Management of fatigue

Introduction

Symptom control increasingly is recognized as an important component in the multidisciplinary management of cancer patients, as it allows for the successful completion of treatment and improves the quality of life (QoL) throughout the course of the disease. Fatigue is one of the most common symptoms of cancer and cancer treatments. In one large study of cancer patients, those with advanced cancer had a high prevalence of fatigue, second only to pain. Another survey of cancer patients found that fatigue affects more patients more often than any other symptom, and is rated by patients as being more important to manage than either pain or nausea/vomiting.

Cancer-related fatigue (CRF) is defined as a distressing, persistent, and subjective sense of tiredness or exhaustion that is not proportional to activity and that interferes with usual function. It is one of the most prevalent adverse side effects during and after therapy, with 80% to 100% of patients reporting that they experienced fatigue. CRF is exacerbated by co-occurring cancer-related side effects such as depression, anxiety, sleep disturbance, and pain .

There is a wide range of fatigue occurrences among patients receiving radiation therapy (RT), likely due to differences in type and stage of cancer, patient populations, types of radiotherapy, and assessment scales used. Severe subjective fatigue was reported by more than 75% of patients with advanced cancer in palliative care units, by 66% of patients with advanced cancer referred for palliative RT, and by 59% of patients with advanced lung cancer. There is limited research on CRF in patients receiving palliative radiation, and the available literature on fatigue is complicated by the multidisciplinary nature of cancer treatment. Furthermore, fatigue often is found as part of a cluster of symptoms, such as shortness of breath, anxiety, pain, and depression, which contributes to the difficulty of identifying the sensitivity and specificity of treatments targeting CRF.

Background and significance

CRF reduces a patient’s ability to complete medical treatments for cancer and to participate in essential and valued life activities, thus potentially reducing overall survival and undermining QoL. The etiology of CRF is complex and not well understood. The causes and mechanisms may be associated with the cancer itself or with its treatment, or with a potential genetic predisposition, an accompanying physical or mental illness, or behavioral and environmental factors. The following pathophysiological pathways have been discussed in the literature: dysregulation of inflammatory cytokines, disturbance of hypothalamic regulatory circuits, changes in the central nervous system (CNS) serotoninergic system, and disturbance of circadian melatonin secretion and the sleep-wake rhythm. For a detailed review on mechanisms and treatments for CRF, see Bower (2014).

Review of the literature

Determining one specific etiology of CRF is highly unlikely, as it is difficult to distinguish the effects of surgery, chemotherapy, radiation, mood, medications, physical comorbidities, and tumor factors from each other ( Table 27.1 ). Fatigue is influenced by many factors which change over time, and the relative contribution of each factor will fluctuate throughout the disease course. The complexity of multiple etiological factors is best addressed by a multidisciplinary team approach that individualizes treatment to the goals of each patient.

There is considerable overlap of symptoms of depression and fatigue, and both may coexist in patients with cancer. One way to explore if a depressive disorder is underlying the fatigue is to ask specifically about the presence of hopelessness, feelings of worthlessness or guilt, suicidal ideation, and a family history of depression and suicide. Patients with advanced cancer may think about death, as they are aware that they may be approaching death or are likely to die of their cancer. In a depressive disorder, thoughts are more focused on a desire to die, rather than contemplation of death as an event or its meaning. Extreme fatigue itself is a suicide risk factor in cancer patients, which underscores the importance of symptom control in patients with cancer. Early psychiatric involvement is of the utmost importance in patients who are deemed high risk for suicide. Research has not demonstrated any benefit to using antidepressants in patients with CRF who do not also have a depressive disorder. ^,

Given the multifactorial nature of CRF, the relationship between various forms of palliative RT and fatigue is a complicated one, and elucidating the nature of that relationship remains a challenge. RT clearly has systemic effects, as well as direct local effects. A systemic effect, such as the release of cytokines into the systemic circulation, could be anticipated to cause a systemic reaction, such as fatigue. It now is well accepted that the abscopal effects of RT, i.e., effects that occur well outside of the treatment fields, are of importance in the tumor response to treatment regimens that combine immunotherapy and RT. It is possible that similar “remote” effects contribute to RT-related fatigue. However, the precise mechanisms by which irradiation results in fatigue remain unclear.

It is generally assumed that the occurrence and magnitude of RT-associated fatigue are related to body site irradiated, size of the treatment field, dose delivered, and use of concurrent systemic therapies and/or interaction with medications. However, the exact relationship of fatigue to specific courses of RT remains to be defined. The measure of fatigue in many studies is subjective, relying on self-reporting in a nonquantitative fashion. Additionally, fatigue rarely is the primary endpoint of any RT-related study; rather, it is a symptom frequently included as part of neurocognitive assessments or health-related QoL questionnaires.

Some authors have attempted to determine whether CRF is of central origin (loss of voluntarily activated muscle because of mechanisms proximal to the neuro-muscular junction) versus peripheral origin (failure of the muscle excitation/contraction mechanism or metabolic changes within the muscle). An extrapolation of this construct may be useful in approaching RT-related fatigue by considering fatigue of “central” origin, i.e., fatigue related to irradiation of the CNS, as opposed to fatigue of “peripheral” origin, i.e., that related to the treatment of non-CNS sites, separately. This may not be applicable to all situations, however, in that some patients receive RT to both CNS and non-CNS sites concurrently. For example, in total body irradiation as part of bone marrow transplant conditioning, fatigue would be of both central and peripheral origin. Furthermore, it may be that physiologic effects induced by CNS irradiation differ from those induced by non-CNS irradiation.

