suppressor protein p-53 is required for most DNA-damage-induced apoptosis. Unfortunately, mutations in the p-53 gene are observed in upwards of 70% of human cancer cases, thus reducing the efficacy of some therapies (63-14). After surgery to remove a tumour (lumpectomy or mastectomy), high levels of ionizing radiation are used to destroy any remaining breast cancer cells in the breast, chest wall, or axillary area. Cell death from radiation therapy occurs primarily during mitosis, when extensive DNA damage makes duplication of the genome impossible (mitotic cell death). P-53 Dependent apoptosis occurs at the G1 checkpoint of the cell cycle and ensures that DNA carrying genomic defects is not replicated. However, in the absence of p53, or when p53 is not functional, the cells become insensitive to low doses of radiation. A high dose of radiation induces necrosis and cytoplasmic constituents being released into the surrounding tissue, which serves as potent inflammatory signals (Bower et al., 2009). Recent data suggest that the fatigue experienced with radiation therapy is associated with the activations of proinflammatory cytokines (Bower et al., 2009). 23 Systemic therapy is prescribed in several types of cancer. This treatment may be chemotherapy, hormone therapy and immunotherapy. Chemotherapy is administered intravenously or orally, in repeated cycles during 2-4 weeks from 3 to 6 months. Chemotherapy may cause some adverse effects such as fatigue, anorexia, nausea, neutropenia, peripheral neuropathies, ataxia and cardio toxicity. Furthermore, approximately 55% of patients are submitted to adjuvant chemotherapy during the intervention. Chemotherapy drugs can disrupt the cell cycle at several critical steps and thereby induce apoptosis. Taxane drugs work to bind and stabilize cell microtubules to prevent them from separating chromosomes during cell division (anaphase of mitosis), thereby arresting cell cycle; doxorubicin (adriamycin) prevents DNA replication by inhibiting the enzymes, topoisomerases, that cut on strand of the DNA to unwind it during replication; and 5-fluorouracil (5FU, adrucil) inhibits thymidylate synthetase that functions to incorporate the thymine nucleotide into DNA during replication. Some of the more rapidly dividing normal, healthy cells are damaged (e.g. hair follicles, blood cells), subsequent mitosis from resident stem cells can soon replace those lost to chemotherapy or radiation (Clarkson & Kaufman, 2010). Over the past years, different studies have shown that fluorouracil, doxorubicin and cyclophosphamide (FAC) regimen as an adjuvant therapy for early stage of breast cancer is an effect treatment. Moreover, the doxetaxel, doxorubicin and cyclophosphamide regimen (TAC) has recently shown significant improvements in the rates of disease-free and overall survival even more than FAC (Lee et al., 2009). Some studies showed that TAC was more toxic than FAC with respect to neutropenic fever events and many extra hematological side effects such as asthenia, stomatitis, diarrhea and myalgia (Martin et al., 2005). Moreover, breast cancer patients who received TAC as treatment had less QOL scores, compared with FAC after the end of chemotherapy. Nevertheless, these differences gradually disappeared in different scales of QOL lasting for months after finishing chemotherapy (Bastani & Ahmad Kiadaliri, 2011). So, during follow-up period, patients in the TAC group experienced a higher improvement than FAC group. Hormone therapy is administered orally and can have several side effects such as weight gain, loss of muscular mass, accumulation of fat mass in the torso 24 and face, osteoporosis, fatigue and increased susceptibility to infections (Demark-Wahnefried et al., 2012). Lastly, immunotherapy is a recent form of treatment that maximizes the effect of other drugs as well as the defence mechanisms against cancerous cells. However, currently, in several clinical cases a combination of various types of treatment is being applied. In this situation, the timing and the treatment sequence depends on the staging and type of cancer. Consequently, it is possible that some cancer survivors may be treated on several occasions with different forms of treatment (Courneya, 2003). The supply of oxygen to the mitochondrion is a critical factor in the regulation of energy production. An adequate supply of energy to the cells requires the integrity of all the stages in the capture cascade, transport and use of oxygen. Anatomical and functional alterations due to the treatment of cancer can affect cells’ oxygen supply. On the other hand, the treatment itself, in inducing cardiovascular toxicity, can cause a dysfunction of the left ventricle (indicated by diminished systolic volume), ventricular contractility alterations and consequently diminished cardiac debt. Furthermore, pulmonary toxicity resulting from the treatment may cause a reduction of the lung’s full capacity, diminished vital capacity, a reduction of the inspiratory and diffusion capacities which, in its turn, compromise O2 and CO2 gas exchanges (Schneider et al., 2007). Moreover, diminished pulmonary volume due to illness (pulmonary metastases and pleural effusion) or as a sequel of the treatment (lobotomy, pulmonary fibrosis after radiotherapy) may alter the ventilation-perfusion ratio, causing difficulty to the saturation of haemoglobin (Lucia et al., 2003). Therefore, the treatment of cancer can reduce O2 transport capacity through the aerobic path by the different path of physiological mechanisms (Dimeo, 2000; Lucia et al., 2003). This toxicity is often observed in women with breast cancer during and after treatment. However, these negative effects can be attenuated through the intervention of an exercise programme. By means of an exercise intervention of 3 weekly training sessions over a period of 6 months, between 45-75% HRmax, Schneider et al. (2007) observed, in breast cancer survivors, improved systolic arterial pressure (-2.6%), diastolic arterial pressure (-3.4%), and cardiac frequency at rest (-4.0%), while pulmonary capacity assessed by vital capacity 25 improved (+2.8%), as did maximum oxygen consumption (+15.1%). In the specific case of chemotherapy, the marrow may be affected, which consequently diminishes the production of red blood cells. Cardiotoxic cytostatic agents, such as anthracycline and cyclosfosfamide, can reduce blood flow to the musculo-skeleton (Dimeo, 2000). The loss of muscular function induced by a prolonged period of bed rest can result in a substantial loss of muscular mass, plasmatic volume and reduced cardiac debt that impairs energetic efficiency (Levine et al., 1997). This clinical status is very similar to being bedridden, since 6 weeks in this condition was enough to induce diminished left ventricular mass in 8.0+2.2% and is connected to reduced final diastolic volume on the second week in 14+1.7% (Perhonen et al., 2001). Furthermore, treatment with high doses of corticosteroids results in diminished muscular mass. Inducing immunosuppression using cyclosporine (CsA) may result in mitochondrial myopathy, loss of capillary density and, consequently, loss of physical capacity (Zbreski et al., 2006). CsA is an immunosuppressant commonly used in organ transplants. This drug acts as a cytosolic phosphatase protein inhibitor in T-Killer lymphocytes. In the Zbreski et al. (2006) study, the administration of CsA resulted in muscular atrophy, inducing a 22% decrease in fiber cross-sectional area. These last occurrences are clinically indistinguishable from alterations caused by detraining or by reducing physical activity. The majority of breast cancers are estrogen receptor-positive, although estrogen receptor negative disease is more frequent in premenopausal (37%) than postmenopausal women (21%) (Anderson et al., 2002). Breast cancers that occur in younger women are of concern because these cancers are often hormone receptor negative (estrogen receptor ER- and progesterone receptor PR-), are high grade, and are diagnosed at advanced stages (KlauberDeMore, 2005). Current treatment guidelines recommend that premenopausal women with hormone receptor-negative disease receive adjuvant chemotherapy, and that those with hormone-positive disease receive adjuvant endocrine therapy (tamoxifen +- ovarian function suppression) with or without adjuvant chemotherapy based on the biology and extend of the primary tumor within the breast and regional lymph nodes (Burstein et al., 2010). Among the 32 levels. There is growing evidence that aerobic exercise programs can reduce fatigue in cancer patients receiving chemotherapy (Adamsen et al., 2004; Adamsen et al., 2006; Dimeo et al., 2003; Dimeo et al., 1999; Quist et al., 2006; Schwartz et al., 2001; Winningham et al., 1989). Mock et al. (2001) studied the effect of home-based exercise at least 90 min per week for three or more days in women with breast cancer who reported significantly less fatigue and emotional distress as well as higher functional ability and QOL than the women who were less active during treatment. The literature describes exercise as having potential importance in the quantitative reduction of fatigue. The qualitative data in this study highlight the experience of cancer patients having a comfortable sense of fatigue while simultaneously improving their physical form and increasing their strength. Data from Adamsen et al. (2004) describe different forms of fatigue in cancer patients. The sensation of fatigue which results from exercising (i. e. exercise induced fatigue) is experienced as a positive and natural tiredness and is furthermore associated with an after-effect of improved physical well-being, tranquillity, release, relaxation, and, for some, typically improved sleep (Cella et al., 2002). It is a sense of fatigue that is desirable because the after-effects are familiar as they were experienced during sports activities prior to their illness (Watson & Mock, 2004). This contrasts with fatigue induced by chemotherapy which can be characterized as negative because of its connection with the experience of physical discomfort. It is not a sense of fatigue that is desired but rather is imposed on the body from the outside through medication, and usually leads to a passive physical state. Adamsen et al. (2004) showed that cancer patients can transform the nature of fatigue – from a negative chemotherapy induced fatigue into a positive exercise induced fatigue. The impact of exercise on fatigue was significant and reflects the effectiveness of low to moderate intensity regular exercise in maintaining functional ability and reducing fatigue in patients with breast cancer. Exercise was consistently associated with reducing fatigue the day of exercise and one day afterward over the first two cycles of chemotherapy in breast cancer patients (Schwartz et al., 2001). However, current level of fatigue increased when exercise exceeded 60 33 Treatment Disease Detraining F Fa at ti ig gu ue e Attenuated fatigue Physical Activity / exercise Sedentary habits State of “chronic” fatigue minutes, probably due to changes in nutrition and hydration states (Schwartz et al., 2001). In short, physical inactivity induces an accentuated loss of muscular mass and loss of cardiorespiratory capacity. Therefore, lack of physical activity causes a tendentiously perpetual condition of diminished activity leading to fatigue and vice-versa (Figure 1). This mechanism may explain persistent fatigue and physical performance impairment in several patients, even years after ceasing of treatment (Dimeo, 2000; Lucia et al., 2003). Image 1: Effect of treatment, disease and detraining in Cancer Related Fatigue (Adapted from Rundle, (Rundle, 2005). In a cross sectional study, 3 years after breast cancer treatment, persistent pain and sensory disturbances remain clinically significant problems among 47% breast cancer patients who received surgery (Gartner et al., 2009). In fact, fatigue and pain overlap, and both seem to be additionally associated with mental health (Gartner et al., 2009). The cause of pain in cancer patients and in general, remains unclear. A 4 year follow-up showed an increase in pain symptoms in those women taking tamoxifen at baseline; in those reporting depression or stressful life events during the first 12 months after enrolment. Nevertheless, exercise at baseline had a beneficial effect on pain recovery (Rief et al., 2011). So, pain should be a major outcome in evaluations of cancer treatment and rehabilitation programs. 