Radiotherapy induced fatigue and its correlates

Received: 21-Aug-2023, Manuscript No. OAR-23-110786; Accepted: 12-Sep-2023, Pre QC No. OAR-23-110786 (PQ); Editor assigned: 26-Aug-2023, Pre QC No. OAR-23-110786 (PQ); Reviewed: 01-Sep-2023, QC No. OAR-23-110786 (Q); Revised: 10-Sep-2023, Manuscript No. OAR-23-110786 (R); Published: 15-Sep-2023

Introduction

Cancer of the Breast is the second most frequent type of cancer among women globally and the primary cause of cancer death in these individuals. Breast cancer is the second most common cause of death from cancer in women, exceeded only by lung cancer, with approximately 316,000 patients diagnosed with breast cancer annually [1]. Treatment for breast cancer is dependent on the stage. Stage 0 includes Ductal carcinoma in situ, (a non-invasive malignancy that can advance to invasive cancer in up to 40% of patients) is treated with lumpectomy and radiation or with mastectomy. Ductal carcinoma in situ when Estrogen receptor–positive (ER positive), patients can also receive endocrine therapy. Early invasive stages (I, IIa, IIb) and locally advanced stages (IIIa, IIIb, IIIc) are non-metastatic which have three treatment phases (preoperative, surgical and postoperative phase). The preoperative phase utilizes systemic endocrine or immunotherapies when tumours express estrogen, progesterone, or ERBB2 receptors. Preoperative chemotherapy may also be used and is the only option when tumors have none of those three receptors. The surgical phase has two options with similar survival rates; a lumpectomy with radiation if the tumor can be excised completely with good cosmetic results, or a mastectomy. Radiation, endocrine therapy, immunotherapy, and chemotherapy are part of the third phase i.e. postoperative phase. Stage IV (metastatic) breast cancer is treatable but not curable. Treatment goals include improving the length and quality of life [2].

Literature Review

Breast cancer is a leading health concern among women due to its high mortality and morbidity rate. The five-year survival rate in metastatic breast cancer is less than 30%, even with adjuvant chemotherapy [3]. Breast cancer incidence is more common in high-income countries [4] than in low-income counties, Epidemiological studies correlated different factors for breast cancer risk development or progression [5, 6]. Risk factors including late age for marriage, first childbirth, and menopause are strongly associated with disease development [7-9] (Figure 1).

Radiotherapy related fatigue

Fatigue, characterised by tiredness, weakness or lack of energy, involves physical, cognitive and emotional aspects. Its aetiology is not well defined and the prevalence ranges from 30%–70% in women with breast cancer, reaching up to 80% when they are undergoing radiotherapy. This is one of the most frequent side effects of radiotherapy, and it may interfere with self-esteem, social activities and quality of life [10]. Adjuvant Radio-Therapy (RT) is the standard treatment for more than 90% of Breast Cancer (BC) patients, aiming to decrease locoregional recurrence and improve overall survival [11, 12]. Despite its beneficial role, numerous side effects are associated with RT, and among the most common is Right-Induced Fatigue (RIF) [13]. In particular, up to 77% of BC patients who undergo RT suffer from RIF as a disorder, characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities [11, 14]. Despite the high incidence rate, the symptom lacks a clear definition. The National Comprehensive Cancer Network (NCCN) defined RIF as a clinical subtype of Cancer-Related Fatigue (CRF) that either arises during RT (acute RIF) or continues afterwards (chronic RIF). RIF is a distressing, persistent, and subjective sense of physical, emotional, or cognitive tiredness or exhaustion, related to cancer or cancer treatment that is not proportional to recent activity, and interferes with normal functioning [15, 16]. Although RIF possibly compromises patients' treatment adherence, it is still underreported, underdiagnosed and undertreated [10, 17].

Radiotherapy induced fatigue-pathophysiology:

Multiple factors have been proposed to cause RIF. Some factors include genetics (e.g., DNA damage and telomere length), hypothalamic-pituitary-adrenal axis dysregulation, 5- hydroxytryptophan neurotransmitter dysregulation, and alterations in the Adenosine Tri-Phosphate (ATP) muscle metabolism. Other factors include endocrine disturbances (reduction in estrogen and testosterone), mitochondrial dysfunction, cytokine dysregulation, inflammation and immune response, anaemia, circadian rhythm disruption, disruption in the blood-brain barrier, and psychological mechanisms [13, 18-24].

Radiotherapy induced fatigue severity and assessment: In general, fatigue can be classified according to its severity by using grades from 1 to 3. Grade 1 would be “fatigue relieved by rest,” “fatigue not relieved by rest, limiting instrumental activities of daily living” is grade 2, and “fatigue not relieved by rest, limiting self-care activities of daily living” is grade 3. Apart from this classification, objective measurement of fatigue remains a challenge. There is no fatigue-specific standardized assessment tool or scoring system to define the severity grade accurately [19, 25]. For both Cancer Related Fatigue (CRF) and Radiotherapy Induced Fatigue (RIF),assessment by a single-item symptom checklist has led to a certain underestimation in several studies. Currently, subjective questionnaires like the Cancer Fatigue Scale, Multidimensional Fatigue Inventory, Revised Piper Fatigue Scale, Brief Fatigue Inventory, Lee Fatigue Scale, Functional Assessment of Chronic Illness Therapy, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, or the Visual Analogue Scale are used to assess CRF [26-28].

Radiotherapy induced fatigue-impact on patients: It is well known that the prevalence, duration, and severity of fatigue depend on the type of RT, the irradiated volume and dose scheme, and on the combination with other treatments, as patients receiving combined therapies (e.g., chemotherapy plus RT) showed the highest fatigue scores. Pre-treatment fatigue levels have been proposed as an essential risk factor for fatigue development during RT. Diagnosing fatigue and recognizing it as a predictor for this condition during treatment within the first appointments seems to be of uttermost importance. Other factors influencing the grade of severity of RIF that have been described in the literature include the diurnal rhythm, where morning fatigue appears to be more affected by biologic factors and evening fatigue by behavioral factors. Another factor is smoking, with smokers experiencing considerably more fatigue than nonsmokers. Time- to-hospitalization appears to influence the grade of severity of RIF, with significantly worse symptoms of fatigue in patients who had to travel 2 hours or more hours compared to patients who had to travel <2 h. Factors such as stress, anxiety, depression, a weakened physical condition, diarrhea, malnourishment, and anemia possibly further deteriorate fatigue [29-32].

Definitive radiotherapy with or without chemotherapy has been found to increase fatigue which further impacted the QOL [33, 34]. Up to 40% of patients were still suffering from RIF 1 year after completing adjuvant RT [35], or even 5 years -10 years following the completion of adjuvant RT [36]. This phenomena is known as chronic fatigue syndrome. The description included requiring a person to experience 6 or more months of chronic fatigue of new or definite onset that is not substantially alleviated by rest, not the result of on-going exertion, and results in substantial reductions in occupational, social, and personal activities [37].