Fatigue related to central nervous system irradiation

North American cooperative group trials have a long history of attempting to document neurocognitive function in patients who receive whole brain radiation therapy (WBRT) for treatment of brain metastases. As a corollary, these trials track treatment-related toxicity, and in some trials, fatigue has been reported as part of toxicity. For example, RTOG 0614 studied the use of memantine as a protector against NMDA-receptor-mediated neurotoxicity in adults receiving WBRT. The trial included 508 adults with brain metastases randomized to receive 24 weeks of either memantine or placebo within the first 3 days of initiating WBRT (37.5 Gy delivered in 15 daily fractions over 3 weeks). A secondary aim of the trial was to assess adverse effects, and fatigue was measured using CTCAE v3.0 for toxicity assessment. No differences in progression-free survival, overall survival, or toxicity were observed between the two groups. Grade 3 and 4 events that were attributable to treatment were reported for 14% of patients on each treatment arm, with the most common side effects being fatigue, alopecia, nausea, and headache; there was no grade 5 treatment-related toxicity, and no additional information on fatigue was reported.

In an attempt to separate treatment-related fatigue from the fatigue which may be associated with brain metastases, studies evaluating the QoL in patients receiving prophylactic WBRT for small cell and non–small cell lung cancers (NSCLCs) may be helpful. In RTOG 0214, a randomized trial of prophylactic cranial irradiation (PCI) versus observation in patients with stage III NSCLC who completed definitive therapy without progression, there were no statistically significant differences at 6 or 12 months from baseline among any QoL components including fatigue, although four patients in the PCI arm developed grade 3 late toxicities, including fatigue. In another trial evaluating PCI in lung cancer, the authors reported fatigue within 90 days of RT in 22% (grade 1, 11%; grade 2, 9%; grade 3, 2%) of the patients on the PCI arm; there was no mention of fatigue in the control arm.

The advent of stereotactic radiosurgery (SRS) for the treatment of patients with brain metastases has afforded a mechanism to evaluate the effect of irradiated CNS volume on fatigue, through several randomized studies conducted to compare the efficacy and toxicity of WBRT versus SRS. The first major trial published was a multicenter Japanese study that randomized 132 patients with 1 to 4 brain metastases to WBRT and SRS or SRS alone. The authors reported neurologic toxicity but did not report specific data on fatigue except to note one case of “slight lethargy” in the WBRT+SRS group. Similarly, an European Organization for Research and Treatment of Cancer (EORTC) trial enrolled patients with 1 to 3 brain metastases treated initially with SRS or surgical resection and randomized them to WBRT or observation. This trial reported that mild acute reactions occurred in 27% of patients, mainly asthenia and fatigue, but additional analysis of these reactions was not reported. Grade 1 and 2 late somnolence was reported by 39% and 44% of patients in the observation and WBRT arms respectively.

In a single-institution phase III trial at MD Anderson Cancer Center, Chang et al. randomized patients with 1 to 3 brain metastases to SRS alone versus SRS plus WBRT with a primary endpoint of neurocognitive function. In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) attributed to radiation treatment was reported; however, fatigue was not reported as a measurement.

In an North Central Cancer Treatment Group (NCCTG) study, Brown et al. reported the results of a randomized trial comparing SRS alone to SRS plus WBRT for 1 to 3 brain metastases with a primary endpoint of cognitive function and various QoL measurements as a secondary endpoint. QoL was assessed using the Functional Assessment of Cancer Therapy-Brain (FACT-Brain), where scores range from 0 to 200 and higher scores indicate better QoL. There was better QoL at 3 months with SRS alone in terms of physical well-being and functional well-being, but fatigue was not reported as a discrete measurement. In a subsequent study from the NCCTG comparing WBRT versus SRS to the surgical cavity in patients with resected brain metastases, fatigue was reported in the adverse event summation, and grade 1 and 2 fatigue occurred in 9% of the SRS alone patients and 22% of the WBRT patients.

Perhaps the most dramatic aspect of CNS-related fatigue is the so-called “somnolence syndrome.” Initially described in children who received whole cranial RT as part of the treatment regimen for acute lymphoblastic leukemia (ALL), it occurs during the subacute phase of post-whole brain RT (WBRT) toxicity, typically several weeks to months after radiotherapy administration. It is attributed to transient demyelination and radiologic worsening of brain vasculature. Clinically, it involves a combination of worsening cognitive status and the development of profound fatigue; patients often present with extreme lethargy, sleeping upwards of 20 hours during a 24-hour period. The symptoms of somnolence syndrome are typically reversible and resolve over time.

Fatigue related to irradiation of non–central nervous system sites

Fatigue associated with non-CNS RT has been most frequently evaluated in women receiving irradiation for breast cancer. Many of these studies include patients who have received or are receiving concurrent systemic treatment, and this confounds the contribution of RT to overall fatigue. Furthermore, the extent of the irradiation fields is frequently not accounted for in many of these studies. In general, patients with higher-stage disease may receive fields encompassing locoregional lymph nodes, resulting in additional volume of normal tissue being irradiated. Additionally, some studies have included patients with localized disease at diagnosis receiving RT as part of primary treatment (with or without adjuvant chemotherapy) as well as patients with metastatic disease, further confounding the contribution of RT to overall fatigue.