Primary brain tumors are a heterogeneous group of neoplasms that are thought to arise from the constituent cells of the brain. Despite their malignant phenotype, they rarely spread outside the central nervous system. Median survival time varies from approximately 1 year for high-grade (grade 4) tumors, such as glioblastoma, to 5 to 15 years for low-grade (grade 2) tumors. Regardless of tumor grade, patients often suffer from neurologic symptoms such as headaches, weakness, and seizures at the time of diagnosis and throughout the disease trajectory.1, 2 For most patients, initial therapy consists of a surgical procedure to obtain tissue for diagnosis and remove tumor if medically feasible.
Tumor cell infiltration into surrounding brain parenchyma is characteristic of all malignant tumors (grade 2 and higher), and even resection of all visible tumor is unlikely to eradicate all malignant cells.3, 4 Therefore, other therapies are often needed after surgical resection as the initial tumor treatment. Other therapies include radiation therapy, chemotherapy, or a combination of both. The most common treatment approach is radiation therapy. These therapies and other concomitant medications, such as corticosteroids and anticonvulsants, often cause additional symptoms that further limit functional status and overall quality of life (QOL).2
Similar to patients with other solid tumors, fatigue is among the most common and most troublesome symptoms for primary brain tumor patients throughout the disease trajectory.5, 6 In a survey evaluating QOL of patients at various times in the trajectory of illness and with a variety of primary brain tumors, 42% reported “quite a bit low” or “very low” energy levels.7, 8 Radiation therapy is the most common treatment modality for all tumor grades. Standard treatment with radiation therapy for grade 2 and 4 tumors is 60 grays (Gy) delivered in 2–Gy fractions over a 6-week period to the gross total tumor volume plus a 2- to 3-cm margin. Lovely and colleagues reported that >80% of primary brain tumor patients report fatigue during radiation therapy.9 Fatigue has been reported to occur as early as within 1 week of the first radiation treatment, and tends to increase with the number of radiation fractions.2
Fatigue that occurs during radiation therapy may continue into the postradiation period. Faithfull and Brada reported on the occurrence of a somnolence syndrome in the immediate postradiation period.10 This syndrome included fatigue, excessive drowsiness, feeling clumsy, and inability to concentrate. In this study, patients were observed during the immediate postradiation period. After completion of radiation therapy, the reported symptoms had a cyclical pattern, with increased severity during Day 1 to 21 and then Day 30 to 35 after treatment. Fatigue has been reported to persist for 1 to 3 months after the completion of treatment, but may be more chronic for some individuals.11 The applicability of these findings to current treatment are limited by the small sample size (n = 19), lack of baseline measurement, and changes in delivery and radiation field determination used with modern treatment.
Clinically, a variety of other factors may contribute to the frequency and intensity of the fatigue. These include concomitant medications such as anticonvulsants and corticosteroids, metabolic disturbances, and psychosocial issues such as depression and anxiety. Most patients require corticosteroids to treat brain edema and anticonvulsants for seizure management. These medications have been reported to contribute to fatigue in this patient population.2, 12 Depression and anxiety have been reported to occur in 16% to 50% of patients during the early stages of the disease.13, 14 Although not evaluated in relation to fatigue in the primary brain tumor population, depression, anxiety, and distress have been reported as being associated with fatigue in other solid tumor patients.15-17
Fatigue may also persist for years after diagnosis and completion of therapy. A recent report explored the occurrence of fatigue in patients with low-grade gliomas who were at least 3 years from completion of tumor therapy.18 In this study, 39% of patients reported severe fatigue >8 years after completion of therapy. The only variable found to predict fatigue was continued anticonvulsant use. Findings of this study are limited by the small sample size, lack of information on type of anticonvulsant prescribed, seizure activity, and use of chemotherapy in this patient population.