34 In 2009, with support from Siteman Cancer Centre and the Oncology Nursing Society, the ACSM convened an expert roundtable to review the literature on exercise in cancer survivors and issue guidelines for activity, along with recommendations on exercise testing and prescription (Schmitz et al., 2010). The ACSM guidelines for cancer survivors emphasis on returning to normal daily activities as quickly as possible after surgery and continuing these activities as much as possible during any adjuvant treatments (Wolin et al., 2012). Low to moderate exercise interventions of variable duration seem to be the standards applied across existing studies. Predominantly, those studies have examined the effects of a single activity, e.g. cardiovascular training on stationary bicycles, rather than resistance to the exercise as the one of modality (Galvao & Newton, 2005). More studies are needed to provide evidence of whether specific patient groups, at different stages of the disease and/or with different diagnoses and treatments, can benefit from exercise. So, due to the lack of evidence, no recommendations can be issued at present (Lucia et al., 2003). A multidimensional 6 weeks high intensity exercise training design intervention in cancer patients with different types of solid tumours and haematological malignancies undergoing chemotherapy, increased VO2max in 16% and dynamic strength of 40%. Furthermore, it was observed a significant reduction in treatment-related symptoms and significantly improved their general well-being and quality of life specifically with a reduction of fatigue and pain (Adamsen et al., 2006). In accordance with these results, Kolden et al. (2002) verified through a supervised 16 week program involving cardiovascular, resistance and flexibility training, 1h three times a week in 40 sedentary women with breast cancer, an increase in strength of 36% and in cardiovascular capacity of 15%. These results suggest that cancer patients undergoing chemotherapy may benefit from a multidimensional exercise interventions. Knutsen et al. (2006) reported any adverse effects such as unintentional physical reactions, cardiac, or respiratory arrest, or hypotension during VO2max and 1RM strength test in cancer patients undergoing chemotherapy. The study 35 showed that patients felt significantly safer in performing the maximum physical capacity tests and in using their bodies in a 6 week high intensity training. 2.2. Cancer, exercise and quality of life Investigation regarding exercise in cancer survivors began in the early 80’s but published articles became consistent in the late 90’s only. The Alberta University in Edmonton, Canada, by means of investigator Kerry Courneya, has been a driving force in clinical trials in this area (Courneya, 2003; Courneya et al., 2008; Courneya & Friedenreich, 2011). The positive effect and the advantage of exercise in cancer patients were described for the first time by (Winningham et al., 1989). Physical exercise is one of the foremost areas of research in cancer control with potential to improve the lives of cancer; the context “cancer survivor” indicates any person who has or had cancer, from the time of diagnosis onward (Ingram & Visovsky, 2007). The psychological and physical symptoms resulting from cancer and its treatments (e.g., pain, fatigue, nausea, vomiting, depression) will contribute to excessive patterns of rest and also contribute to immobility. Bed rest will precipitate muscle weakness, atrophy, and functional impairment (Ingram & Visovsky, 2007). Evidence of the benefits of exercise for cancer survivors has mounted steadily over the past in the areas of psychology and quality of life outcomes. Recently, improvements in physical functioning, body weight and composition, muscle strength and endurance (Quist et al., 2006), and immune function have been reported. The exercise interventions are low to moderately intense (exercise intensity between 55% and 85% HRmax) with very similar protocols throughout the various studies (Courneya & Friedenreich, 1999; Dimeo et al., 1999). These rules are in accordance with ACSM guidelines, that state that 6 to 7 weeks of training are enough to obtain significant muscular hypertrophy gains. As to the frequency of training, two to three weekly training sessions are sufficient to promote the desired adaptations (Garber et al., 2011). 36 Several clinical trials have studied the relationship between clinical exercise, quality of life and psychosocial parameters in cancer survivors. The exercise programs in the trials consisted mainly of 3 weekly sessions of moderate and vigorous exercise, with a duration that increased progressively up to 45` over a period of 3 to 4 months. These studies demonstrated that exercise reduced anxiety, depression, improved self-esteem and diminished fatigue-related symptoms (Herrero et al., 2006; Quist et al., 2006). One of the best direct indicators of cardio respiratory capacity is VO2max. This variable is an excellent indicator of a person’s health condition and an independent mortality predictor in healthy or unhealthy individuals (Garber et al., 2011). Initially, some authors alerted to the possibility that vigorous exercise, including maximal physical evaluation tests, could impair the cancer patient’s health during chemotherapy due to the administered drugs’ adverse effects. However, contrary to what was expected, the study carried out by Knutsen et al. did not observe adverse effects such as hypotension, cardiac or respiratory arrests, during the assessment of aerobic and muscular functions following maximum protocols (Knutsen et al., 2006). Obesity is a risk factor for some of the most common cancers in the western world, such as post menopausal breast cancer and colorectal cancer. This is one of the reasons why cancer patients are overweight or obese at the time of diagnosis (Brown et al., 2003). Furthermore, there is strong evidence that excessive weight increases the recurrence risk in several cancers, as well as increased mortality risk (Eheman et al., 2012). At present, the International Agency for Research on Cancer estimates that 25% of cancer cases are caused by excessive weight, obesity and a sedentary life (Ahlberg et al., 2003). The current tendency of increasing number of adults and children that are overweight or obese and, simultaneously, have low levels of physical activity makes the connection of their lifestyle with cancer a matter of public health (Campbell & McTiernan, 2007). Therefore, exercise has been used as a mean to reduce obesity and to promote a healthy lifestyle. Empirically, strength training is generally inappropriate for people with an illness as well as for cancer survivors, and for this reason there is still little investigation on the potentials of this type of training. However, several studies have 37 observed improved quality of life in cancer patients even when the exercise program is discontinued for a period of time due to a specific reason (anemia, infections and demotivation). An 8-week exercise program of aerobic training combined with strength exercises, with 3 weekly 90 minute sessions, in women with breast cancer, significantly increased muscular mass and reduced fat mass and these improvements were linked to an improved quality of life (EORTC QLQ-C30) (Herrero et al., 2007). On top of that, in breast cancer survivors, even after an 8-week detraining period QOL was not diminished, as were not dynamic force and specific functional tasks of muscular capacity. However, the same period of detraining reduced cardio respiratory capacity by ~6ml.Kg.min-1 (VO2peak) (Herrero et al., 2007). Therefore, cardiorespiratory adaptations are quickly lost. Nevertheless, strength training should be integrated as a component in a training program since it attenuates muscular atrophy induced by treatment and sedentary habits in cancer survivors (Inui, 2002). In this case, ACSM guidelines recommend that 6 to 7 weeks of training are enough to obtain significant muscular hypertrophy gains. As far as frequency is concerned, 2 to 3 weekly training sessions are sufficient for both men and women (Schmitz et al., 2010). In fact, aerobic and strength training improves quality of life in a way that is practically unparalleled in patients with various types of cancer, that is to say, an increase of almost 43% in dynamic muscular force accompanied by a 21% increase in the improvement of QOL after 18 weeks of aerobic and strength training (De Backer, Van Breda, et al., 2007). In another recent study, during the hospitalization of patients submitted to highdose chemotherapy, an exercise program of aerobic resistance that consisted of pedaling for 30 minutes on a reclined cycle ergometer, reduced fatigue and loss of physical performance. On the other hand, chemotherapy-related complications, namely aplasia (quantity of neutrophils < 500/mL and platelets < 20,000/mL) and duration of hospitalization, were significantly inferior in the trained group, when compared to the control group (Dimeo et al., 1999). In the specific case of prostate cancer treatment, the deprivation of androgens can cause an adverse effect – bone mineral density loss, progressing to osteoporosis. It is described that this bone mineral density loss, of 3 to 5% in the first years of treatment, results in a higher incidence of fractures 38 (Friedenreich, 2001). Therefore, not only has exercise an important role in preventing prostate cancer but it also prevents the adverse effects that can occur during therapy (Campbell & McTiernan, 2007). Since approximately 60% of cancer survivors are 65 years old or more, there has been an interest in studying the potentials of exercise in these ages. In fact, since aging is connected to a decline in neuromuscular function and diminished capacity to synthesize proteins, the scientific community questions whether the elderly are subject to physical exercise’s positive adaptations. Besides, studies in the last decades have demonstrated that the elderly revealed improved physiologic function and positive adaptations such as those that were observed in younger adults (Drouin, 2004). Exercise, in this type of population, requires some precautions in several situations due to some contraindications. Psychological factors also have an important function in the aetiology of cancerrelated fatigue’s genesis. In this particular case, depression is considered a contributing factor to fatigue in cancer patients. The effect of physical activity is not limited to improved muscular and cardiovascular functions. In fact, improved physical performance can increase a patient’s sensation of control, independence and self-esteem; this improved self-esteem can result in better social interaction, reduced anxiety and fear (Dimeo, 2000). Segal et al. (2001) did not observe any effect of structured exercise on aerobic fitness and in HRQOL in breast cancer patients during treatment. These results are, to some extend, in line with (Thorsen et al., 2005) who did not observed any beneficial effect on fatigue, mental distress and HRQOL parameters of the 14-week supervised home-based training program intervention shortly after chemotherapy. The fact that patients performed multiple supervised activities by themselves could represent additional stress for them. However, VO2max increased by 6.4 ml/kg/min-1 in the patients in the interventions group and only 3.1 ml/Kg/min-1 in the patients in the control group corresponding to 23% and 10%, respectively) showing a beneficial effect on CRF in young and middleaged cancer patients. Opposite to this findings Segal et al. (2003) demonstrated a positive effect of a 12-week supervised strength-training program on fatigue and overall HRQOL in men receiving androgen deprivation for prostate cancer. 