Radiotherapy induced fatigue-Prevention: Anticipation and early recognition of the individual risk for RIF could lead to possible preventive measures, such as prehabilitation instead of rehabilitation. A multimodal, multidisciplinary approach may be necessary to prevent RIF, including psychosocial intervention, physical exercise, and medications to address the contributing factors of RIF. As heme levels seem to have an impact on the incidence of RIF upon completion of EBRT, their stabilization is vital to prevent the worsening of fatigue symptoms during treatment [38]. Patients with increased age and high baseline fatigue levels are at risk of experiencing severe RIF [39].

In 2004 Wratten et al., reported that RIF appeared to plateau between week 4 of treatment and 2 weeks after treatment among patients with early stage BC undergoing adjuvant RT; they found fatigue began to settle by 6 weeks after treatment. In their study, significant fatigue was predicted by a higher baseline fatigue score, red blood cell count, neutrophil count, and D-dimer levels. Baseline fatigue correlated with higher body mass index and altered levels of C-reactive protein, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, interleukin-6, ICAM-1, hemoglobin, red blood cells, monocyte, and neutrophil counts. The most predictive factors for RIF in their study were a higher baseline fatigue level and more elevated baseline neutrophils and red blood cell counts. Results of a feasibility study presented in 2018, aiming to evaluate behavioral interventions in early BC patients with RIF, are awaited and they will undoubtedly be of interest in this context [40].

Radiotherapy induced fatigue-treatment approaches: Clinical practice guidelines are available to assist physicians in the management of RIF [41-45]. According to the NCCN, physical therapy and occupational therapy are recommended as the interventions of choice in patients with RIF. The NCCN also recommends psychosocial interventions, such as cognitivebehavioural therapy, psycho-educational therapy, supportiveexpressive therapy, nutritional guidance, hygiene, stimulus control, and sleep restriction [46]. Besides the non-pharmaco logic treatment approaches, the NCCN advises the use of psychostimulants, such as methylphenidate and modafinil, after excluding other causes of fatigue like pain, anxiety, depression, anemia, sleep alteration, nutritional factors, and other comorbidities. Non-pharmacologic treatment approaches include laughter yoga, mat pilates, foot bath foot reflexology, music therapy, and polarity therapy [47-52]. During and after RT, patients are recommended to take 150 min of “moderateintensity exercise” per week (e.g., walking 30 min 5 days per week). Most of these exercises involve range of motion/ flexibility, muscle strength, aerobic training, and mind/body fitness [53].

Sleep quality: Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments [54]. Despite being used commonly in sleep medicine, the term “sleep quality” has not been rigorously defined. Sleep is a multidimensional construct, often referred to as in terms of its quality. Sleep quality has been a well-recognized predictor of physical and mental health , cognitive status, wellness and overall vitality [55-62].

Sleep quality-effects of its dearth: Chronic sleep deprivation has serious negative impacts on health, quality of life and neuro-cognitive performance [63-67]. Breast cancer patients often complain of sleep problems; it is estimated that the prevalence of poor sleep in breast cancer patients range from 20%-70% [68]. The proportion of sleep disturbances in this population is higher than the observed in healthy adults [69, 70]; and in other oncological patients [71].

Sleep quality-causes: The aetiology of sleep disturbances in breast cancer patients is multi-factorial; in fact, demographic, environmental and lifestyle factors, psychological disturbances and comorbid medical disorders have been pointed to as main factors contributing for its occurrence [72, 73]. Cancer-related treatments, and their wide range of side effects, are other important feature frequently associated with the occurrence of sleep disturbances [74,75]. In addition, breast cancer diagnosis and associated treatments, may also contribute for worsening pre-existing sleep problems [76].

Sleep quality-circadian regulation: The disturbance of the biological clock in those diagnosed with cancer is evidenced by the alteration of the circadian rest-activity rhythm 46 and the sleep-wake cycle [77]. Circadian disruption in cancer has been unrecognized and overlooked until recently; however, patients with breast cancer experiencing disturbed rhythms have shorter overall survival than others with robust rhythms [78].

Sleep quality-immunity, metabolic regulation: Strong preclinical and clinical evidence exists for the role of inflammatory processes in the development of behavioral symptoms, including sleep disruption and fatigue. Proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, are immune mediators released by activated immune cells in response to pathogen invasion, tissue damage/injury, and cytotoxic factors, including chemotherapeutic agents. Fatigue and sleep problems represent key features of these cytokine-induced behavioral alterations [79- 81 ]. Cancer drugs can enhance pro-inflammatory cytokine release from healthy and/or malignant cells, and high levels of serum cytokines (TNF-α, IL-1, and IL-6) have been associated with chemotherapy-induced fatigue [82-84] Sleep plays an important role in metabolic regulation, and sleep disruption has been linked with weight gain. Overweight is associated with a chronic low-grade inflammatory state characterized by increased levels of inflammatory markers, including C-reactive protein and proinflammatory cytokines [85].

Sleep quality-behavioral factors: The development of sleep disturbance in patients with breast cancer can be understood by using a well-known behavioral model of sleep disturbance, and later refined by Morin [86, 87]. In women with breast cancer, sleep disturbance might occur as a result of having a predisposition for sleep disturbance. Factors that can predispose someone to sleep disturbance include female sex, trait anxiety, and a family history of sleep problems. When women are diagnosed with breast cancer, they experience a myriad of precipitating factors for sleep disturbance. These factors may involve the stress related to the diagnosis of breast cancer, cancer treatments and the associated side effects, and psychiatric and physical factors, such as anxiety, depression, pain, and frequent urination. Patients might respond to their sleep disturbance by spending more time in bed to compensate for lost sleep, shifting their sleep phase by either delaying sleep or wake time, and taking naps. These behaviors, although initially adaptive for acute short-term illness, are maladaptive for patients who have chronic illness and chronic sleep disruption. 80 Sleep disturbance in breast cancer is often related to psychological sequelae that include depression and fatigue [88, 89]. Psychological stress can have a significant impact on sleep and is a precipitating factor for the development of insomnia. With more than 20% to 30% of women with breast cancer reporting depression, and depression worsening with moreadvanced breast cancer, the combination of cancer and depression acts synergistically to hamper sleep [90, 91].

