Relationship of fatigue with depressive symptoms and level of physical activity in women with breast cancer diagnosis

Breast cancer is the most frequent in women, resulting in fatigue and depressive symptoms as consequence of treatment, but physical activity can help in this process. The aim of this study was to investigate the relationship between fatigue, depressive symptoms and practice of physical activity of women with breast cancer during treatment or after cancer treatment. This is a cross-sectional study with 179 women (56.89 ± 9.4 years) from the Oncology Research Center CEPON, using questionnaire on general and clinical information, fatigue (Piper Fatigue Scale) depressive symptoms (Beck Depression Inventory) and physical activity (IPAQ short version). Women with moderate to severe fatigue underwent physiotherapy (p = 0.001) and women with no fatigue had minimum depressive symptoms (p ≤0.001). Level of physical activity was not associated with fatigue, with most women being insufficiently active and women with mild fatigue had longer walking time than those without fatigue (p = 0.049). Women with depressive symptoms were almost three times more likely of having mild to severe fatigue and those who underwent physiotherapy were twice as likely of having mild to severe fatigue. Women with fatigue had greater presence of depressive symptoms. Professionals working in the field of oncology should recommend the practice of physical activity in order to minimize the side effects of treatment and observe depressive symptoms and fatigue in these women.


INTRODUCTION
Cancer is now a worldwide public health problem; in 20 years, it is estimated that the number of new cancer cases is expected to increase by 57% 1 . Breast cancer, on a worldwide scale, is in second place among the most common types of cancer, and in women, it is the most frequent, reaching 25% of all cancers 1 . In Brazil, for the 2018-2019 years, approximately 600 thousand new cases of cancer are expected to occur; in women, breast cancer is the most frequent (60 thousand), which corresponds to 29.5% with estimated risk of 56.33 cases per 100 thousand women 2  Characterized as a multifactorial disease that results from the uncontrolled and abnormal multiplication of breast cells, in which some of the symptoms include presence of nodule, thickening, swelling, distortion, sensitivity, skin irritation, redness, scales and nipple abnormalities or spontaneous nipple secretion 3 . Treatment options are varied, and for this specific type of cancer, surgery, radiotherapy, chemotherapy and hormone therapy are mainly indicated 4 .
When submitted to treatment, women may suffer physical, psychological, emotional or social consequences 5 . Fatigue, defined as an unpleasant physical sensation, with symptoms of extreme tiredness and exhaustion, is considered one of the most prevalent consequences in cancer patients, severely impacting quality of life, decreasing daily functional capacity 6 . Another consequence present in these women is depressive symptoms 6,7 , which after breast cancer diagnosis, are normally related to treatment with chemotherapy and surgery 7 .
Thus, an alternative and non-pharmacological treatment may be the practice of physical activity, which has been related to improvement of the functional declines of women undergoing breast cancer treatment 8 . Evidence shows positive effects of duly prescribed and well-oriented physical activities 9 and that women with higher levels of physical activity have decreased fatigue, depressive symptoms and better quality of life in general 10 . There are several activities that can be performed, including yoga 11 , dance 12 , Tai chi 13 , walking 14 , among others.
However, little is known about the relationship between fatigue and the presence of depressive symptoms, which is linked to the treatment modalities for breast cancer. These side symptoms can also be related to the practice of physical activity in order to improve the quality of life of these women. Given the importance of breast cancer in public health worldwide, the negative effects of treatment and its relationship with physical activity, the aim of this study was to investigate the relationship between fatigue, depressive symptoms and physical activity in women with breast cancer undergoing treatment or after treatment.