39 Dimeo, Fetscher, et al. (1997) observed a positive effect of an interval exercise, using a cycle ergometer in bed, on fatigue and psychological distress in cancer patients during hospitalization. Courneya et al. (2003) reported a positive effect on fatigue and in overall HRQOL in breast cancer patients several months after treatment. Burnham and Wilcox (Burnham & Wilcox, 2002) observed a significantly higher overall HRQOL improvement in the exercise group compared with the control group but mental distress between groups was the same. Mock et al. (1997) demonstrated a positive effect of a 6-week individualized self-paced progressive walking program on fatigue and anxiety in breast cancer patients during radiotherapy. However, there were no significant differences between the exercise group and the control group in depression. The magnitude of changes in mental distress, fatigue, and HRQOL parameters in trials in this area are not consistent. It is not clear enough whether these differences of outcome are the result of differences in the patients characteristics and/or the type and the timing of the intervention or if these variations are explained by different methods of assessment (Thorsen et al., 2005). The application of the principles of exercise training (specificity, overload, progression, initial values, reversibility and diminishing returns) in a design of an exercise prescription ensures the most appropriate type and dose of exercise to promote de desired outcome (Campbell et al., 2011). De Backer et al. (2009) conducted a systematic review to summarize the research of previous studies that used resistance training with cancer patients. The duration of the resistance training programs ranged from 3 to 24 weeks, with an average of 12 weeks and most of them prescribed two or three sessions per week. Furthermore, most of the studies applied resistance with aerobic training. Few studies described the number of sets and repetitions, and among 10 of them, intensities ranged from 30-60 to 60-85% of 1RM. With regard to aerobic exercises, treadmill walking and stationary cycling were the most frequently prescribed sessions. Intensities of aerobic exercises varied from 40% to 90% of heart rate maximum. Studies incorporating resistance training prescribed either exercises using machines or resistance bands (Spence et al., 40 2010). As outcomes measures, most of the studies assessed muscle strength (1RM), endurance tests (maximal number of repetitions at 60-75% of 1RM), hand grip tests. The results demonstrate that increases in muscular strength occur in women with breast cancer who receive resistance training (Loprinzi & Cardinal, 2012). Evidence suggests that health professionals might encourage breast cancer’s patients to increase physical activity in a consistent way during treatment, because regular practice of exercise, as soon as possible after surgery and during treatment, may reduce secondary effects. Patients with breast cancer should start to increase gradually their physical activity to a 150 minutes per week within an moderate intensity or to a 75 minutes per week at a vigorous intensity as soon as they finish their chemotherapy or radiotherapy treatments; as well as patients reaching progressively the minimum exercise guidelines, should be persuaded to increase their physical activity level to 180 minutes per week of moderate intensity up to vigorous intensity, because these activity levels are necessary to prevent the recurrence of breast cancer (Holmes et al., 2005). 41 3 3. . O Ob bj je ec ct ti iv ve es s 48 serious illness or medical condition, which could contraindicate exercise, patients not capable of training (severe knee arthrosis, ligament or cartilage injuries at lower extremities), severe anemia (<8 g/dL) or platelet count lower then 50.109/L. The Karnofsky performance status (KPS) was used as an observer-rated measure of functional ability (Brown et al., 2005). The patients had a Karnofsky performance status of 60 or higher. All patients signed an informed consent. Participants were stratified by treatment and then randomly assigned into exercise and control groups (figure 2). Subjects were also informed that participation in the study was voluntary, all data would be confidential, and that they were free to abandon the study at any time without incurring changes in their usual cancer treatment. Figure 2: Flow of breast cancer patients through the study. 49 The Healthy control group (n= 15) was essentially a convenience sample, selected to match the anticipated age and gender profile of the patients with breast cancer. These women were not known to have cancer. The ethical committee of Sports Faculty of University of Porto and the Ethical committee of Mama Help - Support Centre for Breast Cancer Patients approved the study protocol. The project was carried out in accordance with Helsinki Declaration. Measurements made at baseline and at follow-up after the 12-week period Patient Function The Karnofsky performance status (KPS) was used as an observer-rated measure of functional ability. Body composition Fat mass percentage was calculated through bioelectrical impedance analysis (InBody 230 Biospac, Seoul, Korea). Body mass index (BMI) was calculated as weigth (kg) / height (m)2. Handgrip performance Maximal grip strength and fatigue resistance were measured using a mechanical handgrip dynamometer (Grip-D TKK5401, Tokyo, Japan). The elbow joint angle was flexed at a 90º angle with the wrist as close to 0º as possible. Trials were performed in an alternating bilateral sequence for a total of six attempts (three with each arm), and a rest period of 30 seconds was required between each trial to standardize test procedures. The patient was given clear instructions when to start and stop the contraction and was encouraged during the test to squeeze the handgrip as hard as possible. The mean of the three trials was calculated and averaged for each patient. We nominated the arm where the surgery was performed as the handrip C and the opposite as handrip D. 50 Functional muscle performance Functional muscle performance was determined using a sit-stand test. For this test, we used a straight-backed chair (40cm high) and asked each subject to sit and stand, at their fastest pace, during 30 seconds with their arms folded across the chest. The final test score is the number of times that the patient rises to a full stand from the seated position with arms folded within 30 seconds. Maximal isometric leg extension Maximal leg extension was measured using a strain gauge (Globus, Codogne, Italy). In a seated position, in a chair with a knee angle joint at 90º and harms folded across the chest, patients realized at a command signal, maximal strength with quadricipets up to force reached maximum values. Trials were conducted with three attempts with an interval of two minutes between them; the average of the three tests was used as reference value. Health-related quality of life The assessment of HRQOL was performed by using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionary C30 (EORTC QLQ-C30), which is a psychometrically instrument designed to be applicable to a broad range of cancer patients (Aaronson et al., 1993). The instrument has been evaluated with regard to both validity and reliability (Fayers, 2001). QOL was measured using the questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC): the EORTC QLQ-C30 (third version 3.0). The EORTC QLQ-C30 comprises five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, pain, nausea and vomiting), and six single items assessing additional symptoms commonly reported by cancer patients. It also includes two questions on patients overall quality of life and overall health condition, providing a global quality-of-life score. In the present study, the dimension of physical function, emotional function, role function, cognitive function and global quality of life were considered. Furthermore, symptoms of fatigue and pain were also analyzed. These scales 51 were transferred to a 0 to 100 scale, which was calculated by using the scoring manual provided by the EORTC (Fayers, 2001). For the physical function, emotional function, role funtion, cognitive function and global quality-of-life scales, a higher score indicates better level of functioning, whereas increasing values on the fatigue and pain scale indicate more symptoms. The breast cancer module is meant for use among patients varying in disease stage and treatment modality (i.e. surgery, chemotherapy, radiotherapy and hormonal treatment). The module comprises 23 questions assessing disease symptoms (arms symptoms and breast symptoms), side effects of treatment (surgery, chemotherapy, radiotherapy and hormonal treatment), body image, sexual functioning and future perspective. In the present study, for the BR23 questionary the arm symptoms and body image were considered. The scoring approach for the QLQ-BR23 is identical in principle to that for the function and symptom scales. Cardiorespiratory fitness All cardiorespiratory exercise tests were performed under similar environmental conditions (temperature ~20 ºC; relative humidity 45 – 55%; barometric pressure – 720mmHg) on an electrically braked cycle ergometer (BH Fitness Tesis, Barcelona, Spain). After a warm-up period, of 5 min with no load, power output was increased from an initial value of 20 W by 10W.min-1. The cadence monitor was placed in view of the subject during each test, and an exercise cancer physiologist insured that they maintained the required pedalling cadence throughout the duration of the test. The test was terminated upon volitional exhaustion and/or when cadence could not be maintained at a minimum of 60 rev.min-1. (Herrero et al., 2006) Subjects refrained from performing physical activity during the 24h-period before the tests. Expired respiratory gas fractions were measured using an open circuit breath – by-breath automated gas-analysis system (Cortex, Metalyzer, 3B, Leipzig, Germany). Before each test, flow, volume and gases were calibrated. HR was measured and recorded every 5 seconds using a HR monitor (Vantage NV, 52 Polar Electro, Kempele, Finland) that was connected with the gas-analyzer system. Maximal oxygen uptake (VO2max) and peak respiratory exchange ratio (RERpeak) were recorded as the highest value obtained for any continuous 20second period. The workload eliciting the VO2 at ventilatory threshold (VO2VT) was determined using the criteria of an increase in both ventilatory equivalent oxygen (VE.VO2-1) and end tidal pressure of oxygen (PetO2), with no increase in the ventilatory equivalent of carbon dioxide (VE.VCO2-1). Description of the Exercise Intervention Program The patients in the intervention group received written information about some simple principles of training physiology. The exercise objectives, specified for breast cancer patients were set by literature search (Campbell et al., 2011; Herrero et al., 2006; Knutsen et al., 2006; Schmitz et al., 2010; Velthuis et al., 2010) and by seeking advices from cancer caregivers. Moreover, the exercise methods were developed in close cooperation with physiotherapists experienced in reahabilitation programs for cancer. Based on results from medical and cancer history, physical examination, and initial physiological and pychological assessment, an individualized exercise prescription was developed. Before each training session, a cancer exercise specialist, asked each participant a series of questions that would clarify the need to alter the exercise intervention, if necessary. Questions focused on how the patient felt after the last exercise session, if patient had muscle soreness or specific problems that would affect training (Schneider et al., 2007). Each exercise program was individualized according to baseline health and fitness levels. Patients trained in groups of four to six members and each session was supervised by the same experienced investigator. The patients in the exercise group trained two times per week for a 60 minutes period. The 60 minutes exercise program include a warming up (5 minutes), aerobic and muscle strength (50 minutes) and a cooling down (5 minutes). 