Sleep quality-impact by radiotherapy: Breast cancer treatments have several associated side effects, which may contribute to impaired sleep in these patients. The cumulative effect of toxic agents on body functions, the physical impact of distressing symptoms (including nausea, vomiting, diarrhoea, urinary frequency or skin reactions related with radiotherapy), changes in body image and hospitalization, as well as other comorbid-related conditions (e.g.: pain, fatigue, depression, anxiety, stress), are frequently reported as the main cause or aggravating factor for sleep disturbances in this population [72, 73, 92] Breast cancer patients submitted to radiotherapy tended to report higher levels of sleep disturbances than those not submitted to this type of treatment [93-96]. However, as previously mentioned, when radiotherapy was compared with chemotherapy, lower levels of sleep disturbances were observed [96, 97]. For a better understanding of the relation between breast cancer treatment and sleep disturbances, more prospective studies with baseline evaluations before treatment are needed. In fact, previous studies have shown that women with breast cancer frequently report higher levels of sleep disturbances prior to treatment [98-100] whereas for some patients the onset of insomnia followed the breast cancer diagnosis and others reported that cancer either caused or aggravated their sleep difficulties [76].

Anxiety

Anxiety is a normal emotion. Anxiety is the feeling of fear that occurs when faced with threatening or stressful situations. It is a normal response when confronted with danger, but, if it is overwhelming or the feeling persists, it could be regarded as an anxiety disorder [101]. Most cancer survivors adjust well to life after cancer but some experience persisting negative mood, such as cancer-related fears, posttraumatic stress, anxiety, or depression. Mood fluctuations may not reach criteria for a clinical diagnosis but subclinical symptoms can interfere with quality of life [102]. After cancer treatment, many survivors report feeling alone or even abandoned following the intensive support provided during their treatment. Many survivors experience emotional distress that does not meet the clinical criteria for anxiety disorder.

Anxiety in cancer patients-factors affecting: Nearly half of cancer patients report having a lot of distress. Patients with lung, pancreatic, and brain cancers may be more likely to report distress, but in general, the type of cancer does not make a difference. Factors that increase the risk of anxiety and distress are not always related to the cancer.

The following are risk factors for high levels of distress in patients with cancer:

1. Trouble doing the usual activities of daily living. 2. Physical problems and side effects of treatment (such as fatigue, nausea, or pain). 3. Problems at home. 4. Unmet social and spiritual needs. 5. Depression, cancer-related post-traumatic stress, or other emotional problems. 6. Being diagnosed with advanced-stage cancer. 7. Having experienced childhood abuse. 8. Being younger, female, or non-White. 9. Having a lower level of education.

Patients who have a high level of distress when they are diagnosed with cancer are more likely to have continued high levels of distress after their diagnosis.

Anxiety in cancer patients-symptoms: Symptoms of autonomic over-activity include palpitation and sweating. Anxious behaviours such as restlessness and reassurance-seeking are a feature. Changes in thinking include apprehension, worry and poor concentration, and physical symptoms such as muscle tension or fatigue may occur.

Since anxiety is a frequent response to threat, it is found in all clinical populations. It can be adaptive, but in certain circumstances it becomes maladaptive or morbid. Such pathological anxiety is identified by:

1. Being out of proportion to the level of threat

2. Persistence or deterioration without intervention

3. A level of symptoms which are unacceptable regardless of the level of threat (these include recurring panic attacks, severe physical symptoms, and abnormal beliefs such as thoughts of sudden death)

4. A disruption of usual or desirable functioning

It is difficult to judge when anxiety is disproportionate to the threat of cancer, since the disease is always associated with some real threat. The level of anxiety must be judged against the proximity of threat. For example, it is normal to experience considerable anxiety for a period of 7–10 days after receiving bad news [103], but as the degree of real threat varies throughout the history of the cancer, so therefore do levels of normal anxiety.

Anxiety in cancer patients-diagnosing breast cancer patients: Given the scope of mood problems cancer survivors may experience, clinicians need easy to administer methods for screening so that they can make appropriate recommendations and referrals. Numerous methods for screening and diagnosing mental health needs in survivors have been validated that balance ease of use and sensitivity and specificity for defining treatment needs.

Anxiety in cancer patients-its impact on effectiveness of radiotherapy: Currently 458000 people live with cancer in the UK [104]. Over 50% of these patients will be managed with radiotherapy, [105, 106] which can cause procedural anxiety, with approximately 49% of patients experiencing anxiety and psychological distress [107, 108]. Procedural anxiety refers to excessive worry or fear of medical procedures [109] and is a phenomenon exacerbated by new developments in radiotherapy, for example, stereotactic and adaptive radiotherapy, that require long treatment times. High levels of distress during radiotherapy can directly impact the accuracy and efficacy of the procedure [110] Procedural anxiety is not limited to radiotherapy and also occurs during diagnostic imaging, and other invasive procedures performed on a conscious patient. Between 2% and 5% of MRI scans are terminated due to procedural anxiety this equates to a significant financial cost [111, 112].

Anxiety in cancer patients: Effect of radiotherapy: Data indicate that cancer inpatients as a group report greater anxiety over the circumstances of hospitalization than inpatients receiving treatment for non-malignant conditions [1113].

Radiation therapy patients might therefore report substantial distress at all points of assessment. Second, post-operatively cancer patients report greater and more lasting state anxiety, general feelings of experiencing a crisis, and feelings of helplessness than are reported by general surgery patients [114]. Thus, a general decline in state anxiety for patients undergoing radiation might not be evidenced; instead distress may be maintained or possibly increased when a treatment is over. Third, radiation therapy also differs from many of the surgery and diagnostic procedures studied in that rather than a single episode; most patients undergo repeated radiotherapy treatments. Kendall et al.’s research with cardiac catherization patients and Shipley et al.’s research with endoscopy patients suggest, however, that even patients with non-malignant diseases fail to adapt when undergoing repeated diagnostic procedures [115, 116]. Radiation therapy patients may also not adapt to treatment, and thus be as anxious when anticipating their second treatment as their first.

Depression

Depression is a common and recurrent mental illness with a complicated etiology, but the specific p athogenesis i s n ot c lear. Depression is a leading cause of disability, and women diagnosed with breast cancer are at a higher risk of mental illness when compared to the general population. Rapid advances in the understanding of tumor immunology and neuroimmunology have provided new evidence for the pathogenesis of depression. Dysfunction of immune cells and cytokines cause depression by affecting tryptophan metabolism, serotonin levels, and blood-brain barrier permeability. Dysregulation of cytokines or intestinal flora may be shared between patients with depression and breast cancer.

It has also been found to play a critical role of depression/ anxiety as an independent factor in predicting breast cancer recurrence and survival. It has been demonstrated that BC patients have high levels of anxiety, depressive symptoms and lower QoL [117-120]. These alterations in mood in oncological patients can result, furthermore, in non-compliance with treatment, longer hospitalization, wrong prognosis and increased mortality [121-123]. Studies have revealed that the longer the time passed since diagnosis, the higher the levels of S/A and depressive symptoms. We also found a significant relation between severe anxiety and check-up situation. Some studies have reported that when cancer is initially diagnosed, anxiety increases in a natural way, then diminishes with time as the patient adapts to the illness, but that it can increase again at a later point if the symptoms become more serious [124]. The prevalence of depression is high during the first year a fter br east ca ncer di agnosis. A st udy demonstrated in a very large sample of cancer patients that the prevalence of depression among breast cancer survivors was about 32.8%.