METHOD
This is a cross-sectional study with the participation of 179 women with mean age of 56.89 ± 9.4 years, who were selected from the database of the master's thesis "Physical activity, quality of life and associated factors in women after breast cancer diagnosis" held at the Center for Oncological Research -CEPON. CEPON is characterized as a public service of reference in the treatment of cancer patients in the state of Santa Catarina, as well as a reference center of WHO -World Health Organization for palliative medicine in Brazil.
Inclusion criteria were a) women diagnosed with stage I to III breast cancer; b) age group of 40-80 years and c) undergoing treatment or following post-treatment at CEPON / SC. Exclusion criterion was defined as being illiterate.
For data collection, self-administered questionnaire in the form of individual interview composed of validated instruments was used, being divided into four parts: (a) General and clinical information; (b) Fatigue; (c) Physical activity; (d) Depressive symptoms. pre-obesity and obesity (BMI> 30.0). For statistical analysis and due to the small sample size, weight status was as follows: normal weight, considering thin and eutrophic groups; and overweight, including pre-obesity and obesity groups. Socioeconomic classification was made according to IBGE 16 . The population is classified into economic levels through the average monthly family income. The 2014 minimum wage of R$ 724.00 was adopted. Socioeconomic classes are: (1) Class A, those that receive monthly family income above 20 minimum wages; (2) Class B, those receiving 10 to 20 minimum wages; (3) Class C, including those receiving 4 to 10 minimum wages; (4) Class D, those who receive 2 to 4 minimum wages; and (5) class E, receiving up to 2 minimum wages. For statistical purposes, and due to the small sample size in each category, profile was categorized as high economic level (A and B), medium economic level (C), and low economic level (D and E); b) Fatigue: Piper Fatigue Scale (PFS), which considers the patient's fatigue perception in a subjective and self-reported way 17 with 22 items divided into 3 domains: behavioral (items 2 to 7), which includes functional capacity with personal issues, social activities and sexual relationships; affective (items 8 to 12), which seeks to find the meaning given to fatigue; sensory / psychological (items 13 to 23), which recognize self-perception, emotional and cognitive components in the presence of fatigue. Each item is scored on a scale ranging from 0 to 10. Scores of domains and total score also vary between 0 and 10 and were obtained by summing the score of each item and dividing it by the number of items in each domain, or 22, when calculating the total score. Scores were categorized as follows: 0 as absence; between 0.1 and 4.9 as mild fatigue; between 5 and 10 as moderate or intense fatigue. c) Depressive symptoms: Beck's Depression Inventory (BDI), a selfadministered questionnaire originally developed by Beck et al. 18 . It has 21 multiple-choice objective questions related to depressive symptoms with four answer options that vary in scores from zero to three (0-3) The sum of scores of each item provides a total score, which ranges from 0 to 63 The closer to 0, the greater the absence of depressive symptoms, and the closer to 63, the higher the degree of depressive symptoms. The symptoms considered by BDI are: sadness, pessimism, feeling of failure, dissatisfaction, feeling of guilt, expectation of punishment, low self-esteem, self-criticism, suicidal ideas, crying crisis, irritability, social withdrawal, indecision, body image distortion, inhibition to work, sleep disorders, fatigue, loss of appetite, weight loss, somatic concern and decreased libido 19 . The interpretation of scores occurred according to the standardization of the Cognitive Therapy Center used in studies with cancer patients: scores from 0 to 10, absence of symptoms; scores from 11 to 18, mild depressive symptoms; scores from 19 to 29, moderate depressive symptoms; scores from 30 to 63, severe depressive symptoms 20 . d) Physical activity: International physical activity questionnaire (IPAQ -short version) 21 . IPAQ is a self-administered instrument, which seeks to verify the number of times the individual practices at least 10 continuous minutes of walking, moderate and vigorous physical activity per week. For