53 The exercise program was composed of combination of cardiovascular training (cycle-ergometer), strength training, balance and core training, patient-specific rehabilitation and flexibility which were classified as either high or low intensity. Heavy resistance training and stationary bicycling who rise significantly the heart rate were categorized as high-intensity activities whereas patient-specific rehabilitation and flexibility, requiring lower energy expenditure, were termed lower intensity activities. The program was conducted in in specially designed workout room located in Mama Help - Support Centre for Breast Cancer Patients. High intensity training At the beginning of the program, aerobic training consisted of pedaling on a cycle-ergometer for a 15 minutes at 70% of maximal heart rate (HRmax), during the first four weeks, observed during the pre-training cardiorespiratory test. After week 4, we increased 5 minutes per week to allow patients to complete 30 minutes of continuous pedaling. For subjects with poorer physical condition, it was sometimes necessary to divide the first sessions into shorter time intervals to complete the 15 or 20 minutes workout in stationary bicycle (e.g., bouts of 5 minutes). The aerobic training was intended to be near to the anaerobic threshold but mostly aerobic. Nevertheless, individual anaerobic threshold could have been exceeded temporarily during the training. Resistance training included exercise engaging major muscle groups (chest press, leg squat, leg calf rise, leg extension, adductor / adductor, abdominal crunch, arm extension, arm curl, dorsal). All exercises were performed through the full range of motion normally associated with the correct technique for each exercise. During the first 6 weeks, patients performed one and two set of exercises for large (e.g., Leg Squat) and small muscle groups (e.g. arm extension), respectively, and all sets were performed at a resistance that allowed 12 – 15 repetitions. Thereafter, the resistance used was individually adjusted and increased to allow the completion of 8-10 repetitions for four sets for large muscle groups and 3 sets for small muscle groups. Abdominal and lower back exercises were performed in 15-20 repetitions. 54 Steps aerobics exercises were also used in resistance training and consisted of several, typical step movements resulting in a total of 150-200 jumps (Thorsen et al., 2005). Moreover, Circuit-training consisted of 5 to 6 different vigorous exercises such as abdominal, squats, leg extension, chest press and leg calf rise. Duration of each circuit training movement varied from 30 to 40 seconds with half resting period between consecutive movements. During training sessions, the training intensity was occasionally monitored with heart rate measurements to ensure the consistency between self-rated and actual exertion levels. Furthermore, patients were advised to maintain their exercise intensity comparable to a level between 12 and 14 (slightly strenuous to strenuous) of the Borg scale, a numerical scale used to rate perceived exertion (Borg et al., 1985). Low intensity training The exercise sessions concluded with an extremely low-intensity cool down that targeted all major muscle groups, as flexibility or balance exercises. Flexibility comprised some exercises that emphasized all major muscle groups. Contraindications In accordance with the guidelines and safety precautions defined by Dimeo et al. (1999), pre-exercise screening and monitoring was performed. Patients undergoing chemotherapy or radiotherapy and with one of the following criteria were instructed to interrupt physical training on the specific day: leukocyte <0.5 x 109/L, hemoglobin <6mmol/L, thrombocyte concentration <20 x 109/L, respiratory frequency >20, pulse at rest <100 bpm, and temperature above 38 ºC. In cases of infection, a pause in training was recommended until the patient had been asymptomatic for a day and then training can be slowly resumed (Pedersen & Saltin, 2006). 55 Control Group Patients assigned to the control group received usual care, i. e., no exercise intervention. They will be asked to mantain their habitual physical activity pattern but after completion of the present study, control subjects were offered participation in a rehabilitation programme for cancer patients (Schmitz et al., 2010). Statistical Analyses Characteristics of the patients at baseline and after 12-weeks intervention were expressed either as means and standard deviations or proportions. Baseline differences in each characteristic between intervention group and control group were tested with unpaired sample t-tests and Pearson chi-squares tests. Paired sample t-tests were used to compare each characteristics over time (baseline and 12-week follow-up). General linear model (GLM) for repeated measures was used to compare each characteristic over time (baseline and 12-week follow-up) with group assignment and time x group interaction included as fixed effects. For each characteristic analyzed, change scores were calculated as the difference between baseline and 12-weeks values; the difference was then divided by the initial value to estimate percentage or relative change. None of the measures showed significant deviations from a normal distribution (ShapiroWilk test). Significance level in all analyses was set at 0.05. Statistical analyses were conducted using SPSS version 20.0. 56 57 5 5. . R Re es su ul lt ts s 64 with a decrease of 20.4-points (67.1%) and 16.4-points (40.7%) respectively. After the intervention, more than fifty percent (global health status: 23/40; role function: 21/40; cognitive function: 22/40), sixty percent (physical function: 25/40; emotional function: 26/40; social function: 25/40; arm function: 25/40) and seventy percent (body image: 30/40) of breast cancer patients increased their health-related quality of life measurements. It is noticeable that more than seventy percent (Fatigue: 29/40) and eighty percent (Pain: 35/40) of the participants reported, respectively, less fatigue and pain. After the intervention, while 7.5% (3/40) exhibited more fatigue, none of the patients reported more pain. Figure 4: Score change from baseline to 12 week in quality of life, physical function, role function, emotional function cognitive function, fatigue and pain in breast cancer patients. *Statistically significance difference (p<0.005). 9,8 7,4 16,6 14,8 12,1 17,5 -16,4 -20,4 -30 -20 -10 0 10 20 30 QL PF RF EF CF SF FA PA Score diference in HRQOL Function and Symptom Scales 90 92,5 90 90 2,5 2,5 7,5 5 7,5 5 2,5 5 0 10 20 30 40 50 60 70 80 90 100 VO2max Power Output Sit-stand Leg extension Percent Increase Deacrese No Change Figure 5. Percent of patients that increased, deacreased, or did not change in VO2max, power output sit-stand and leg extension, from baseline to 12 weeks of supervised exercise. Figure 6. Percent of patients that increased, deacreased, or did not change in global QOL, physical function, emotional function, fatigue and pain, from baseline to 12 weeks of supervised exercise. * * * * * * * * 65 Table 4. Baseline and 12-week muscle strength and cardiorespiratory fitness components in intervention group and control group. Intervention group Control group GLM repeated measures Measures Baseline1 12-week1 %Δ2 Baseline1 12-week 1 %Δ2 Time3 Group3 Time*Group3 VO2max (ml/kg/min-1) 21.2 (3.5) 24.8 (4.9) 17.0 19.4 (3.3) 20.9 (3.4) 7.7 <0.001 0.045 0.007 Power Output (W) 63.1 (11.7) 92.5 (18.9) 46.6 67.2 (19.5) 70.5 (19.4) 4.9 <0.001 0.096) <0.001 Ventilation (L/min) 38.3 (9.6) 46.0 (10.5) 20.1 42.7 (15.0) 44.4 (14.9) 3.9 <0.001 0.705 0.026 VO2VE (ml/kg/min-1) 17.2 (3.2) 19.9 (4.1) 15.7 16.7 (2.2) 17.4 (2.6) 4.1 0.027 0.141 <0.001 Handgrip right (kg) 24.7 (4.3) 25.6 (3.9) 3.6 23.4 (4.2) 22.9 (4.8) 2.1 0.734 0.163 0.265 Handgrip left (kg) 24.3 (3.8) 24.1 (4.0) -0.8 22.0 (3.7) 21.1 (3.5) - 4.1 0.244 0.053 0.481 Sit-stand (#) 18.1 (5.1) 22.6 (5.3) 24.8 16.8 (3.6) 19.0 (3.7) 13.0 <0.001 0.147 <0.001 Leg extension (kg) 34.9 (11.8) 39.6 (13.9) 13,4 32.0 (5.0) 32.0 (4.8) 0 0.147 0.209 0.001 1Data presented as mean (standard deviation) 2 Data presented as percentage of change 3Data presented as p values 66 Table 5. Baseline and 12-week health-related quality of life subscales (EORTC QLQ-C30/BR23) in intervention group and control group. Intervention group Control group GLM repeated measures Measures Baseline1 12-week1 S.Change Baseline1 12-week 1 S.Change Time2 Group2 Time*Group2 EORTC QLQ-C30 Global Health Status 62.7 (17.4) 72.5 (14.9) 9.8 58.3 (19.9) 67.6 (19.7) 9.3 0.002 0.401 <0.001 Physical Function 76.8 (13.5) 84.2 (10.5) 7.4 71.8 (16.9) 74.8 (12.8) 3.0 0.025 0.087 <0.001 Role Function 69.2 (26.2) 85.8 (17.9) 16.6 53.7 (31.0) 70.4 (27.4) 16.7 0.001 0.705 <0.001 Emotional Function 65.6 (24.3) 80.4 (15.3) 14.8 55.5 (30.9) 55.4 (39.6) -0.1 0.117 0.022 <0.001 Cognitive Function 70.8 (28.9) 82.9 (17.1) 12.1 66.7 (27.6) 75.9 (31.3) 9.2 0.005 0.511 <0.001 Social Function 65.4 (24.3) 82.9 (20.3) 17.5 51.8 (26.9) 64.8 (25.9) 13.0 0.001 0.033 <0.001 Fatigue 40.3 (22.2) 23.9 (19.1) -16.4 51.9 (26.1) 48.2 (28.4) -3.7 0.003 0.021 <0.001 Pain 30.4 (25.0) 10.0 (14.0) -20.4 40.7 (18.8) 37.1 (29.8) -3.6 0.002 0.009 <0.029 BR23 Body Image 73.3 (21.5) 82.5 (18.6) 9.2 69.4 (25.0) 76.8 (20.8) 7.4 0.021 0.484 0.801 Arm Symptons 23.3 (21.5) 19.2 (17.4) -4.1 27.1 (11.3) 23.4 (13.0) -3.7 0.041 0.541 0.901 1Data presented as mean (standard deviation) 2 Data presented as p values 67 Changes in muscle strength, cardiorespiratory fitness and HRQOL between intervention group and control group At follow-up, a significant main effect for time and a significant time by group interaction effect were evident for the majority of muscle strength and cardiorespiratory fitness measures (Table 4). From baseline to 12-weeks, there was a statistical significant increase in VO2max, power output, ventilation (p<0.001) and sit and stand (p<0.001). The significant results suggest that the time effects in the muscle strength and cardiorespiratory fitness measurements were different between intervention group and control group (Figure 7). In the intervention group, mean values significantly improved (p<0.05). In the control group values remained rather constant at follow-up (p>0.05). In fact, from baseline to after 12-weeks, intervention group showed significantly greater changes in VO2max (17.0% versus 7.7%), power output (46.6% versus 4.9%), ventilation (20.1% versus 4.9%), VO2 at ventilatory threshold (15.7% versus 4.1%), sit-stand (24.8% versus 13.0%) and leg extension (13.4% versus 0%) compared to control group. No significant intervention effects were observed for handgrip measures. Figure 7. Percentage of change from baseline to 12 week in VO2max, power output, sit-stand test and leg extension from exercise program and control group of breast cancer patients. *Statistically significance difference (p<0.005). Regarding quality of life measures, from baseline to 12 weeks, a significant main effect for time and group and a significant time by group interaction effect 17,0 46,6 24,8 13,4 7,7 4,9 13,0 0 0,0 10,0 20,0 30,0 40,0 50,0 60,0 VO2max Power Output Sit-Stand Leg Extension % Change from baseline to follow up Intervention Control * * * * 68 was evident for the majority of measurements. Across the intervention, there was a statistical significant increase in all values. Intervention group had a significantly higher increase in global health status (9.8 versus 9.3 points), physical function (7.4 versus 3.0 points), emotional function (14.8 versus -0.1 points), cognitive function (12.1 versus 9.2 points), social function (17.5 versus 13.0 points), body image (9.2 versus 7.4 points) and arm symptoms (-4.1 versus -3.7 points) than control group. It was also observed a significant higher decrease in fatigue (-16.4 versus -3.7 points) and pain (-20.4 versus -3.6 points). The significant interactions suggest that the time effects in the quality of life differed between intervention group and control group (Figure 8). Among intervention group, mean values significantly improved with the intervention (p<0.05), whereas they remained rather constant at follow-up in control group (p>0.05). Figure 8: Score change from baseline to 12 week in quality of life, physical function, role function, emotion function, cognitive function, social function, fatigue and pain in breast cancer patients intervention group and control group. QOL PF RF EF CF SF Fatigue Pain Intervention 9,8 7,4 16,6 14,8 12,1 17,5 -16,4 -20,4 Control 9,3 3,0 16,7 -0,1 9,2 13,0 -3,7 -3,6 -30 -20 -10 0 10 20 30 Change in score points in HRQOL in baseline and follow up Intervention Control 69 Table 6. Baseline and 12-week muscle strength and cardiorespiratory fitness components in intervention group and healthy group. Measures Healthy group Intervention group Baseline differences 12-week differences Baseline 12-week Difference1 (%) p2 Difference3 (%) p4 VO2max (ml/kg/min-1) 30.7 (4.0) 21.2 (3.5) 24.8 (4.9) 9.5 (30.9%) <0.001 5.9 (19.2%) <0.001 Power Output (W) 114.6 (20.4) 63.1 (11.7) 92.5 (18.9) 51.5 (44.9%) <0.001 22.2 (19.3%) <0.001 Ventilation (L/min) 63.2 (11.8) 38.3 (9.6) 46.0 (10.5) 24.9 (39.4%) <0.001 17.2 (27.2%) <0.001 VO2VE (ml/kg/min-1) 23.7 (2.9) 17.2 (3.2) 19.9 (4.1) 6.5 (27.4%) <0.001 3.7 (16.0%) 0.002 Handgrip right (kg) 29.2 (3.5) 24.7 (4.3) 25.6 (3.9) 4.5 (15.4%) 0.001 3.6 (12.3%) 0.003 Handgrip left (kg) 28.5 (2,7) 24.3 (3.8) 24.1 (4.0) 4.2 (14.7%) <0.001 4.4 (15.4%) <0.001 Sit-stand (#) 27.4 (5.2) 18.1 (5.1) 22.6 (5.3) 9.3 (33.9%) <0.001 4.8 (17.5%) 0.04 Leg extension (kg) 48.9 (10.2) 34.9 (11.8) 39.6 (13.9) 14.0 (28.6%) <0.001 9.3 (19.0%) 0.022 1 Difference between baseline intervention group values and healthy group values, then dividing each result by baseline intervention group values. 