Depression in cancer patients - factors affecting: Negative mood symptoms such as anxiety and depression often co-occur. In a population-based, longitudinal study, 9% of survivors had both anxiety and depressive symptoms.

1. In a heterogeneous sample of adult cancer survivors, a diagnosis of melanoma, survivors not in remission, and smoking.

2. Females [61]

3. A higher number of comorbid conditions [36, 63, 74]

4. Negative body image for women [75, 76]

5. Financial problems [64, 71, 77, 78]

6. Within the first 2 years of survivorship [79]

7. Prior history of depression [33, 35]

8. A sedentary lifestyle [33, 35] 9. Loneliness [80]

Longitudinal studies have examined depressive symptoms following a cancer diagnosis. Revealing that most could be classified as having very low or low depressive symptoms while few had consistently borderline scores. Some patients also reported with high depressive scores at first diagnosis which declined over time after treatment was completed. Depression has been found to be associated with a 24% increase in the risk of cancer recurrence and is associated with a 30% increase in the risk of all-cause mortality. Some studies have reported that when cancer is initially diagnosed, anxiety increases in a natural way, then diminishes with time as the patient adapts to the illness, but that it can increase again at a later point if the symptoms become more serious [124]. The time of diagnosis, the course of CT treatment and the months following the end of the treatment are times of bad adaptation to the transition and of fluctuating anxiety [125]. Other studies, however, have found that patients diagnosed with BC felt anxious and depressed, but this tended not to change significantly during the therapeutic procedures [119], and it was found that these symptoms persisted for long periods 126. It has been suggestedthat psychological symptoms are a result of both the cancer itself and the harmful effects of its treatment [118].

Nutritional status

Nutrition in cancer is now a topic of acknowledged significance. Traditionally, undernutrition has dictated clinical concerns, although the evidence indicated that 8% to 84% of the patients would suffer from undernutrition throughout the disease course. A clarification of that wide interval was overlooked; nonetheless, recent evidence draws our attention to the increase of excess body weight and obesity in oncology. Robust findings, from recent epidemiological studies, show that obese subjects have higher rates of some forms of cancer [10]. Moreover, once the disease is installed, obese patients have a significantly reduced survival compared with those of adequate weight, and obesity has been consistently associated with cancer recurrence after antineoplastic treatments and/or surgery. In addition, of acknowledgeable relevance is the fact that cancer patients who are of normal weight, overweight, or obese are likely to have depleted muscle mass; this clinical condition has been associated with poorer performance status and decreased survival. Undernutrition and overweight/ obesity have distinct implications and bear a negative prognosis in cancer. Repetitive and intensive nutritional counseling is necessary to improve QOL and to prevent deterioration of nutritional status in cancer patients receiving RT.

Progressive deterioration in nutrition in cancer patients is known as tumour cachexia. The clinical picture is characterised by anorexia, loss of weight and poor general status, all of which can lead to the death of the patient. Although the principal clinical characteristics are anorexia and weight-loss, other complex clinical and analytical alterations are produced. These include asthenia, premature satiety, alterations in immune function, muscle atrophy, modifications in body image, anaemia, hypoalbuminaemia, hypolipoproteinaemia, hypertriglyceridaemia and hyperlactacidaemia. The causes of the malnutrition can be diverse, among which are the effects of the tumour, the site of the tumour, the production of specific cytokines and the effects of the anti-tumour therapy administered.

The cachexia–anorexia syndrome occurs frequently in cancer patients; the approximate incidence being 50%. The prevalence of cachexia/weight-loss varies as a function of the phase of the disease 144 and the tumour site. In advanced phases, it is present in up to 80%-90% of the patients, and between 20% and 25% of the cancer patients die directly as a result of the cachexia. Malnutrition/ weight-loss is associated with a lower survival, poor response and a decreased tolerance to the anti-cancer therapy. Further, there is a decrease in the patient's general status together with a higher health-care cost and longer hospitalisation. Among the different prognostic factors such as the type of tumour, the stage of the disease, the general status of the patient and the weight-loss/ malnutrition, it is the weight-loss/malnutrition that is the most amenable to intervention therapy. Despite the importance of the theme, there have been few large-scale studies assessing the prevalence of malnutrition in patients with cancer, and nutritional status has not been systematically evaluated in standard clinical practice in any of the major centres in India.

Survivors with better nutritional status have been found to have better functioning scales and experienced fewer clinical symptoms. It appears important to provide educational and nutritional screening programs to improve cancer survivor quality of life. The scored PG-SGA is a nutrition assessment tool that identifies malnutrition in ambulatory oncology patients receiving radiotherapy and can be used to predict the magnitude of change in QoL. Nutritional risk and poor performance status were associated with a higher occurrence of death in women with breast cancer. The use of these two indicators improves their predictive accuracy for mortality.

Given the positive effect of the educational-supportive intervention on reducing stress and improving nutritional status, it can be incorporated into training and care programs to improve nutritional status and reduce stress in patients with breast cancer. Malnutrition has a high prevalence in Iranian cancer patients and has a close relationship with mortality, morbidity and treatmentrelated problems and also quality of life. Therefore, periodical assessment by PG-SGA to detect malnutrition in patients should be made so that appropriate nutritional interventions can be provided. The high prevalence of malnutrition, has been found to be due to the fact that patients presented to treatment at locally advanced or metastatic stages. In order of early detection of situations at risk of malnutrition, the assessment of nutritional status should be an integral part of the overall taken care of patients with breast cancer.