the final calculation of physical activity, the duration and frequency of the different types of activities were summed (walking + moderate + vigorous). The classification used was that of the instrument itself 21  Statistical analysis was performed using the SPSS software version 20.0 using inferential statistics. The Chi-Square test was used to associate general and clinical variables with fatigue, classifying women with no fatigue, mild fatigue, and moderate to severe fatigue. To verify data normality, the Kolmogorv Smirnov test was used. Since data normality was not found, the Kruskal Wallis non-parametric test and Dunn's post hoc test was used to compare fatigue levels with physical activity and depressive symptoms (p <0.05). For the relationship between fatigue, depressive symptoms and physical activity, crude and adjusted binary logistic regression was also used, in which the dependent variable was fatigue, and for its analysis in a dichotomous way, groups were classified into absence of fatigue and mild to intense fatigue, being the presence of mild to intense fatigue as reference category. Independent variables (exposure factors) used in the regression analysis were: depressive symptoms (absence or presence of depressive symptoms), level of physical activity (insufficiently active or sufficiently active), physiotherapy (yes or no), type of surgery (no surgery, mastectomy or conservative surgery), concluded treatment (yes or no) and presence of lymphedema (yes or no). For adjusted analysis, only variables that presented p <0.20 in the crude analysis were included. Table 1 shows the general and clinical characteristics of women with breast cancer who participated in this study. Most patients had partner, had up to elementary school, low socioeconomic class (D + E), overweight and had one or more children. Regarding clinical characteristics, most had no other diseases in addition to cancer and underwent mastectomy without breast reconstruction, were under treatment with chemotherapy, at menopause, without self-report of lymphedema and not undergoing physiotherapy. When depressive symptoms and physical activity were observed, most women had minimal or mild depressive symptoms, and were insufficiently active. Table 2 shows the general and clinical characteristics of women according to fatigue. It is important to note that most women who had mild fatigue had partner and were overweight; women who reported absence of fatigue had three or more children. There was significant relationship with women who underwent physiotherapy (p = 0.001), and with those who participated in sessions had moderate to intense fatigue and those who did not participate presented absence of fatigue. In the other variables, no significant associations were found.  Data in Table 3 show the presence of depressive symptoms and level of physical activity according to fatigue perception. Significant association can be observed between depressive symptoms and fatigue (p≤0.001), in which most women who reported absence of fatigue had minimal depressive symptoms (76.1%), and most women who presented moderate to severe fatigue showed moderate depressive symptoms (40.0%). The level of physical activity did not show significant relationship with fatigue, but it can be highlighted that most women with moderate to intense fatigue (75.6%) were also insufficiently active. A comparison of physical activity intensities was performed according to fatigue (table 4). Women with mild fatigue had significantly longer walking time than those with no fatigue and the other variables did not show significant differences. However, it is important to highlight that all practice time averages were lower in women who reported moderate to intense fatigue. In table 5, a binary logistic regression analysis was performed for the odds ratio of presence of mild to severe fatigue and it was observed that women who reported presence of depressive symptoms were almost three times more likely of having mild to severe fatigue when compared to those with no depressive symptoms, both in the crude analysis (p = 0.001) and in the adjusted analysis (p = 0.005). Likewise, patients who were undergoing physiotherapy were twice more likely of having mild to severe fatigue when compared to those who were not undergoing physiotherapy, both in the crude analysis (p = 0.011) and in the adjusted analysis (p = 0.037).