2p values obtained from the independent t-tests comparing baseline intervention group and healthy control group mean values. 3 Difference between 12 week intervention group values and healthy group values, then dividing each result by 12 week intervention group values. 4p values obtained from the independent t-tests comparing 12-week intervention group and healthy control group mean values. 70 Changes in muscle strength and in cardiorespiratory fitness Table 6 displays muscle strength and cardiorespiratory fitness components in intervention group at baseline and 12-weeks and compares each time with healthy group values. As expected, at baseline and 12-weeks, independent ttests showed significant differences in all measures favoring healthy group (p<0.05). At baseline the differences between both groups were approximately from 31% to 40% in cardiorespiratory components and from 34% to 28% in muscle strength measures. However, 12 weeks of supervised exercise intervention, resulted in significant improvements in strength and aerobic capacity in breast cancer patients (see table 2; except handgrip measures) and consequently resulted in a lower difference compared to the healthy group. The data collected after the 12-weeks, showed approximately 20% to 27% lower cardiorespiratory fitness in the intervention group. Regarding muscle strength measures, the differences compared to the healthy group were from 15% to 19%. Figure 9: Comparison of percent of change decrease in VO2max, power output, sit stand test and leg extension from baseline to week 12, between healthy group and breast cancer patients in intervention exercise program. 30,9 44,9 33,9 28,6 19,2 19,3 17,5 19,0 0 5 10 15 20 25 30 35 40 45 50 VO2max Power Output Sit Stand Leg Extension Percent Baseline Follow up 71 6 6. . D Di is sc cu us ss si io on n 72 73 Despite the demanding nature of this exercise intervention, 40 of 43 patients (93%) were able to complete a 12-week exercise program, which indicates a high level of compliance, very similar to previous studies comprising breast cancer patients (Cheema et al., 2008; Courneya et al., 2003; Nikander et al., 2007). Moreover, the compliance is higher when compared to other studies involving patients with different diagnosis (Quist et al., 2006). The combination of a training facility at the Mama HelpSupport Centre for Breast Cancer Patients with professional supervision, was crucial, to convince patients that the exercise program was a complement to the ongoing medical treatment. No major adverse effects and no major health problems were noted in the subjects of both groups, over the 12-week period. The number of studies examining the benefits of exercise for breast cancer patients, has tremendously increased, in recent years. However, the majority of published works show inadequacies in design regarding principles of exercise training, and also lack detailed exercice prescription and report of patients adherence to the programme (Campbell et al., 2011). Therefore, there is shortage of information for developing specific exercise prescription to reduce side effects of cancer treatment. As far as exercise intensity is concerned, it has been reported that texercise dose and reported adherence rate were significantly and inversely correlated (r=-0.62, p=0.002 for weekly dose; r=-0.82, p<0.001 for total dose) implying that lower prescribed dose of intervention presented greater adherence rate (Carayol et al., 2012). Our study shows that a 12-week planned supervised training program, combining resistance and cardio respiratory exercises, brings positive changes to cardiorespiratory components, strength, muscle function, and quality of life outcome in breast cancer patients. These results are important, as cancer related fatigue decreases the QOL, which can be maintained, even after treatment, in 30% of patients with cancer (Stasi et al., 2003). Several studies have shown that exercise may improve cancer patients' physical fitness and well-being (Cheema et al., 2008; Herrero et al., 2006; Nikander et al., 2007; Schneider et al., 2007; Schwartz et al., 2001). However, 80 During radiation therapy for breast cancer, muscles of the chest wall may be irradiated, and a typical radiation dose used in breast cancer treatment is 1.82.0 Gy/day, 5 days/week, over 6 weeks (total of about 54-60 Gy). These muscles include pectorals (major and minor), subclavius and anterior serratus. Depending on the irradiation treatment area, muscles of the back, particularly the rhomboid layer and underlying deep muscles, may be exposed to radiation as well. Common resistance exercises, like bench press, push ups and lat pulldowns, involve chest wall and back muscles (Clarkson & Kaufman, 2010) and may be eventually affected due to side effects of radiotherapy. In our study, the muscle function values, handgrip and sit stand test, are clearly inferior to those of the Healthy control group, which, in a certain way, may be one of the reasons why, in baseline, the intervention and control group showed persistent fatigue and pain signs. In the study elaborated by Kilgour et al. (2010), upper and lower body muscle strength, had significant predictors of CRF. In a study with advanced lung cancer patients, when compared to healthy ones, it was found beyond correlation between fatigue and strength in leg extension, the best parameters which related to CRF were the 30s-timed sitstand tests and the KPS (p<0.001), showing that a lower functionality translates into a higher fatigue score (Brown et al., 2005). Considering the quadriceps muscle function in the several tests used to evaluate the functional performance in patients with cancer (e.g. sit-stand test, timed up and go, and 6-min walk test), there is, clearly, a necessity for studying the lower members strength in order to understand functional adaptations of a training program in patients with cancer (Kilgour et al., 2010). These elements demonstrate the intervention of efficacy in this study, as it was verified that 12 weeks of training reduced the difference in leg extension from 40.1% to 23.5%, and, in the sit-stand test, the result varied from 51.3% to 21.2% comparing to the Healthy group. Intervention exercise time is a factor that may influence results. In a specific study about intervention time, cardio respiratory capacity parameters as well as those of QOL, were compared, using from 3 to 6 months interventions (Sprod et al., 2010). It was demonstrated that 3 months of training improved 81 cardiovascular endurance, fatigue and depressing symptoms, in women with breast cancer. However, only the group of patients with cancer who trained for 6 months, showed an improvement of lung function, evaluated by FVC and FEV1, when comparing to the control group. On the other hand, although3-month training is considered to be sufficient to improve strength in leg press, 6 months of training allowed to increase strength even more (Sprod et al., 2010). Although in our study the intervention group had an increase in lower body strength of 13.4% (p<0.001), Drouin et al. (2006) found increases of 38% after 6 months of training. So, we can speculate that if our exercise program was extended in time, we could find even more significant improvements in muscular function. Identically Sprod et al. (2010) verified that after 12 weeks of training, fatigue was substantially reduced, demonstrating that 12 weeks of training is an enough time period to promote decreases in fatigue. In a study by Herrero et al. (2006), sixteen breast cancer patients were randomly assigned to a training or to a non-exercise group. The results from patients in the exercise group were compared to those in a control group, over a short period of 8-week exercise program. The program consisted of 3 weekly sessions of 90 minutes, with resistance and aerobic training. VO2max improved by 3.9 ml/kg/min-1 and performance in leg press improved (17.9Kg), demonstrating that a short exercise program improves fitness and QOL in women with breast cancer. In our study, outcomes related to quality of life, improved significantly after exercise intervention. We verified a difference of more than 10 points, in global health status, role, emotional, cognitive and social function, as well as in fatigue and pain. Besides, physical function improved by 7 points. In these cases, an increase of 20 points on what concerns fatigue and more than 15 points in pain reflects a very high increase. Since the control group had daily health care support during the intervention period, this group also improved the global quality of life and social functioning. However, in agreement with our study, patients in the intervention group had a slightly better outcome for some HRQOL dimensions than patients in the control 82 group (Courneya et al., 2003; Mock et al., 2001). These findings are consistent with Naumann et al. (2012), who reported an increase of more than 10 points in QOL, in individual home-based and group-based training, in breast cancer survivors, after 9 weeks of exercise. Contrary to our study, Thorsen et al. (2005) verified a slightly better outcome for some HRQOL dimensions in the control group than in patients in the intervention group. The magnitude of changes in mental distress, fatigue, and HRQOL parameters in trials in this area, are not consistent. It is not clear whether these disparities of outcome are the result of differences in patient characteristics and/or the type and timing of intervention, or whether these variations can be explained by different methods of assessment. The most frequently reported symptom, resulting from treatment, is fatigue, which may last months and years after treatment (Bower et al., 2009; Erickson, 2004; Ryan et al., 2007; Stasi et al., 2003). Cardiovascular toxicity can result in left ventricular dysfunction evidences, by an increase time to peak filling of the left ventricle, lower left ventricular ejection fraction, abnormal left ventricular contractility, reduced cardiac output and stroke volume, weak lead to lower oxygen and nutrition delivery (Brockstein et al., 2000; Gianni et al., 2001). Furthermore, pulmonary toxicity can occur as a result of cancer treatments and lead to shortness of breath, decrease of total lung capacity, vital capacity, inspirable capacity and decreased diffusion capacity, which, in turn, can compromise oxygen delivery and carbon dioxide removal (Brockstein et al., 2000). With the increasing prevalence of cancer fatigue and treatment toxicities on the quality of life, determining how to manage and promote efficacious strategies for overcoming these alterations should be investigated during and after cancer treatment (Schneider et al., 2007). In the present study, exercise induced a pronounced decrease in fatigue and pain symptoms, which is in line with literature results referring that exercise may help to manage fatigue during and after treatments (Adamsen et al., 2004; Dimeo, Stieglitz, et al., 1997; Dimeo et al., 1999; Mock et al., 2005; Mock et al., 2001; Stricker et al., 2004). However, the alteration of this symptom should be interpreted with some prudence. We use the symptom scale fatigue from 83 EORTC QLQ C-30 but, probably, it is important the use of a domain-specific instrument when fatigue is the primary outcome. Knobel et al. (2003) validated the fatigue scale in EORTC QLQ C-30 against the Fatigue questionnaire, the latter measuring both physical and mental fatigue. The analysis demonstrated that the fatigue scale in EORTC QLQ C-30 correlated higher with the physical fatigue scale (r=0.67 to 0.75) than with mental fatigue scale (r= 0.49 to 0.61). Fatigue measured by EORTC QLQ-C30 does not differentiate between acute and chronic fatigue (Thorsen et al., 2005). So, these authors recommend for studies with fatigue as defined end point,, a domain-specific instrument, which is more suitable to evaluate fatigue (Stone et al., 1998). Besides, in patients with advanced lung cancer, a correlation between FACT-Fatigue questionnaire and EORTC QLQ C-30 fatigue scales (r=0.712; p<0.001) was verified, showing that the questionnaire which was used in this study may help to understand the fatigue intensity in our work. In our program, patients in the intervention program reported less fatigue than patients in the control group, suggesting that exercise may