Conclusion

Radiotherapy-induced fatigue is a common early and chronic side-effect of irradiation. In BC patients who undergo adjuvant RT, RIF is underreported, underdiagnosed and undertreated. RIF may become a chronic state with subsequent non-compliance, which further compromises treatment efficacy. It is frequently underestimated by medical and nursing staff and its reasons, correlates and prevalence are poorly understood. Knowledge on the therapeutic options in management of radiotherapyinduced fatigue is still limited. It is essential to evaluate patients for their potential risk and to adequately inform them about predisposing factors and treatment options to prevent and treat fatigue. Standardization of the evaluation and assessment tools need to be established to ensure the full reliability of study results. Significant reduction in fatigue, tension, depression and anger has been observed in the out-patients undergoing curative or palliative radiotherapy. Several interventions have been tested in the management of radiotherapy-related fatigue and some randomized studies have been recently published. Although an optimal method has not yet been established, some promising results have been reported with relaxation therapy, group psychotherapy, physical exercise and sleep. Adequate management should involve an early start after cancer diagnosis and before commencing cancer treatment using a multimodal, multidisciplinary approach to prevent high severity. Further methodologically correct studies are warranted to define better the causes, optimal prevention and management of this symptom.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer journal for clinicians. 2019 ;69:7-34. Google Scholar Cross Ref
2. Trayes KP, Cokenakes SEH. Breast cancer treatment. Am Fam Physician. 2021;104:171–8. Google Scholar Cross Ref
3. Riggio AI, Varley KE, Welm AL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer. 2021;124:13–26. Google Scholar Cross Ref
4. Varley Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68:394–424. Google Scholar Cross Ref
5. Sun Y-S, Zhao Z, Yang Z-N, Xu F, Lu H-J, Zhu Z-Y, et al. Risk factors and preventions of breast cancer. Int J Biol Sci. 2017;13(11):1387–97. Google Scholar Cross Ref
6. Gandhi AK, Kumar P, Bhandari M, Devnani B, Rath GK. Burden of preventable cancers in India: Time to strike the cancer epidemic. J Egypt Natl Canc Inst. 2017;29:11–8. Google Scholar Cross Ref
7. Gold EB. The timing of the age at which natural menopause occurs. Obstet Gynecol Clin North Am 2011;38:425–40. Google Scholar Cross Ref
8. Rivera-Franco MM, Leon-Rodriguez E. Delays in breast cancer detection and treatment in developing countries. Breast Can (Auckl). 2018;12:1178223417752677. Google Scholar Cross Ref
9. Marphatia AA, Ambale GS, Reid AM. Women’s marriage age matters for public health: A review of the broader health and social implications in South Asia. Front Public Health. 2017;5:269. Google Scholar Cross Ref
10. Alcântara-Silva TR, de Freitas-Junior R, Freitas NMA, de Paula Junior W, da Silva DJ, Machado GDP, et al. Music therapy reduces radiotherapy-induced fatigue in patients with breast or gynecological cancer: A randomized trial. Integr Cancer Ther. 2018;17(3):628–35. Google Scholar Cross Ref
11. Lipsett A, Barrett S, Haruna F, Mustian K, O’Donovan A. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: A systematic review and meta-analysis. Breast. 2017;32:144–55. Google Scholar Cross Ref
12. Cancer statistics, 2019
13. Jereczek-Fossa BA, Marsiglia HR, Orecchia R. Radiotherapy-related fatigue. Critical reviews in oncology/hematology. 2002 Mar 1;41:317-25. Cross Ref
14. Manir KS, Bhadra K, Kumar G, Manna A, Patra NB, Sarkar SK. Fatigue in breast cancer patients on adjuvant treatment: course and prevalence. Indian J Palliat Care. 2012;18:109–16. Google Scholar Cross Ref
15. Berger AM, Mooney K, Alvarez-Perez A, Breitbart WS, Carpenter KM, Cella D, et al. Smith C; National comprehensive cancer network. Cancer-Related Fatigue, Version 2. J Natl Compr Canc Netw. 2015;13:1012–39. Google Scholar Cross Ref
16. Piper BF, Cella D. Cancer-related fatigue: Definitions and clinical subtypes. J Natl Compr Canc Netw. 2010;8:958–66. Google Scholar Cross Ref
17. Morrow GR, Andrews PLR, Hickok JT, Roscoe JA, Matteson S. Fatigue associated with cancer and its treatment. Support Care Cancer. 2002;10:389–98. Google Scholar Cross Ref
18. Albuquerque K, Tell D, Lobo P, Millbrandt L, Mathews HL, Janusek LW. Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer. BMC cancer. 2012 Dec;12:1-2. Google Scholar Cross Ref
19. Hsiao C-P, Daly B, Saligan LN. The Etiology and management of radiotherapy-induced fatigue. Expert Rev Qual Life Cancer Care. 2016;1:323–8. Google Scholar Cross Ref
20. Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, et al. Inflammatory Biomarkers and Fatigue during Radiation Therapy for Breast and Prostate Cancer Inflammation and Fatigue during Radiation Therapy. Clinical Cancer Research. 2009;15:5534–40. Google Scholar Cross Ref
21. Feng LR, Suy S, Collins SP, Saligan LN. The role of TRAIL in fatigue induced by repeated stress from radiotherapy. J Psychiatr Res. 2017;91:130–8. Google Scholar Cross Ref
22. Courtier N, Gambling T, Enright S, Barrett-Lee P, Abraham J, Mason MD. Psychological and immunological characteristics of fatigued women undergoing radiotherapy for early-stage breast cancer. Support Care Cancer. 2013;21:173–81. Google Scholar Cross Ref
23. Torres MA, Pace TW, Liu T, Felger JC, Mister D, Doho GH, Kohn JN, Barsevick AM, Long Q, Miller AH. Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B. Cancer. 2013;119:1951-9. Google Scholar Cross Ref
24. Wratten C, Kilmurray J, Nash S, Seldon M, Hamilton CS, O’Brien PC, et al. Fatigue during breast radiotherapy and its relationship to biological factors. Int J Radiat Oncol Biol Phys. 2004;59:160–7. Google Scholar Cross Ref
25. Filler K, Saligan LN. Defining cancer-related fatigue for biomarker discovery. Support Care Cancer. 2016;24:5–7. Google Scholar Cross Ref
26. Dhruva A, Dodd M, Paul SM, Cooper BA, Lee K, et al. Trajectories of fatigue in patients with breast cancer before, during, and after radiation therapy. Cancer Nurs. 2010;33:201–12. Google Scholar Cross Ref
27. Luthy C, Cedraschi C, Pugliesi A, Di Silvestro K, Mugnier-Konrad B, et al. Patients’ views about causes and preferences for the management of cancer-related fatigue-a case for non-congruence with the physicians? Support Care Cancer. 2011;19:363–70. Google Scholar Cross Ref