In summary, there are limited studies to date exploring the occurrence of fatigue and evaluating associated variables in patients with primary brain tumors. In patients with other solid tumors, fatigue is often the most common and severe symptom associated with the disease and treatment.15, 19 Fatigue has been demonstrated to cluster with other symptoms, including pain, distress, insomnia, and depression, and to influence outcomes such as perceived health and functional status.16, 20 In the limited studies to date in patients with primary brain tumors, fatigue has been identified as a common symptom occurring in patients with both low- and high-grade tumors. Fatigue occurs during radiation therapy and also occurs in long-term survivors of low-grade brain tumors. Most studies are limited to descriptive reports exploring fatigue in relation to a particular treatment,10, 21 tumor type,9 or stage of disease.18 None of these reports explored the occurrence of fatigue in relation to other symptoms and throughout the illness trajectory to uncover clinical factors that may be associated with the severity of fatigue in primary brain tumor patients. Evaluating these clinical factors is a critical first step to model the occurrence of fatigue longitudinally and to explore potential biologic correlates that may be associated with these factors.
The aim of this study was to determine individual demographic characteristics and clinical characteristics that may be associated with moderate to severe fatigue in the primary brain tumor population. Such patient characteristics include demographics such as age and sex as well as clinical characteristics such as tumor grade, disease status, tumor size, concomitant medications, cancer treatment, and performance status. We also wanted to identify the association of moderate to severe fatigue with the occurrence of other symptoms and the interference that symptoms have in daily life. Identification of risk factors related to fatigue severity may allow for individualized approaches to symptom management and determine key variables to explore in elucidating the biologic bases of fatigue in this patient population.
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- MATERIALS AND METHODS
- CONFLICT OF INTEREST DISCLOSURES
Cancer-related fatigue is defined as a “distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning” (Mock et al,31 page 1). Cancer-related fatigue has been recognized as having multiple causes in patients with solid tumors, including the direct effect of the cancer and cancer treatment, comorbid conditions (such as anemia, infection, malnutrition, and cardiac disease), psychological factors (depression and anxiety), and concurrent symptoms (pain and sleep disturbances). Furthermore, the severity of fatigue varies among individuals. In this study, 73% of patients who were diagnosed with brain tumors reported having fatigue, with 40% reporting fatigue as moderate to severe.
Among the 22 reported symptoms, fatigue was the most prevalent symptom in this patient group, similar to reports in patients with other solid tumors. Patients reporting moderate to severe fatigue also showed significantly higher overall symptom severity and more interference with daily life activities than did patients reporting low fatigue. These findings support the prevalence and significance of fatigue in the primary brain tumor population as well.
The findings of this study support that there is an important relationship between fatigue and other concurrent symptoms such as pain, distress, drowsiness, and weakness in patients with brain tumors. In addition, worse overall symptom severity and the burden of symptoms on daily life activities such as mood, work, ability to walk, and interactions with others were demonstrated for those with more severe fatigue. Studies in patients with other solid tumors have also indicated that symptoms can occur concurrently and be multiplicative with other symptoms. It has been postulated that symptoms such as pain, fatigue, and insomnia may have a shared biologic mechanism, such as the sickness behavior seen in relation to cytokine administration or production.32, 33 Further studies are needed to evaluate the concordance of these symptoms over time and the relationship to shared biologic mechanisms in this patient population.
In patients with primary brain tumors, prior studies have identified that fatigue occurs commonly in patients undergoing radiation therapy and that chronic fatigue may occur in patients with low–grade tumors. In this study, patient performance status, sex, and having active disease were the strongest predictors of fatigue. Performance status was the single strongest predictor of fatigue severity and may represent the impact of neurologic impairment on the occurrence of fatigue in this unique cancer population. Overall, patients with a poor performance status were almost 6× as likely to report moderate to severe fatigue. When sex difference was considered, for men, poor KPS was associated with 12× the risk of moderate to severe fatigue. For women, KPS did not remain in the model, but this might have been the result of having only a small number of women with a poor KPS (n = 5). The strong association of fatigue and performance status has not been previously reported. The relationship among neurologic disability, depression, and fatigue has been reported in patients with other more chronic neurologic diseases, including multiple sclerosis,34, 35 muscular disease,36 and Parkinson disease.37 As noted, performance status, which is primarily associated with neurologic disability in the primary brain tumor patient population, was the strongest predictor of more severe fatigue in primary brain tumor patients overall. This may reflect a different etiology for fatigue in primary brain tumor patients as compared with those with other solid tumor malignancies, or alternatively a higher susceptibility to otherwise minor inciting factors in patients with neurologic disability.