reduce fatigue. Nevertheless, in the healthy control group, fatigue was not evaluated. After radiotherapy, Smets, Visser, Willems-Groot, Garssen, Oldenburger, et al. (1998) concluded that fatigue in breast cancer patients increased by 46% compared to a healthy control group. Moreover, after 9 months in disease-free patients, 26% of patients worried about their fatigue and, patients' overall quality of life was negatively related to fatigue (r = -0.46) and was significantly associated with gender, physical distress, pain rating, sleep quality, functional disability, psychological distress and depression, but not with medical or treatment-related variables (Smets, Visser, Willems-Groot, Garssen, Schuster-Uitterhoeve, et al., 1998). On the other hand, Geinitz et al. (2001) observed an increase in fatigue during 5 weeks of adjuvant radiotherapy in patients with breast cancer. Nevertheless, fatigue returned to pretreatment levels 2 months after treatment. No evidence was found about anxiety, depression, serum levels of IL-1beta, IL-6, tumor necrosis factor-alpha, or declining hemoglobin levels being responsible for the treatment- 84 induced fatigue. Fatigue is common in depression, and both fatigue and depression are common in cancer patients (Stone et al., 1998). In some studies, consistent associations were found between fatigue and psychological distress (Stone et al., 2000). Moreover, Stone et al. (2000) found an association between fatigue severity and global quality of life suggesting that fatigue is an important contributor to quality of life in both health and disease, and has a high impact on the well-being among cancer patients. Contrary to our study, Thorsen et al. (2005) did not observe any beneficial effect on fatigue, mental distress and HRQOL parameters from the 14-week supervised home-based program training intervention shortly after chemotherapy. The fact that patients themselves performed multiple supervised could represent additional stress. However, VO2max increased by 6.4 ml/kg/min-1 in patients in the intervention group and only 3.1 ml/Kg/min-1 inpatients in the control group, corresponding to 23% and 10%, respectively), showing a beneficial effect on CRF in young and middle-aged cancer patients. The dose-effect relationship of exercise with fatigue needs more investigation. Nevertheless, some results revealed that a greater decrease in fatigue and an increase in QOL were observed with weak targeted exercise doses, <12MET h/week, as well as with long duration interventions (>18weeks) for QOL (Carayol et al., 2012). These findings generate the hypothesis that the prescription of a 20-week exercise program targeting 8-10 MET h/week could be well adapted for patients with breast cancer receiving adjuvant therapy (Carayol et al., 2012). In this case, combined aerobic and resistance (2 sessions of moderate intensity aerobic exercise and one resistance session for principal muscular groups) during 30-45 minutes is recommended (Carayol et al., 2012). In our program, each exercise session had a limit time of 60 minutes, because the fatigue state may be aggravated by longer sessions (Schwartz et al., 2001). The reason for this is unclear, perhaps prolonged exercise provokes muscular fatigue and the feeling of fatigue associated with changes in nutrition and hydration states can increase the sensation of the current level of fatigue. Determining the optimal dose of exercise to reduce fatigue is elusive. In our study, women were instructed to exercise at an intensity of 70-85% of VO2max 85 but it was important that intensity was symptom limited. This exercise intensity was acceptable for breast cancer patients and did not worsen their symptoms during exercise. Schwartz et al. (2001) showed that fatigue was significantly reduced on exercise days compared with non-exercise days. Furthermore, the amount of exercise, measured as the number of minutes exercised, was significantly associated with fatigue levels. In a meta-analysis, the authors observed a positive relationship, meaning that larger amounts of targeted aerobic activity were associated with substantial QOL improvements, but the studies included various cancer sites, both controlled and uncontrolled trial and mixed intervention periods with most of the studies involving post adjuvant therapy intervention (Ferrer et al., 2011). In our study, women did not show an increase in body weight (not an outcome measure of our study). Nevertheless, besides being a quality of life contributor, exercise may also be a strategy for weight control since weight gain is common in both pre and postmenopausal women after diagnosis (Demark-Wahnefried et al., 2000) as well as during and after adjuvant treatments (Harvie et al., 2004; Sestak et al., 2012) and during the five-year follow-up (Makari-Judson et al., 2007). Furthermore, the weight gains also tend to be linked to an increase in fat mass and the recent findings of Winters-Stone et al. (2008) showed that higher percentage of body fat reported more fatigue compared to leaner women. Moreover, using separate correlation analysis, using lean mass and fat mass, the later was significantly and positively associated with fatigue rather than lean mass (Winters-Stone et al., 2008). Upon diagnosis, and as a consequence of receiving treatment, being overweight or obese elevates risk up to 4-fold of developing multiple other diseases such type II diabetes, asthma, chronic back pain, osteoarthritis and cardiovascular disease (Rock & Demark-Wahnefried, 2002). A meta-analysis included 43 studies that enrolled women diagnosed with breast cancer between 1963 and 2005 with a sample size ranged from 100 to 42 4168. demonstrated that obesity is associated with poorer overall and breast cancer-specific survival (Protani et al., 2010). Weight gain is critical to patients, 86 as it relates to body image, but it is also a risk factor for impairment and poorer outcomes of treatment (Demark-Wahnefried et al., 2012). Weight control in women with breast cancer is important because the weight (BMI> 25.0) may increase the lymphedema probability. In the study of Swenson et al. (2009), through the multivariable analysis, axillary radiation, more extensive surgery, chemotherapy were predictive of lymphedema but, the only factor significantly associated with lymphedema, was overweight (p = 0.022). Being overweight is an important modifiable risk factor for lymphedema. Furthermore, the results indicate a lower lymphedema incidence in women with breast cancer who were submitted to resistance training strength (Swenson et al., 2009). The main strengths of the present study are the several measurements of physical performance and HRQOL. Opposite to other intervention studies of exercise, we chose a multi-structured exercise program, supervised in clinical context. We pretended to adequate the individuality of the exercise and to apply the principles of training in each exercise sessions, as the answer to exercise and to treatment varies among patients with breast cancer. The exercise program also intended to reduce the drop out percentage and to increase motivation for physical exercise practice, during and after treatment. A high adhesion to the programwas evident, which also confirms that women with breast cancer are able to tolerate high intensity aerobic exercises. To our knowledge, this is one of the first studies which analyses and compares the muscle and aerobic fitness through a multidisciplinary exercise program using a healthy control group. These results may be important for future studies with the outcome of returning to work since a poor physical condition may impair the productivity. The main limitation of the study is the small sample size and the heterogeneity of the case group due to variations in adjuvant treatments. A larger sample would also allow the possibility to access the relationship between the amount and intensity of exercise and respective changes in outcome. Using a fatigue specific questionnaire as the FACT-Fatigue, would help to have a better 87 understanding of the different fatigue categories and show a more solid analysis of the fatigue changes during the intervention. Using a fatigue protocol will probably give more information about the effect of a training program in breast cancer patients, with the aim to evaluate the strength of the upper members. The results of this study demonstrate the importance of exercise to reduce fatigue in women with breast cancer during treatment. Although in opposition to standard practice, it appears that women with breast cancer who are regular exercisers should be encouraged to continue their exercise program and women who are not regular exercisers should be given guidance and instruction to begin an exercise program. 88 89 7 7. . C Co on nc cl lu us si io on n 96 Bigland-Ritchie, B., Rice, C. L., Garland, S. J., & Walsh, M. L. (1995). Taskdependent factors in fatigue of human voluntary contractions. Adv Exp Med Biol, 384, 361-380. Blair, S. N., Kampert, J. B., Kohl, H. W., 3rd, Barlow, C. E., Macera, C. A., Paffenbarger, R. S., Jr., & Gibbons, L. W. (1996). Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA, 276(3), 205-210. Borg, G., Ljunggren, G., & Ceci, R. (1985). The increase of perceived exertion, aches and pain in the legs, heart rate and blood lactate during exercise on a bicycle ergometer. Eur J Appl Physiol Occup Physiol, 54(4), 343349. Bower, J. E., Ganz, P. A., Tao, M. L., Hu, W., Belin, T. R., Sepah, S., Cole, S., & Aziz, N. (2009). Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin Cancer Res, 15(17), 55345540. Brenner, H., Gondos, A., & Arndt, V. (2007). Recent major progress in longterm cancer patient survival disclosed by modeled period analysis. J Clin Oncol, 25(22), 3274-3280. Brinton, L. A., Sherman, M. E., Carreon, J. D., & Anderson, W. F. (2008). Recent trends in breast cancer among younger women in the United States. J Natl Cancer Inst, 100(22), 1643-1648. Brockstein, B. E., Smiley, C., Al-Sadir, J., & Williams, S. F. (2000). Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant, 25(8), 885-894. Brown, D. J., McMillan, D. C., & Milroy, R. (2005). The correlation between fatigue, physical function, the systemic inflammatory response, and psychological distress in patients with advanced lung cancer. Cancer, 103(2), 377-382. Brown, J. K., Byers, T., Doyle, C., Coumeya, K. S., Demark-Wahnefried, W., Kushi, L. H., McTieman, A., Rock, C. L., Aziz, N., Bloch, A. S., Eldridge, B., Hamilton, K., Katzin, C., Koonce, A., Main, J., Mobley, C., Morra, M. 97 E., Pierce, M. S., & Sawyer, K. A. (2003). Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin, 53(5), 268-291. Burnham, T. R., & Wilcox, A. (2002). Effects of exercise on physiological and psychological variables in cancer survivors. Med Sci Sports Exerc, 34(12), 1863-1867. Burstein, H. J., Prestrud, A. A., Seidenfeld, J., Anderson, H., Buchholz, T. A., Davidson, N. E., Gelmon, K. E., Giordano, S. H., Hudis, C. A., Malin, J., Mamounas, E. P., Rowden, D., Solky, A. J., Sowers, M. R., Stearns, V., Winer, E. P., Somerfield, M. R., & Griggs, J. J. (2010). American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol, 28(23), 3784-3796. Campbell, K. L., & McTiernan, A. (2007). Exercise and biomarkers for cancer prevention studies. J Nutr, 137(1 Suppl), 161S-169S. Campbell, K. L., Neil, S. E., & Winters-Stone, K. M. (2011). Review of exercise studies in breast cancer survivors: attention to principles of exercise training. Br J Sports Med. Carayol, M., Bernard, P., Boiche, J., Riou, F., Mercier, B., Cousson-Gelie, F., Romain, A. J., Delpierre, C., & Ninot, G. (2012). Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed? Ann Oncol. Castell, L. M., Yamamoto, T., Phoenix, J., & Newsholme, E. A. (1999). The role of tryptophan in fatigue in different conditions of stress. Adv Exp Med Biol, 467, 697-704. Cella, D. (1997). The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol, 34(3 Suppl 2), 13-19. Cella, D., Lai, J. S., Chang, C. H., Peterman, A., & Slavin, M. (2002). Fatigue in cancer patients compared with fatigue in the general United States population. Cancer, 94(2), 528-538. 