28. Andrykowski MA, Schmidt JE, Salsman JM, Beacham AO, Jacobsen PB. Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer. J Clin Oncol. 2005;23:6613–22. Google Scholar Cross Ref
29. Murchison S, Soo J, Kassam A, Ingledew P-A, Hamilton S. Breast cancer patients’ perceptions of adjuvant radiotherapy: An assessment of pre-treatment knowledge and informational needs. J Cancer Educ. 2020;35:661–8. Google Scholar Cross Ref
30. Langston B, Armes J, Levy A, Tidey E, Ream E. The prevalence and severity of fatigue in men with prostate cancer: a systematic review of the literature. Support Care Cancer. 2013;21:1761–71. Google Scholar Cross Ref
31. Schwartz AL, Nail LM, Chen RNS, Meek P, Barsevick AM, et al. Fatigue patterns observed in patients receiving chemotherapy and radiotherapy. Cancer Invest. 2000;18:11–9. Google Scholar Cross Ref
32. Ahlberg K, Ekman T, Gaston-Johansson F. The experience of fatigue, other symptoms and global quality of life during radiotherapy for uterine cancer. Int J Nurs Stud. 2005;42:377–86. Google Scholar Cross Ref
33. Van der Laan HP, Van den Bosch L, Schuit E, Steenbakkers RJHM, van der Schaaf A, et al. Impact of radiation-induced toxicities on quality of life of patients treated for head and neck cancer. Radiotherapy and Oncology. 2021; 160:47–53. Google Scholar Cross Ref
34. Lilleby W, Stensvold A, Dahl AA, et al. Fatigue and other adverse effects in men treated by pelvic radiation and long-term androgen deprivation for locally advanced prostate cancer. Acta oncologica. 2016;55:807-13. Google Scholar Cross Ref
35. Noal S, Levy C, Hardouin A, Rieux C, Heutte N, et al. One-year longitudinal study of fatigue, cognitive functions, and quality of life after adjuvant radiotherapy for breast cancer. Int J Radiat Oncol Biol Phys. 2011;81:795–803. Google Scholar Cross Ref
36. Donovan KA, Jacobsen PB, Andrykowski MA, Winters EM, Balducci L, et al. Course of fatigue in women receiving chemotherapy and/or radiotherapy for early stage breast cancer. J Pain Symptom Manage. 2004;28(4):373–80. Google Scholar Cross Ref
37. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953–9. Google Scholar Cross Ref
38. Feng L, Chen M-K, Lukkahatai N, Hsiao C-P, Kaushal A, et al. Clinical predictors of fatigue in men with non-metastatic prostate cancer receiving external beam radiation therapy. Clin J Oncol Nurs. 2015;19:744–50. Google Scholar Cross Ref
39. Taunk NK, Haffty BG, Chen S, Khan AJ, Nelson C, et al. Comparison of radiation�induced fatigue across 3 different radiotherapeutic methods for early stage breast cancer. Cancer. 2011 Sep 15;117:4116-24. Google Scholar Cross Ref
40. Courtier N, Gaze S, Armes J, Smith A, Radley L, et al. ACTIVE - a randomised feasibility trial study protocol of a behavioral intervention to reduce fatigue in women undergoing radiotherapy for early breast cancer: study protocol. Pilot Feasibility Stud. 2018;4. Google Scholar Cross Ref
41. Bower JE. Cancer-related fatigue-mechanisms, risk factors, and treatments. Nat Rev Clin Oncol.. 2014;11:597–609. Google Scholar Cross Ref
42. Mücke M, Mochamat, Cuhls H, Peuckmann-Post V, Minton O, et al. Pharmacological treatments for fatigue associated with palliative care: executive summary of a Cochrane Collaboration systematic review: Pharmacological treatments for fatigue associated with palliative care. J Cachexia Sarcopenia Muscle. 2016;7(1):23–7. Google Scholar Cross Ref
43. Mustian KM, Alfano CM, Heckler C, Kleckner AS, Kleckner IR, et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis. JAMA oncology. 2017 ;3:961-8. Google Scholar Cross Ref
44. Bennett S, Pigott A, Beller EM, Haines T, Meredith P, Delaney C. Educational interventions for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2016;11:CD008144. Google Scholar Cross Ref
45. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012;11:CD006145. Google Scholar Cross Ref
46. Berger AM, Abernethy AP, Atkinson A, Barsevick AM, Breitbart WS, et al. NCCN Clinical Practice Guidelines Cancer-related fatigue. J Natl Compr Canc Netw. 2010;8:904–31. Google Scholar Cross Ref
47. Namazinia M, Mazloum SR, Mohajer S, Lopez V. Effects of laughter yoga on health-related quality of life in cancer patients undergoing chemotherapy: a randomized clinical trial. BMC Complement Med Ther. 2023;23:192. Google Scholar Cross Ref
48. Torres DM, de Menezes Fireman K, Fabro EAN, Thuler LCS, Koifman RJ, et al. Effectiveness of mat pilates on fatigue in women with breast cancer submitted to adjuvant radiotherapy: randomized controlled clinical trial. Support Care Cancer. 2023;31:362. Google Scholar Cross Ref
49. Mazloum SR, Rajabzadeh M, Mohajer S, Bahrami-Taghanaki H, Namazinia M. Comparing the effects of warm footbath and foot reflexology on the fatigue of patients undergoing radiotherapy: A randomized clinical trial. Integr Cancer Ther. 2023;22:15347354231172940. Google Scholar Cross Ref
50. Montgomery GH, Kangas M, David D, Hallquist MN, Green S, et al. Fatigue during breast cancer radiotherapy: an initial randomized study of cognitive-behavioral therapy plus hypnosis. Health Psychol. 2009;28:317–22. Google Scholar Cross Ref
51. Moadel AB, Shah C, Wylie-Rosett J, Harris MS, Patel SR, et al. Randomized controlled trial of yoga among a multiethnic sample of breast cancer patients: effects on quality of life. J Clin Oncol. 2007;25:4387–95. Google Scholar Cross Ref
52. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, et al. Effect of paroxetine hydrochloride (Paxil™) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005;89:243–9. Google Scholar Cross Ref
53. Stubbe CE, Valero M. Complementary strategies for the management of radiation therapy side effects. J Adv Pract Oncol. 2013;4:219–31. Google Scholar Cross Ref
54. Vasey C, McBride J, Penta K. Circadian rhythm dysregulation and restoration: the role of melatonin. Nutrients. 2021 Sep 30;13:3480. Google Scholar Cross Ref
55. Ohayon M, Wickwire EM, Hirshkowitz M, Albert SM, Avidan A, Daly FJ, et al. National Sleep Foundation’s sleep quality recommendations: first report. Sleep Health. 2017;3(1):6–19. Google Scholar Cross Ref
56. Alhola P, Polo-Kantola P. Sleep deprivation: Impact on cognitive performance. Neuropsychiatr Dis Treat. 2007;3:553–67. Google Scholar Cross Ref
57. Asif N, Iqbal R, Nazir CF. Human immune system during sleep. Am J Clin Exp Immunol. 2017;6:92–6. Google Scholar Cross Ref
58. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463:121–37. Google Scholar Cross Ref
59. Freeman D, Sheaves B, Goodwin GM, Yu L-M, Nickless A, Harrison PJ, et al. The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis. Lancet Psychiatry. 2017;4:749–58. Google Scholar Cross Ref
60. Lim J, Dinges DF. A meta-analysis of the impact of short-term sleep deprivation on cognitive variables. Psychol Bull. 2010;136(3):375–89. Google Scholar Cross Ref
61. Simon B, Walker E. Sleep loss causes social withdrawal and loneliness. Nat Commun. 2018;9(1). Google Scholar Cross Ref
62. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–7. Google Scholar Cross Ref
63. Korfage IJ, Essink�Bot ML, Borsboom GJ, Madalinska JB, Kirkels WJ, Habbema JD, et al. Five�year follow�up of health�related quality of life after primary treatment of localized prostate cancer. Int J Cancer. 2005 Aug 20;116:291-6. Google Scholar Cross Ref
64. Tobaldini E, Costantino G, Solbiati M, Cogliati C, Kara T, Nobili L, et al. Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. Neurosci Biobehav Rev. 2017;74:321–9. Google Scholar Cross Ref
65. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3:S7-10. Google Scholar Cross Ref
66. Chee MWL, Chuah LYM, Venkatraman V, Chan WY, Philip P, Dinges DF. Functional imaging of working memory following normal sleep and after 24 and 35 h of sleep deprivation: Correlations of fronto-parietal activation with performance. Neuroimage. 2006;31:419–28. Google Scholar Cross Ref
67. Killgore WDS. Effects of sleep deprivation on cognition. Prog Brain Res. 2010;185:105–29. Google Scholar Cross Ref
68. Fiorentino L, Ancoli-Israel S. Insomnia and its treatment in women with breast cancer. Sleep Med Rev. 2006;10:419–29. Google Scholar Cross Ref
69. Carpenter JS, Elam JL, Ridner SH, Carney PH, Cherry GJ, Cucullu HL. Sleep, fatigue, and depressive symptoms in breast cancer survivors and matched healthy women experiencing hot flashes. Oncol Nurs Forum. 2004;31:591–5598. Google Scholar Cross Ref
70. Carlson LE, Campbell TS, Garland SN, Grossman P. Associations among salivary cortisol, melatonin, catecholamines, sleep quality and stress in women with breast cancer and healthy controls. J Behav Med. 2007;30:45–58. Google Scholar Cross Ref
71. Savard J, Villa J, Ivers H, Simard S, Morin CM. Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period. J Clin Oncol. 2009 Nov 1;27:5233-9. Google Scholar Cross Ref
72. Lee K, Cho M, Miaskowski C, Dodd M. Impaired sleep and rhythms in persons with cancer. Sleep Med Rev. 2004;8:199–212. Google Scholar Cross Ref
73. Vena C, Parker K, Cunningham M, Clark J, McMillan S. Sleep-wake disturbances in people with cancer part I: an overview of sleep, sleep regulation, and effects of disease and treatment. Oncol Nurs Forum. 2004;31:735–46. Google Scholar Cross Ref
74. Kotronoulas G, Wengström Y, Kearney N. A critical review of women's sleep–wake patterns in the context of neo-/adjuvant chemotherapy for early-stage breast cancer. The Breast. 2012 Apr 1; 21:128-41. Google Scholar Cross Ref
75. Knobf MT, Sun Y. A longitudinal study of symptoms and self-care activities in women treated with primary radiotherapy for breast cancer. Cancer Nursing. 2005 May 1; 28:210-8. Google Scholar
76. Savard J, Simard S, Blanchet J, Ivers H, Morin CM. Prevalence, clinical characteristics, and risk factors for insomnia in the context of breast cancer. Sleep. 2001; 24:583-90. Google Scholar Cross Ref
77. Koopman C, Nouriani B, Erickson V, Anupindi R, Butler LD, Bachmann MH, et al. Sleep disturbances in women with metastatic breast cancer. Breast J. 2002;8:362–70. Google Scholar Cross Ref
78. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92:994–1000. Google Scholar Cross Ref
79. Krueger JM, Majde JA. Microbial products and cytokines in sleep and fever regulation. Crit Rev Immunol. 2017;37:291–315. Google Scholar Cross Ref
80. Palesh O, Aldridge-Gerry A, Ulusakarya A, Ortiz-Tudela E, Capuron L, Innominato PF. Sleep disruption in breast cancer patients and survivors. J Natl Compr Canc Netw. 2013;11:1523–30. Google Scholar Cross Ref
81. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130:226–38. Google Scholar Cross Ref
82. Rich T, Innominato PF, Boerner J, Mormont MC, Iacobelli S, Baron B, et al. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res. 2005;11:1757–64. Google Scholar Cross Ref
83. Mills PJ, Parker B, Dimsdale JE, Sadler GR, Ancoli-Israel S. The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer. Biol Psychol. 2005;69:85–96. Google Scholar Cross Ref
84. Schubert C, Hong S, Natarajan L, Mills PJ, Dimsdale JE. The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain, behavior, and immunity. 2007;21:413-27. Google Scholar Cross Ref
85. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112(12):1785–8. Google Scholar Cross Ref
86. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987;10(4):541–53. Google Scholar Cross Ref
87. Morin CM, Stone J, Trinkle D, Mercer J, Remsberg S. Dysfunctional beliefs and attitudes about sleep among older adults with and without insomnia complaints. Psychol Aging. 1993;8(3):463–7. Google Scholar Cross Ref
88. Palesh OG, Collie K, Batiuchok D, Tilston J, Koopman C, Perlis ML, Butler LD, Carlson R, Spiegel D. A longitudinal study of depression, pain, and stress as predictors of sleep disturbance among women with metastatic breast cancer. Biological psychology. 2007;75:37-44. Google Scholar Cross Ref
89. Palesh O, Koopman C. Post-traumatic stress disorder-prevalent and persistent. Nat Revi Clini Oncol. 2013;10:252–4. Google Scholar Cross Ref
90. Vin-Raviv N, Hillyer GC, Hershman DL, Galea S, Leoce N, Bovbjerg DH, et al. Racial disparities in posttraumatic stress after diagnosis of localized breast cancer: the BQUAL study. J Natl Cancer Inst. 2013;105:563–72. Google Scholar Cross Ref
91. Kim H-J, McDermott PA, Barsevick AM. Comparison of groups with different patterns of symptom cluster intensity across the breast cancer treatment trajectory. Cancer Nurs. 2014;37:88–96. Google Scholar Cross Ref
92. Desai K, Mao JJ, Su I, Demichele A, Li Q, Xie SX, et al. Prevalence and risk factors for insomnia among breast cancer patients on aromatase inhibitors. Support Care Cancer. 2013;21:43–51. Google Scholar Cross Ref
93. Colagiuri B, Christensen S, Jensen AB, Price MA, Butow PN, Zachariae R. Prevalence and predictors of sleep difficulty in a national cohort of women with primary breast cancer three to four months postsurgery. J Pain Symptom Manage. 2011;42:710–20. Google Scholar Cross Ref