Cancer-related fatigue has been shown to have a temporal relationship to treatment and variability during the course of treatment in other solid tumor malignancies.19 This has also been identified in primary brain tumor patients undergoing radiation therapy.9, 10 However, most studies have not identified a relation of increased fatigue with longer disease duration, stage, and recurrence.18 We identified an association with active disease status and the occurrence of more severe fatigue, with those with active disease being 2.2× as likely to report moderate to severe fatigue, and those with active disease and a good KPS 2.3× as likely. Why this association occurs is not known, but it may be related to underlying brain neurochemical changes that are associated with the disease and treatment, and related brain injury resulting in disability. In patients with systemic cancer, fatigue also has been shown to be associated with the production of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor-α, which are thought to trigger sickness behaviors through bidirectional communication with the brain.33-37 In patients with primary brain tumors, the disease and treatment may centrally impact the production of cytokines or other hormones such as melatonin, resulting in fatigue in patients with active disease.
As with other solid tumor malignancies, sex was also associated with the occurrence of moderate to severe fatigue. Women were 2.5× as likely as men to indicate that they had moderate to severe fatigue and 2.8× as likely when they had a good KPS. Additional predictors of fatigue for women included disease status, indicating the importance of active disease in predicting fatigue severity Corticosteroid use and having a low-grade tumor appeared significant on univariate analysis, but were not in the final model. The strong relationship between corticosteroid use and disease status may have resulted in steroid use not being included in the final model. Opioid and anticonvulsant use was also associated with report of fatigue for men, with those on opioids nearly 3.5× as likely to report moderate to severe fatigue and those on antidepressants over 4× as likely to experience moderate to severe fatigue. Currently, it is not known why the variability in fatigue severity occurs in patients in relation to sex.38 Studies in patients with other solid tumor malignancies have also been limited, primarily reporting on differences in prevalence of fatigue based on sex. The different factors found to be related to the severity of fatigue based on sex in this study support the multidimensional and multifactorial nature of fatigue, and further evaluation in a longitudinal study is warranted to validate these findings, explore potential biologic correlates, and development interventions to reduce the severity of fatigue in both women and men.
This study provides a comprehensive review of demographic, functional, and clinical factors related to the severity of fatigue in the primary brain tumor patient population, and is among the first studies to systematically evaluate fatigue in neuro-oncology. These findings may be limited by the cross-sectional sample, which results in the lack of baseline measurements and evaluation of change in fatigue severity over time, and the small number of patients with a poor KPS who were also undergoing radiation therapy. The comparative impact of the disease versus the impact of treatment and concomitant medications in the individual patient during the course of therapy cannot be adequately assessed in this cross-sectional sample.
Results from this study can assist the care provider in assessment and evaluation of fatigue in this patient population. This is the first report to identify the importance of sex, performance, and active disease status on the severity of fatigue in primary brain tumor patients. Additional methods to assess for the occurrence of fatigue in clinical care are warranted in these groups. Further studies are needed to explore the long-term trajectory of fatigue in this patient population and should include factors indentified in this report in the evaluation of fatigue severity. In addition, interventional trials to reduce fatigue severity should consider stratifying patients based on performance status, sex, disease status, and use of concomitant medications, such as opioids, corticosteroids, antidepressants, and anticonvulsants in research design and data analyses. Fatigue should not be considered a solitary symptom with a unidimensional cause, but a complex symptom related to the severity of other symptoms and having multidimensional etiologies. For example, improving functional status may be an effective way for reducing fatigue severity in patients with poor performance status, whereas modification of concurrent medications may be a more effective way for reducing fatigue severity in others. Furthermore, concurrent evaluation of potential biomarkers of fatigue will further advance the understanding of fatigue and the effectiveness of different interventions in reducing fatigue in this unique and vulnerable patient population.