98 Cheema, B., Gaul, C. A., Lane, K., & Fiatarone Singh, M. A. (2008). Progressive resistance training in breast cancer: a systematic review of clinical trials. Breast Cancer Res Treat, 109(1), 9-26. Chirikos, T. N., Russell-Jacobs, A., & Cantor, A. B. (2002). Indirect economic effects of long-term breast cancer survival. Cancer Pract, 10(5), 248-255. Clarkson, P. M., & Kaufman, S. A. (2010). Should resistance exercise be recommended during breast cancer treatment? Med Hypotheses, 75(2), 192-195. Courneya, K. S. (2003). Exercise in cancer survivors: an overview of research. Med Sci Sports Exerc, 35(11), 1846-1852. Courneya, K. S., Booth, C. M., Gill, S., O'Brien, P., Vardy, J., Friedenreich, C. M., Au, H. J., Brundage, M. D., Tu, D., Dhillon, H., & Meyer, R. M. (2008). The Colon Health and Life-Long Exercise Change trial: a randomized trial of the National Cancer Institute of Canada Clinical Trials Group. Curr Oncol, 15(6), 279-285. Courneya, K. S., & Friedenreich, C. M. (1999). Physical exercise and quality of life following cancer diagnosis: a literature review. Ann Behav Med, 21(2), 171-179. Courneya, K. S., & Friedenreich, C. M. (2011). Physical activity and cancer: an introduction. Recent Results Cancer Res, 186, 1-10. Courneya, K. S., Mackey, J. R., Bell, G. J., Jones, L. W., Field, C. J., & Fairey, A. S. (2003). Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol, 21(9), 1660-1668. Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C. M., Ladha, A. B., Proulx, C., Vallance, J. K., Lane, K., Yasui, Y., & McKenzie, D. C. (2007). Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol, 25(28), 4396-4404. De Backer, I. C., Schep, G., Backx, F. J., Vreugdenhil, G., & Kuipers, H. (2009). Resistance training in cancer survivors: a systematic review. Int J Sports Med, 30(10), 703-712. 99 De Backer, I. C., Schep, G., Hoogeveen, A., Vreugdenhil, G., Kester, A. D., & van Breda, E. (2007). Exercise testing and training in a cancer rehabilitation program: the advantage of the steep ramp test. Arch Phys Med Rehabil, 88(5), 610-616. De Backer, I. C., Van Breda, E., Vreugdenhil, A., Nijziel, M. R., Kester, A. D., & Schep, G. (2007). High-intensity strength training improves quality of life in cancer survivors. Acta Oncol, 46(8), 1143-1151. Demark-Wahnefried, W., Campbell, K. L., & Hayes, S. C. (2012). Weight management and its role in breast cancer rehabilitation. Cancer, 118(8 Suppl), 2277-2287. Demark-Wahnefried, W., Peterson, B., McBride, C., Lipkus, I., & Clipp, E. (2000). Current health behaviors and readiness to pursue life-style changes among men and women diagnosed with early stage prostate and breast carcinomas. Cancer, 88(3), 674-684. Devoogdt, N., Van Kampen, M., Geraerts, I., Coremans, T., Fieuws, S., Lefevre, J., Philippaerts, R., Truijen, S., Neven, P., & Christiaens, M. R. (2010). Physical activity levels after treatment for breast cancer: one-year followup. Breast Cancer Res Treat, 123(2), 417-425. Dimeo, F. (2000). Exercise for cancer patients: a new challenge in sports medicine. West J Med, 173(4), 272-273. Dimeo, F., Fetscher, S., Lange, W., Mertelsmann, R., & Keul, J. (1997). Effects of aerobic exercise on the physical performance and incidence of treatment-related complications after high-dose chemotherapy. Blood, 90(9), 3390-3394. Dimeo, F., Schwartz, S., Fietz, T., Wanjura, T., Boning, D., & Thiel, E. (2003). Effects of endurance training on the physical performance of patients with hematological malignancies during chemotherapy. Support Care Cancer, 11(10), 623-628. Dimeo, F., Stieglitz, R. D., Novelli-Fischer, U., Fetscher, S., Mertelsmann, R., & Keul, J. (1997). Correlation between physical performance and fatigue in cancer patients. Ann Oncol, 8(12), 1251-1255. 100 Dimeo, F. C. (2001). Effects of exercise on cancer-related fatigue. Cancer, 92(6 Suppl), 1689-1693. Dimeo, F. C., Stieglitz, R. D., Novelli-Fischer, U., Fetscher, S., & Keul, J. (1999). Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer, 85(10), 2273-2277. Dowlati, A., R'Zik, S., Fillet, G., & Beguin, Y. (1997). Anaemia of lung cancer is due to impaired erythroid marrow response to erythropoietin stimulation as well as relative inadequacy of erythropoietin production. Br J Haematol, 97(2), 297-299. Drolet, M., Maunsell, E., Mondor, M., Brisson, C., Brisson, J., Masse, B., & Deschenes, L. (2005). Work absence after breast cancer diagnosis: a population-based study. CMAJ, 173(7), 765-771. Drouin, J. S. (2004). Exercise in older individuals with cancer. Topics in Geriatric Rehabilitation, 20(2), 81-97. Drouin, J. S., Young, T. J., Beeler, J., Byrne, K., Birk, T. J., Hryniuk, W. M., & Hryniuk, L. E. (2006). Random control clinical trial on the effects of aerobic exercise training on erythrocyte levels during radiation treatment for breast cancer. Cancer, 107(10), 2490-2495. Eheman, C., Henley, S. J., Ballard-Barbash, R., Jacobs, E. J., Schymura, M. J., Noone, A. M., Pan, L., Anderson, R. N., Fulton, J. E., Kohler, B. A., Jemal, A., Ward, E., Plescia, M., Ries, L. A., & Edwards, B. K. (2012). Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer, 118(9), 2338-2366. Erickson, J. M. (2004). Fatigue in adolescents with cancer: a review of the literature. Clin J Oncol Nurs, 8(2), 139-145. Fayers, P. M. (2001). Interpreting quality of life data: population-based reference data for the EORTC QLQ-C30. Eur J Cancer, 37(11), 13311334. Ferrer, R. A., Huedo-Medina, T. B., Johnson, B. T., Ryan, S., & Pescatello, L. S. (2011). Exercise interventions for cancer survivors: a meta-analysis of quality of life outcomes. Ann Behav Med, 41(1), 32-47. 101 Friedenreich, C. M. (2001). Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev, 10(4), 287-301. Galvao, D. A., & Newton, R. U. (2005). Review of exercise intervention studies in cancer patients. J Clin Oncol, 23(4), 899-909. Garber, C. E., Blissmer, B., Deschenes, M. R., Franklin, B. A., Lamonte, M. J., Lee, I. M., Nieman, D. C., & Swain, D. P. (2011). American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc, 43(7), 1334-1359. Gartner, R., Jensen, M. B., Nielsen, J., Ewertz, M., Kroman, N., & Kehlet, H. (2009). Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA, 302(18), 1985-1992. Geinitz, H., Zimmermann, F. B., Stoll, P., Thamm, R., Kaffenberger, W., Ansorg, K., Keller, M., Busch, R., van Beuningen, D., & Molls, M. (2001). Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer. Int J Radiat Oncol Biol Phys, 51(3), 691-698. Gianni, L., Dombernowsky, P., Sledge, G., Martin, M., Amadori, D., Arbuck, S. G., Ravdin, P., Brown, M., Messina, M., Tuck, D., Weil, C., & Winograd, B. (2001). Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer. Ann Oncol, 12(8), 1067-1073. Groopman, J. E., & Itri, L. M. (1999). Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst, 91(19), 1616-1634. Guise, T. A. (2006). Bone loss and fracture risk associated with cancer therapy. Oncologist, 11(10), 1121-1131. Harvie, M. N., Campbell, I. T., Baildam, A., & Howell, A. (2004). Energy balance in early breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat, 83(3), 201-210. 102 Haykowsky, M. J., Mackey, J. R., Thompson, R. B., Jones, L. W., & Paterson, D. I. (2009). Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin Cancer Res, 15(15), 4963-4967. Hayward, R., Ruangthai, R., Schneider, C. M., Hyslop, R. M., Strange, R., & Westerlind, K. C. (2004). Training enhances vascular relaxation after chemotherapy-induced vasoconstriction. Med Sci Sports Exerc, 36(3), 428-434. Headley, J. A., Theriault, R. L., LeBlanc, A. D., Vassilopoulou-Sellin, R., & Hortobagyi, G. N. (1998). Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Invest, 16(1), 6-11. Herrero, F., San Juan, A. F., Fleck, S. J., Balmer, J., Perez, M., Canete, S., Earnest, C. P., Foster, C., & Lucia, A. (2006). Combined aerobic and resistance training in breast cancer survivors: A randomized, controlled pilot trial. Int J Sports Med, 27(7), 573-580. Herrero, F., San Juan, A. F., Fleck, S. J., Foster, C., & Lucia, A. (2007). Effects of detraining on the functional capacity of previously trained breast cancer survivors. Int J Sports Med, 28(3), 257-264. Holmes, M. D., Chen, W. Y., Feskanich, D., Kroenke, C. H., & Colditz, G. A. (2005). Physical activity and survival after breast cancer diagnosis. JAMA, 293(20), 2479-2486. Hoving, J. L., Broekhuizen, M. L., & Frings-Dresen, M. H. (2009). Return to work of breast cancer survivors: a systematic review of intervention studies. BMC Cancer, 9, 117. Ingram, C., & Visovsky, C. (2007). Exercise intervention to modify physiologic risk factors in cancer survivors. Semin Oncol Nurs, 23(4), 275-284. Inui, A. (2002). Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin, 52(2), 72-91. Itri, L. M. (2000). Optimal hemoglobin levels for cancer patients. Semin Oncol, 27(2 Suppl 4), 12-15; discussion 16-17. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA Cancer J Clin, 61(2), 69-90. 103 Karvinen, K. H., Raedeke, T. D., Arastu, H., & Allison, R. R. (2011). Exercise programming and counseling preferences of breast cancer survivors during or after radiation therapy. Oncol Nurs Forum, 38(5), E326-334. Kilgour, R. D., Vigano, A., Trutschnigg, B., Hornby, L., Lucar, E., Bacon, S. L., & Morais, J. A. (2010). Cancer-related fatigue: the impact of skeletal muscle mass and strength in patients with advanced cancer. J Cachexia Sarcopenia Muscle, 1(2), 177-185. Klauber-DeMore, N. (2005). Tumor biology of breast cancer in young women. Breast Dis, 23, 9-15. Knobel, H., Loge, J. H., Brenne, E., Fayers, P., Hjermstad, M. J., & Kaasa, S. (2003). The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med, 17(8), 664-672. Knobf, M. T., Insogna, K., DiPietro, L., Fennie, C., & Thompson, A. S. (2008). An aerobic weight-loaded pilot exercise intervention for breast cancer survivors: bone remodeling and body composition outcomes. Biol Res Nurs, 10(1), 34-43. Knutsen, L., Quist, M., Midtgaard, J., Rorth, M., & Adamsen, L. (2006). Maximum physical capacity testing in cancer patients undergoing chemotherapy: qualitative findings from an exercise program. Scand J Med Sci Sports, 16(6), 403-411. Kolden, G. G., Strauman, T. J., Ward, A., Kuta, J., Woods, T. E., Schneider, K. L., Heerey, E., Sanborn, L., Burt, C., Millbrandt, L., Kalin, N. H., Stewart, J. A., & Mullen, B. (2002). A pilot study of group exercise training (GET) for women with primary breast cancer: feasibility and health benefits. Psychooncology, 11(5), 447-456. Kosmidis, P., & Krzakowski, M. (2005). Anemia profiles in patients with lung cancer: what have we learned from the European Cancer Anaemia Survey (ECAS)? Lung Cancer, 50(3), 401-412. Langer, C. J., Choy, H., Glaspy, J. A., & Colowick, A. (2002). Standards of care for anemia management in oncology: focus on lung carcinoma. Cancer, 95(3), 613-623. 104 Langer, C. J., Leighton, J. C., Comis, R. L., O'Dwyer, P. J., McAleer, C. A., Bonjo, C. A., Engstrom, P. F., Litwin, S., Johnson, S., & Ozols, R. F. (1995). Paclitaxel by 24or 1-hour infusion n combination with carboplatin in advanced non-small cell lung cancer: the Fox Chase Cancer Center experience. Semin Oncol, 22(4 Suppl 9), 18-29. Laviolette, L., Bourbeau, J., Bernard, S., Lacasse, Y., Pepin, V., Breton, M. J., Baltzan, M., Rouleau, M., & Maltais, F. (2008). Assessing the impact of pulmonary rehabilitation on functional status in COPD. Thorax, 63(2), 115-121. Lee, S. G., Jee, Y. G., Chung, H. C., Kim, S. B., Ro, J., Im, Y. H., Im, S. A., & Seo, J. H. (2009). Cost-effectiveness analysis of adjuvant therapy for node positive breast cancer in Korea: docetaxel, doxorubicin and cyclophosphamide (TAC) versus fluorouracil, doxorubicin and cyclophosphamide (FAC). Breast Cancer Res Treat, 114(3), 589-595. Levine, B. D., Zuckerman, J. H., & Pawelczyk, J. A. (1997). Cardiac atrophy after bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance. Circulation, 96(2), 517-525. Loprinzi, P. D., & Cardinal, B. J. (2012). Effects of physical activity on common side effects of breast cancer treatment. Breast Cancer, 19(1), 4-10. Lucia, A., Earnest, C., & Perez, M. (2003). Cancer-related fatigue: can exercise physiology assist oncologists? Lancet Oncol, 4(10), 616-625. Ludwig, H., & Strasser, K. (2001). Symptomatology of anemia. Semin Oncol, 28(2 Suppl 8), 7-14. Ludwig, H., Van Belle, S., Barrett-Lee, P., Birgegard, G., Bokemeyer, C., Gascon, P., Kosmidis, P., Krzakowski, M., Nortier, J., Olmi, P., Schneider, M., & Schrijvers, D. (2004). The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer, 40(15), 2293-2306. MacVicar, M. G., Winningham, M. L., & Nickel, J. L. (1989). Effects of aerobic interval training on cancer patients' functional capacity. Nurs Res, 38(6), 348-351. 