94. Palesh O, Zeitzer JM, Conrad A, Giese-Davis J, Mustian KM, Popek V, et al. Vagal regulation, cortisol, and sleep disruption in women with metastatic breast cancer. J Clin Sleep Med. 2008;04:441–9. Google Scholar Cross Ref
95. Bardwell WA, Ancoli-Israel S. Breast cancer and fatigue. Sleep Med Clin. 2008;3:61–71. Google Scholar Cross Ref
96. Stein KD, Jacobsen PB, Hann DM, Greenberg H, Lyman G. Impact of hot flashes on quality of life among postmenopausal women being treated for breast cancer. J Pain Symptom Manage. 2000;19:436–45. Google Scholar Cross Ref
97. Berger AM, Farr LA, Kuhn BR, Fischer P, Agrawal S. Values of sleep/wake, activity/rest, circadian rhythms, and fatigue prior to adjuvant breast cancer chemotherapy. J Pain Symptom Manage. 2007;33:398–409. Google Scholar Cross Ref
98. Ancoli-Israel S, Liu L, Marler MR, Parker BA, Jones V, Sadler GR, et al. Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer. 2006;14:201–9. Google Scholar Cross Ref
99. Berger AM, Farr LA, Kuhn BR, Fischer P, Agrawal S. Values of sleep/wake, activity/rest, circadian rhythms, and fatigue prior to adjuvant breast cancer chemotherapy. J Pain Symptom Manage. 2007;33:398–409. Google Scholar Cross Ref
100. Dean E et al. Anxiety. Nursing standard (Royal College of Nursing). 1987;30. Google Scholar
101. Yi JC, Syrjala KL. Anxiety and depression in cancer survivors. Med Clin North Am. 2017;101:1099–113. Google Scholar Cross Ref
102. Holland JC, Rowland JH et al. Handbook of psycho-oncology: Psychological care of the patient with cancer. Oxford University Press; 1989. Google Scholar
103. Google Scholar
104. Delaney G, Jacob S, Featherstone C, Barton M et al. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines: Estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–37. Google Scholar Cross Ref
105. Begg AC, Stewart FA, Vens C et al. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 2011;11:239–53. Google Scholar Cross Ref
106. Elsner K, Naehrig D, Halkett GKB, Dhillon HM et al. Reduced patient anxiety as a result of radiation therapist-led psychosocial support: a systematic review. J Med Radiat Sci. 2017;64:220–31. Google Scholar Cross Ref
107. Holmes N, Williamson K. A survey of cancer patients undergoing a radical course of radiotherapy, to establish levels of anxiety and depression. J Radiother Pract. 2008;7(2):89–98. Google Scholar Cross Ref
108. Choy Y, Stein MB, Hermann R et al. Acute procedure anxiety in adults: Course, screening, assessment and differential diagnosis. Clinical Psychology Review. 2013;27:196–8. Google Scholar
109. Hall H, Dhuga Y, Zheng CY, Clunie G, Joyce E, McNair H, McGregor AH. Patient and practitioner perspectives on the design of a simulated affective touch device to reduce procedural anxiety associated with radiotherapy: a qualitative study. BMJ open. 2022 ;12:e050288. Google Scholar
110. Chapman HA, Bernier D, Rusak B. MRI-related anxiety levels change within and between repeated scanning sessions. Psychiatry Research: Neuroimaging. 2010; 182:160-4. Google Scholar
111. Murphy KJ, Brunberg JA. Adult claustrophobia, anxiety and sedation in MRI. Magn Reson Imaging. 1997 ;15:51-4. Google Scholar
112. Lucente FE, Fleck S. A study of hospitalization anxiety in 408 medical and surgical patients. Psychosomatic Medicine. 1972 ;34:304-12. Google Scholar
113. Choy Y, Stein MB, Hermann R et al. Acute procedure anxiety in adults: Course, screening, assessment and differential diagnosis. Clinical Psychology Review. 2013;27:196–8. Google Scholar
114. Kendall PC, Williams L, Pechacek TF, Graham LE, Shisslak C, Herzoff N. Cognitive-behavioral and patient education interventions in cardiac catheterization procedures: The Palo Alto Medical Psychology Project. J Consult Clin Psychol. 1979;47:49–58. Google Scholar Cross Ref
115. Shipley RH, Butt JH, Farbry JE, Horwitz B. Psychological preparation for endoscopy: Physiological and behavioral changes in patients with differing coping styles for stress. Gastrointestinal Endoscopy. 1977;24:9–13. Google Scholar
116. Izci F, Sarsanov D, Erdogan ZI, Ilgun AS, et al. Impact of Personality Traits, Anxiety, Depression and Hopelessness Levels on Quality of Life in the Patients with Breast Cancer. Eur J Breast Health 2018; 14: 105–111. Google Scholar
117. So WKW, Law BMH, Ng MSN, He X, Chan D, Chan C, McCarthy AL. Symptom clusters experienced by breast cancer patients at various treatment stages: A systematic review. Cancer Med. 2021; 10: 2531–2565. Google Scholar
118. Kim JH, Paik HJ, Jung YJ, Kim DI, Jo HJ, Lee S, Kim HY. A Prospective Longitudinal Study about Change of Sleep, Anxiety, Depression, and Quality of Life in Each Step of Breast Cancer Patients. Oncology 2019; 97: 245–253. Google Scholar
119. Li J, Zhang F, Wang W, Pang R, Liu J, Man Q, Zhang A. Prevalence and risk factors of anxiety and depression among patients with breast cancer: A protocol for systematic review and meta-analysis. BMJ Open 2021; 11: e041588. Google Scholar
120. Gold M, Dunn LB, Phoenix B, Paul SM, Hamolsky D, Levine JD, Miaskowski C. Co-occurrence of anxiety and depressive symptoms following breast cancer surgery and its impact on quality of life. Eur J Oncol Nurs. 2016; 20: 97–105. Google Scholar
121. Jones SMW, Lacroix AZ, Li W, Zaslavsky O, Wassertheil-Smoller S, Weitlauf JC, Brenes GA, Nassir R, Ockene JK, Caire-Juvera G, et al. Depression and quality of life before and after breast cancer diagnosis in older women from the Women’s Health Initiative. J Cancer Surviv. 2015; 9: 620–629. Google Scholar
122. Mitchell AJ, Chan MKY, Bhatti H, Halton M, Grassi L, Johansen C, Meader N. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: A meta-analysis of 94 interview-based studies. Lancet Oncol. 2011; 12: 160–174. Google Scholar
123. Pitman A, Suleman S, Hyde N, Hodgkiss A. Depression and anxiety in patients with cancer. BMJ 2018; 361: 1–6. Google Scholar
124. Montazeri A, Vahdaninia M, Harirchi I, Ebrahimi M, Khaleghi F, Jarvandi S. Quality of life in patients with breast cancer before and after diagnosis: An eighteen months follow-up study. BMC Cancer 2008; 8: 330. Google Scholar
125. Li H, Sereika SM, Marsland AL, Conley YP, Bender CM. Symptom Clusters in Women With Breast Cancer During the First Months of Adjuvant Therapy. J Pain Symptom Manag. 2020; 59: 233–241. Google Scholar