Fatigue in patients with head and neck cancer undergoing radiation therapy: a prospective study

Objective to identify the frequency of fatigue and domains affected in patients with head and neck cancer undergoing radiation therapy, at the beginning, middle and end of treatment. Method longitudinal and prospective study of quasi-experimental design, involving 60 patients with head and neck cancer. It should be highlighted that this article will address only the data of the Control Group. The dependent variables were collected through interview, using the revised Piper Fatigue Scale, which is a multidimensional instrument that assesses global, behavioral, affective and sensory/psychological domains. Data analysis was based on absolute and relative frequencies. Results there was a predominance of males, age group between 41-60 years, low level of education and in regular use of alcohol and cigarettes. All domains in the fatigue scale had their scores increased, presenting median values of greater magnitude in Time 2 and Time 3, when compared to the Time 1 values, indicating an increase in fatigue levels during radiation therapy. Conclusion fatigue increased in the course of the radiation therapy, having all domains affected. Therefore, its evaluation throughout the treatment is important, as fatigue is a common and debilitating symptom on cancer patients.


Introduction
Cancer is the second leading cause of death in the United States, and is considered a major public health problem nowadays. Among the ten most prevalent types of cancers, those in the oral cavity and pharynx occupy the eighth place, with estimate of 51,540 new cases for 2018, being 37,160 new cases in men and 14,380 new cases in women (1) .
The term head and neck cancer (HNC) refers to a heterogeneous group of neoplasms affecting the upper aerodigestive tract, and has as predominant histological type the squamous cell carcinoma, which comprises about 90% of the cases (2) .
HNC affects regions that are responsible for basic functions such as breathing, swallowing and verbal communication. Complications in these regions resulting from cancer and its treatment may lead to mutilation and physiological changes, as difficulties chewing, dysphagia, aspiration, changes in speech and aesthetic changes that negatively compromise the physical and psychosocial aspects of these patients (3)(4) .
The most common therapeutic modalities for this type of cancer are the surgery, with or without reconstruction, the radiation therapy and the chemical therapy, which can be applied exclusively or concurrently. To choose a treatment, several factors are evaluated, such as metastasization, location and size of the tumor, with the purpose of preserving the organs, the functionality and the aesthetic issues (5) .
Radiation therapy is the most common treatment for HNC. It is used in approximately 80% of cases, with the aim of restricting the reproductive potential of cancer cells. Despite the advantage in relation to surgery as to the organ preservation, radiation therapy is also associated with numerous adverse events, since the radiation is not restricted to tumor cells, and thus, the normal cells of adjacent tissues are also affected during the treatment and can result in adverse local and widespread events (6)(7) .
According to the literature, the most prevalent adverse local events of radiation therapy for HNC are: mucositis, xerostomia, secondary infections, radiation caries, trismus, dysgeusia and osteoradionecrosis (6) .
And among the systemic adverse events, fatigue is most frequent symptom, associated with the radiation therapy (8) .
Fatigue is one of the most cited symptoms in the literature when considering cancer patients, and is also one of the most common side effects accompanying radiation therapy (9) . It affects from 50% to 90% of HNC patients undergoing radiation therapy. The most common factors associated with the symptom are those related to the disease itself and treatment, such as stress, decreased hemoglobin levels during treatment, weight loss, and activation of proinflammatory cytokines resulting from radiation therapy (8)(9)(10) .
Cancer-related fatigue (CRF) is a very common and debilitating symptom to the patient, being reported as an overwhelming state of exhaustion, of greater intensity and longer duration than the typical fatigue, and may have implications on therapeutic decisions, such as the interruption of therapy or dose reduction (10) .
In addition, CRF is a multidimensional phenomenon that negatively affects the physical, cognitive, emotional and social domains, interfering in activities of daily living and in the course of the patient's treatment (11) .
A study indicates the difficulty and uncertainty of the patient in reporting the symptom and barriers on the part of the health team involving lack of screening, diagnosis and treatment of the symptom, which despite being a serious and complex clinical problem, can be treated by allopathic and non-allopathic means, thus providing a better quality of life to the patient (12) .
The changes caused by the HNC linked to side effects from treatment can make the patient hopeless toward the situation experienced. In this context, a systematic review with meta-analysis found evidence that nursing intervention has a positive effect in the feeling of hope (13) . Thus, we believe that supplementary nursing interventions assist in the physical and emotional aspects of the cancer patient.
In this context, this research is appropriate considering that fatigue is multidimensional and can affect physical, psychological/emotional and social issues (12) ; thus, it is believed that the nurse has an important role for patients undergoing oncological treatment. Also, to adopt an evaluation during radiation In the present study, only the Control Group (CG) was analyzed in three moments -beginning, middle and end of the radiation therapy -to emphasize the affected domains. In this way, only the procedures of the CG will be described.
The target population of the study consisted of patients with HNC in the beginning of radiation therapy.
To meet the objectives of the study, convenience sample with intentional allocation for each of the groups -Intervention Group and Control Group (IG and CG) -was used. In this sense, the sample of this study consisted of 60 patients, all belonging to the Control Group. There was no lost to follow-up by death or withdrawal from participating in the study.