105 Makari-Judson, G., Judson, C. H., & Mertens, W. C. (2007). Longitudinal patterns of weight gain after breast cancer diagnosis: observations beyond the first year. Breast J, 13(3), 258-265. Martin, M., Pienkowski, T., Mackey, J., Pawlicki, M., Guastalla, J. P., Weaver, C., Tomiak, E., Al-Tweigeri, T., Chap, L., Juhos, E., Guevin, R., Howell, A., Fornander, T., Hainsworth, J., Coleman, R., Vinholes, J., Modiano, M., Pinter, T., Tang, S. C., Colwell, B., Prady, C., Provencher, L., Walde, D., Rodriguez-Lescure, A., Hugh, J., Loret, C., Rupin, M., Blitz, S., Jacobs, P., Murawsky, M., Riva, A., & Vogel, C. (2005). Adjuvant docetaxel for node-positive breast cancer. N Engl J Med, 352(22), 23022313. McKenzie, D. C., & Kalda, A. L. (2003). Effect of upper extremity exercise on secondary lymphedema in breast cancer patients: a pilot study. J Clin Oncol, 21(3), 463-466. Mock, V., Dow, K. H., Meares, C. J., Grimm, P. M., Dienemann, J. A., HaisfieldWolfe, M. E., Quitasol, W., Mitchell, S., Chakravarthy, A., & Gage, I. (1997). Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer. Oncol Nurs Forum, 24(6), 991-1000. Mock, V., Frangakis, C., Davidson, N. E., Ropka, M. E., Pickett, M., Poniatowski, B., Stewart, K. J., Cameron, L., Zawacki, K., Podewils, L. J., Cohen, G., & McCorkle, R. (2005). Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psychooncology, 14(6), 464-477. Mock, V., Pickett, M., Ropka, M. E., Muscari Lin, E., Stewart, K. J., Rhodes, V. A., McDaniel, R., Grimm, P. M., Krumm, S., & McCorkle, R. (2001). Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract, 9(3), 119-127. Monga, U., Jaweed, M., Kerrigan, A. J., Lawhon, L., Johnson, J., Vallbona, C., & Monga, T. N. (1997). Neuromuscular fatigue in prostate cancer patients undergoing radiation therapy. Arch Phys Med Rehabil, 78(9), 961-966. 112 113 9 9. . A At tt ta ac ch hm me en nt ts s Termo de Consentimento Programa de Exercício em Mulheres com Cancro da Mama No âmbito do Doutoramento em Ciências do Desporto na Faculdade de Desporto da Universidade do Porto, está a decorrer uma investigação sobre o efeito do exercício físico na qualidade de vida em Mulheres com cancro da mama. O conhecimento das alterações funcionais e estruturais dos pacientes com cancro durante e após o tratamento, torna-se fundamental para o desenvolvimento de programas de prevenção da fadiga relacionada com o cancro. Este trabalho tem como objectivo geral analisar e descrever o efeito individualizado do treino e exercício, com finalidade terapêutica, nas alterações da função aeróbia e muscular, durante e após o período de tratamento em pacientes com cancro. Para se conseguir executar esta fase do trabalho é necessário avaliar a qualidade de vida, a função muscular e aeróbia através da avaliação em ciclo ergómetro com espirometria. Para o efeito, apela-se à colaboração de pessoas para integrarem a amostra do estudo, pelo que, se solicitam algumas informações e obtenção de consentimento informado. Nome _________________________________________________ Idade _________ Data de Nascimento _________________ B.I. __________________ Declaro, por meio deste termo, que concordo em participar na pesquisa de campo referente a este trabalho sobre “O efeito do exercício em pacientes com cancro”, desenvolvido pelo aluno de Doutoramento, Eduardo Oliveira, sob orientação do Prof. Doutor José Soares e colaboração da Prof. Doutora Maria João Cardoso, Presidente do Centro MamaHelp. Fui informada da garantia de anonimato, de ser submetido(a) a um inquérito sobre Qualidade de Vida através de um questionário bem como ser submetido a um inquérito sobre a História Clínica e Estilo de Vida Declaro que fui informada que serei pesado numa balança de bio-impedância para determinar a composição coporal. A respectiva medição terá de ser realizada sem sapatos e sem meias. Declaro ter sido informada sobre a medição da frequência cardíaca de repouso e da variabilidade da frequência cardíaca. O protocolo desta medição consiste em avaliar a frequência cardíaca em decúbito dorsal durante dez minutos. Declaro ter sido informada sobre o protocolo da medição da força de preensão da mão e medição da força dos membros inferiores nomeadamente do quadricipite. A medição da força é realizada pela capacidade de produzir força com máxima intensidade durante três segundos com recurso a um dinamómetro portátil. Declaro que fui informada sobre a medição da aptidão cárdio-respiratória que é realizada através de uma prova de esforço numa bicicleta estática com um protocolo de exercício que aumenta progressivamente a intensidade. Para esta avaliação é necessário colocar uma máscara que envolve a boca e o nariz com o objectivo de se avaliar os gases inspirados e expirados. Para além disso será colocado um aparelho no peito para registar a frequência cardiaca durante a prova de esforço e monitorizar a intensidade de exercício. Declaro que fui informada que os custos de deslocação MamaHelp serão por mim assumidos (nome) ____________________________. Declaro que fui esclarecida que caso haja necessidade de realizar um hemograma, os custos serão suportados pelo projecto que está a decorrer. Declaro que fui informada que o protocolo de exercício terá a duração de 12 semanas (3 meses) com uma frequência de 2 vezes por semana. Cada sessão de exercício terá a duração de 45 minutos. O programa de exercício poderá ser realizado de duas formas. A primeira possibilidade é realizar o exercício físico no MamaHelp com ajuda de profissionais especializados. A segunda possibilidade é realizar o programa de exercício no domicílio. Neste caso, os exercícios serão explicados previamente no MamaHelp. O protocolo de exercício será constituído por exercícios de reforço muscular. O meio utilizado para se melhorar a funcionalidade muscular será através do recurso a elásticos. Este material será fornecido sendo os custos suportados pelo respectivo projecto. Declaro que fui esclarecida que o protocolo de avaliação terá dois momentos de avaliação com uma distância temporal de 12 semanas entre eles. O primeiro momento de avaliação corresponde à avaliação inicial e segunda e última avaliação corresponde ao términus do programa de exercício (semana 12). Afirmo que aceito participar por minha própria vontade, sem receber qualquer incentivo financeiro e com a finalidade exclusiva de colaborar para o sucesso deste trabalho. ____________________ , ____ de Outubro de 2011 ____________________________________ (Assinatura) Muito obrigado pela colaboração! ! História clínica ! Schneider, C.; Dennehy, C.; Carter, S. (2003) Exercise and Cancer Recovery. (Champaign, IL: Human Kinetics). Usado com permissão do MamaHelp Nome ______________________________________ Data ________________ Morada __________________________________________________________ Código Postal ________-______ Localidade _____________________________ Telefone ____________________ Data Nascimento ___________ Idade _____ Email ___________________________________________________________ Tipo de cancro:_______________________ Data do Diagnóstico:___________ Localização Específica:_____________________ (p. ex. Lado dir/esq do peito) Cirurgia: ___ Sim ___ Não Data da cirurgia: ________________________ Tipo de Cirurgia: __________________________________________________ Outras Cirurgias: __________________________________________________ Sintomas: ________________________________________________________ _______________________ (sintomas que teve que originaram o diagnóstico de cancro: fadiga, náuseas, etc.) Tratamento pós cirurgia (quimioterapia, radioterapia): _____________________ Duração do tratamento: _____________________________________________ Data do último tratamento: __________________________________________ Actualmente realiza quimioterapia? ___sim ___ não Se sim, qual a data último tratamento? _________________________ Actualmente realiza radioterapia? ___ sim ___ não Se sim, qual a data último tratamento? _________________________ Tomas algum tipo de medicação? ___sim ___ não Se sim qual? ______________________________________________ _________________________________________________________________ ! Estilo de Vida / Avaliação da Actividade Física ! Schneider, C.; Dennehy, C.; Carter, S. (2003) Exercise and Cancer Recovery. (Champaign, IL: Human Kinetics). Usado com permissão do MamaHelp ! Nome: ________________________________________ Data: _____________ Tabagismo 1. Alguma vez já fumou? ____________________________________________ 2. Fuma actualmente? ____ Quantidade por dia/semana __________________ 3. Com que idade começou a fumar? ___________________________________ 4. Com que idade deixou de fumar? ____________________________________ Ingestão de bebidas alcoólicas 1. No último mês, quantos dias por semana ingeriu bebidas alcoólicas? _______ 2. No último mês, qual a quantidade de ingerida apenas numa ocasião? _______ Sono 1. Durante a última semana, qual foi a média de horas de sono durante a semana (segunda a sexta feira)? _____________________________________________ 2. Qual foi a média de horas de sono aos fins de semana (Sábado e Domingo)? _ ________________________________________________________________ Exercício 1. Realiza exercício de uma forma regular? ______________________________ 2. Que tipo de exercícios realiza de uma forma regular? ____________________ 3. Quantos dias por semana realiza exercício de uma forma regular? __________ 4. Qual o tempo dispendido numa única sessão de exercício (minutos)? ________ 5. Considera o seu exercício de baixa, moderada ou elavada intensidade? ______ 6. Assinale o seu tipo de ocupação profissional: _____ Inactivo(a) (p.ex. trabalho numa secretária) _____ Trabalho ligeiro (p.ex. trabalhos em casa, jardinagem) _____ Trabalho intenso (p.ex. carregar objectos pesados) 7. Que tipo de actividade física o(a) motiva mais? _________________________ 8. Que tipo de material/equipamento tem disponível para a prática de exercício? _________________________________________________________________ 9. A sua actividade física alterou-se durante o último ano? __________________ _________________________________________________________________ ! Estilo de Vida / Avaliação da Actividade Física ! Schneider, C.; Dennehy, C.; Carter, S. (2003) Exercise and Cancer Recovery. (Champaign, IL: Human Kinetics). Usado com permissão do MamaHelp ! Dieta 1. Neste momento, está satisfeito(a) com o seu peso? _____________________ 2. Qual o peso que gostaria de ter? ____________________________________ 3. Em adulto, qual foi a sua pesagem mais alta? __________________________ 4. Em adulto, qual foi a sua pesagem mais baixa? _________________________ 5. Se já tentou perder peso, que métodos é que abordou? __________________ Registo de actividades diárias 1. Tem dificuldade em realizar algumas das seguintes actividades? ___ Carregar as compras ___ Rotinas de jardinagem ___ Guardar compras / louça ___ Conduzir ___ Lavar roupa / pôr roupa a secar ___ Fazer a cama ___ Passar a roupa a ferro ___ Pegar nos filhos ___ Outra _______________________________________________________ 2. Responda se anteriormente assinalou alguma resposta, a. A dificuldade que referiu começou a manifestar-se antes ou após o tratamento do cancro? ____________________________________________ b. Se conhecida, descreva a causa de ter a respectiva dificuldade. _________ _______________________________________________________________ PORTUGUESE EORTC QLQ-C30 (version 3) Gostaríamos de conhecer alguns pormenores sobre si e a sua saúde. Responda você mesmo/a, por favor, a todas as perguntas fazendo um círculo à volta do número que melhor se aplica ao seu caso. Não há respostas certas nem erradas. A informação fornecida é estritamente confidencial. Escreva as iniciais do seu nome: bbbb A data de nascimento (dia, mês, ano): cececdde A data de hoje (dia, mês, ano): 31 cececdde Não Um Bastante Muito pouco 1. Custa-Ihe fazer esforços mais violentos, por exemplo, carregar um saco de compras pesado ou uma mala? 1 2 3 4 2. Custa-lhe percorrer uma grande distância a pé? 1 2 3 4 3. Custa-lhe dar um pequeno passeio a pé, fora de casa? 1 2 3 4 4. Precisa de ficar na cama ou numa cadeira durante o dia? 1 2 3 4 5. Precisa que o/a ajudem a comer, a vestir-se, a lavar-se ou a ir à casa de banho? 1 2 3 4 Durante a última semana : Não Um Bastante Muito pouco 6. Sentiu-se limitado/a no seu emprego ou no desempenho das suas actividades diárias? 1 2 3 4 7. Sentiu-se limitado/a na ocupação habitual dos seus tempos livres ou noutras actividades de laser? 1 2 3 4 8. Teve falta de ar? 1 2 3 4 9. Teve dores? 1 2 3 4 10. Precisou de descansar? 1 2 3 4 11. Teve dificuldade em dormir? 1 2 3 4 12. Sentiu-se fraco/a? 1 2 3 4 13. Teve falta de apetite? 1 2 3 4 14. Teve enjoos? 1 2 3 4 15. Vomitou? 1 2 3 4 Por favor, passe à página seguinte