RESULTS
Lymphedema was not significant in the adjusted analysis; however, the crude analysis showed that women with lymphedema were almost two times more likely of having mild to severe fatigue when compared to women without presence of lymphedema.

DISCUSSION
This study aimed to investigate the relationship between fatigue, depressive symptoms and physical activity in women with breast cancer undergoing treatment or after treatment. The results indicated significant association between depressive symptoms and fatigue, but there was no relationship between level of physical activity and fatigue; however, the majority of women was insufficiently active (69.6%), and when the practice intensity was compared, women with mild fatigue showed longer walking time. Furthermore, by the binary logistic regression, it was observed that patients with presence of depressive symptoms were more likely of having mild to severe fatigue, and those who underwent physiotherapy were more likely of having mild to severe fatigue.
Fatigue was present in most women in this study, corroborating Panobianco et al. 6 , who found high prevalence of fatigue in women with breast cancer. Even though treatment protocols are currently less aggressive, it was found in literature that declines after breast cancer diagnosis can be associated with chemotherapy and surgery treatments 7 . It is important to highlight that most patients in the present study were undergoing chemo- therapy treatment, and had undergone mastectomy for breast cancer, which can worsen the fatigue perception in more severe degrees 5 . This study showed that women undergoing physiotherapy reported significantly higher levels of fatigue when compared to those who were not and were more likely of having mild to severe fatigue. This relationship is possibly since women who have more severe illnesses are those who most seek and need physiotherapy. In addition, another explanation is the fact that there is great physical and psychological exhaustion related to this practice, since it involves effort, discipline, expectation, commuting to the session location and often unpleasant pain sensations.
In this study, fatigue was also significantly associated with presence of depressive symptoms, which in turn are consequences of breast cancer treatments 6 . As expected, the results indicated that most women who reported absence of fatigue and mild fatigue presented minimal depressive symptoms and none of them had severe depressive symptoms. Most women with moderate to severe fatigue had moderate depressive symptoms. By binary logistic regression, it was found that women who had depressive symptoms were almost three times more likely of having mild to severe fatigue. These results corroborate Panobianco et al. 6 and Ebede et al. 23 , who reported that depression and fatigue can occur concomitantly and directly affect women's quality of life. It is also possible to associate the domains of instruments that assess fatigue and depressive symptoms, which sometimes assess very similar sensations. Fatigue, for example, is included in the assessment of depressive symptoms.
In this study, no significant relationship between fatigue and level of physical activity was found. This finding in consistent with Reis et al. 24 , who with combined training interventions demonstrated that despite reduction in pain, improvement in flexibility and strength, there was no improvement in fatigue in women with breast cancer. Jong et al. 25 investigated the effect of yoga on the fatigue of patients undergoing chemotherapy and found no significant results. However, there is evidence in literature showing the effectiveness of physical activity and physical exercise for women undergoing treatment and after treatment for breast cancer 10 , for example resistance exercise, which proved to be a possibility to reduce fatigue and maintain quality of life during chemotherapy treatment 26 . In a recent meta-analysis, findings indicate that physical exercise can reduce the presence of fatigue and improve the physical function of women with breast cancer 27 .
However, although there is recommendation by the American College of Sports Medicine 22 of at least 150 minutes of moderate to vigorous physical activity to patients diagnosed with breast cancer, in this study, most women demonstrated to be insufficiently active (69.6%). According to results observed in a systematic review that identified that most women in the post-treatment do not reach recommendations for the practice of physical activity 11 .
The shorter physical activity time of these women can be explained by the reduced physical conditions, presence of fatigue as a limiting factor, functional declines and lack of motivation that the disease and the side effects of treatment bring 5 , making it impossible for these women to reach recommendations. When comparing the intensities of activities in relation to fatigue, the results showed significant difference in the walking time, in which women with mild fatigue reported longer walking time compared to those with no fatigue. Walking is a pleasant activity, can be practiced in groups and has easy access, low impact and low cost 16 . In the present study, there were no significant differences in variables time of moderate, vigorous and moderate + vigorous physical activity; however, most women with mild fatigue were those who reported the longest total physical activity time. Women who practiced more time walking and more time practicing total physical activity may be linked and involved in groups of women who share the same experiences and thus collaborate for greater willingness and motivation.
Another finding in this study refers to lymphedema. By binary logistic regression, in the crude analysis, the presence of lymphedema was related to fatigue, showing that women with presence of lymphedema are more likely of having fatigue. Lymphedema is a consequence of breast cancer surgery, being characterized as a chronic condition and affects most women and, corroborating present results, worsens the physical and mental condition 28 . Most women in this study underwent radical surgery and Assis et al. 29 reported that lymphedema, pain and difficulties in relation to the arm can be caused by this type of surgery, accompanied by radical axillary emptying, which refers again to a relationship with fatigue. In addition, the presence of fatigue along with lymphedema can impair women's functional life, worsen their quality of life and be a reason for not returning to work within five years after treatment 30 .
Some limiting factors are related to the use of the questionnaire as an indirect measure for data collection, not having access to the medical records of these patients, which would facilitate the data collection process regarding possible discomfort and the fact that some data of clinical characteristics were self-reported, as is the case of lymphedema. In addition, the use of the IPAQ instrument -short version that evaluates physical activity practice is a questionnaire of subjective measure and of retrospective nature. Finally, the study has cross-sectional design, making it impossible establishing a long-term cause and effect relationship.
This study positively contributes to literature as it makes an alert to the low levels of physical activity of women and, equally, to the relationship between fatigue and depressive symptoms, two conditions very prevalent in women diagnosed with breast cancer, who are faced with painful feelings never experienced and who demand greater attention in policies to encourage healthy practices.

CONCLUSION
Significant results were found regarding the association between fatigue and physiotherapy, depressive symptoms and lymphedema. However, no association was found between fatigue and physical activity, except for variable walking. Most women reported some degree of fatigue and did not meet recommendations for physical activity for breast cancer patients.
Therefore, health professionals should pay more attention and concern to women with depressive symptoms, who are undergoing physiotherapy and with lymphedema. Physical activity programs that can assist in this treatment period and reduce the presence of fatigue in these women should be implemented.

Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Finance Code 001.

Ethical approval
Ethical approval was obtained from the local Human Research Ethics Committee -no. 688.548 and the protocol (no. 818.174) was written in accordance with standards set by the Declaration of Helsinki.