The rPFS adapted to the Brazilian audience (14) consists of 22 items that comprise three dimensions/ domains: behavioral dimension (items 2 to 7), affective dimension (items 8 to 12) and sensory/psychological dimension (items 13 to 23). Each item has a numerical scale ranging from 0 to 10. The total score is calculated by the average of all items of the instrument (items 2 to 23) and the scores of the dimensions were calculated by the average of the items in each dimension. The total score and its dimensions are described on a numerical scale from 0 to 10, given that the higher the score, the greater the indication of fatigue.
The response variables, whether dependent or of outcomes, consisted in the results of the global PIPER evaluation and its behavioral, affective and sensory/ psychological domains, measured at the beginning (T1), middle (T2) and end (T3) of the radiation therapy.     In relation to multiple comparisons of the PIPER scale and its respective domains, Table 3 shows that all the differences of averages were negative (less than zero) and the respective tests indicated statistically significant differences, confirming an increase in fatigue levels during radiation therapy.  (2,(16)(17)(18) .
Twenty-eight (46.67%) patients indicated regular use of alcohol and 40 (66.67%) indicated use of cigarettes, even during the radiation therapy. Other studies also identified a high prevalence of HNC patients who maintained a regular use of these substances during the oncological treatment (16)(17) .
The use of alcohol and cigarettes along with oncological treatment results in a negative impact on the response of the latter, and the use of these substances after diagnosis and during treatment can be a risk factor for a secondary malignancy (17) . In addition, studies indicate that alcohol consumption is also a prognostic factor for this type of cancer, i.e. the heavy alcoholist presents a worse disease prognosis compared to non-heavy alcoholists that have stopped consuming alcohol (19)(20) .
Given this scenario, it is worth mentioning that This study shows that from the 60 participants, 43 (71.67%) are in advanced staging of the disease (III, IV) and, of these, 29 (48.33%) combined the radiation therapy with the surgery, which is consistent with the literature for this audience, which claims that radiation therapy is considered the standard modality for initial stage cancers and, in more advanced cases, the association of radiation therapy with surgery and/or chemical therapy is indicated (5,(22)(23)(24) .
CRF is evidenced by the literature as a serious clinical problem and one of the most frequent and debilitating symptoms that affect HNC patients undergoing radiation therapy. In addition, it is responsible for the main causes of psychological disturbances, reduction of activities of daily living, social isolation, loss of motivation, and reduction of health-related quality of life, and may also influence negatively the conduction and adherence to treatment (25)(26)(27) .
A prospective study held with 40 patients with nasopharyngeal cancer aimed to evaluate the fatigue levels during radiation therapy and the possible causes of the symptom. As a result, the study identified that 60% of patients had acute fatigue during treatment, which persisted after its term. The research associated as possible causes for fatigue induced by radiation the toxicity caused by the treatment, as the increased production of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and Interleukin 1-β of the hippocampus, for example] (8) .
Corroborating the previous study, another recent study conducted in the United States with HNC patients also detected the presence of inflammatory markers, demonstrating that the presence of these markers due to cellular toxicity caused by the radiation therapy is associated with one of the triggering factors of fatigue (28) .
In this sense, one can note that the etiology of the symptom is complex, and can be linked not only to the intensity of the radiation received, but also to the consequence of alterations at a cellular level, especially at signaling ways in the tumor microenvironment, as in the exacerbated release of pro-inflammatory cytokines and chemokines, for example (29)(30) . Thus, the inflammatory process resulting from radiation therapy may also be one of the possible causes of fatigue (25) , besides issues involving the psychological state, as stress and nutritional changes (8)(9)(29)(30) .
A review study corroborates that the CRF etiology is complex and multidimensional, involving several potentially aggravating and contributive elements, including factors related to the tumor itself, psychological conditions, comorbidities and side effects associated with anticarcinogenic therapies or other medicines (12) .  (32)(33) .
The limitations of this study consist of the reduced number of studies that specifically assess the affected domains for a better theoretical basis that serves as a comparison to this research. Most studies that use specific instruments to evaluate fatigue presents a value for total fatigue, or within the symptom subscale in psychometric instruments that assess the health-related quality of life (8,25,28) .
In addition, another limitation refers to the nonrandomization of subjects in IG and CG, due to users' low acceptance of the relaxation and guided imagery ICP; the reduced sample size is also mentioned because this study was carried out in a single center in Brazil.
Thus, further research with similar investigations is recommended to produce studies that will allow the identification of the frequency of fatigue and its influence on different domains (physical, emotional, social), which also influences the choice of the intervention to be adopted, which may be allopathic or not.
The findings of this study contribute to the knowledge of professionals who work providing assistance to cancer patients, in order to motivate the use of psychometric instruments for evaluation of fatigue and identification of the affected domains, because it is an effective and low-cost evaluation, which provides evidence for the implementation of strategies for relief and/or reduction of the symptom.

Conclusion
The In order to provide a holistic treatment, it is important to evaluate the fatigue levels, as well as those of the affected domains, throughout the treatment, since that, as soon as the symptom is detected, health professionals can start applying strategies for fatigue reduction, thus contributing in the conduction of conventional treatment, but also contributing to the patient's well-being.