The Etiology and management of radiotherapy-induced fatigue

Abstract

Fatigue is one of the most common side-effects accompanying radiotherapy, but arguably the least understood. Radiotherapy-induced fatigue (RIF) is a clinical subtype of cancer treatment-related fatigue. It is described as a pervasive, subjective sense of tiredness persisting over time, interferes with activities of daily living, and is not relieved by adequate rest or sleep. RIF is one of the early side-effects and long-lasting for cancer patients treated with localized radiation. Although the underlying mechanisms of fatigue have been studied in several disease conditions, the etiology, mechanisms, and risk factors of RIF remain elusive, and this symptom remains poorly managed. The purpose of this paper is to review and discuss recent articles that defined, proposed biologic underpinnings and mechanisms to explain the pathobiology of RIF, as well as articles that proposed interventions to manage RIF. Understanding the mechanisms of RIF can describe promising pathways to identify at-risk individuals and identify potential therapeutic targets to alleviate and prevent RIF using a multimodal, multidisciplinary approach.

Introduction

Radiotherapy (RT) is one of the major treatment modalities for a wide range of malignant tumors [1]. Localized or total body RT is used as a primary, neo-adjuvant or adjuvant combination modality with surgery, chemotherapy, hormone therapy, or immunotherapy across different stages of cancer [2]. While external beam intensity modulated RT successfully increases disease-free survival rates and life expectancy, ionizing radiation leads to increased treatment-related adverse effects. RT-related side effects include fatigue, dermatologic effects, and site-specific issues such as gastrointestinal symptoms [3], which may influence the compliance and efficiency of cancer treatment, as well as decrease the health-related quality of life (HRQoL) of patients [4,5].

Ionized radiation destroys both cancer cells and normal tissues in the irradiated area, but also in surrounding organs [6]. With the improvement of techniques (e.g. three-dimensional conformal RT, intensity-modulated RT, image-guided RT), the delivery of RT have minimized the side effects by efficiently sparing the surrounding normal tissue [7]. Radiation-related toxicities are experienced by individuals in varying degrees, so it is difficult to predict how these toxicities are manifested clinically. Therefore, preventing these toxicities such as fatigue is imperative.

Aim and method of review

This review aimed to provide an overview of the etiology and management of radiotherapy-induced fatigue (RIF). Specifically, this paper reviews the definition, proposed pathobiology and management of RIF. The National Comprehensive Cancer Network (NCCN) has categorized RIF as a clinical subtype of cancer-related fatigue (CRF) [8]. A search through PubMed, MEDLINE, and CINAHL using key phrases/words: radiation-induced fatigue, radiation-associated fatigue, cancer treatment-related fatigue, CRF as well as radiation therapy and fatigue yield 72 articles that were included in this narrative review. More, exhaustive systematic reviews on CRF were previously conducted [5,9–13]; however, this review focused on articles published within at least 10 years that defined, proposed mechanisms and interventions for RIF.

RIF

Fatigue is one of the early and long-lasting side effects of localized RT [5,6]. RIF is one of the debilitating symptoms most often reported by cancer patients receiving RT, often negatively impacting their HRQoL [5,14,15]. As a subtype of cancer treatment-related fatigue, RIF is described as a pervasive, subjective sense of tiredness persisting over time, interferes with activities of daily living and is not relieved by rest or sleep [4,5,8]. RIF often leads to depression, impaired cognitive function, sleep disturbance, decreased physical activity, and decreased HRQoL [14,16,17]. The prevalence and severity of fatigue is slightly different in cancer patients receiving varying treatments [18]. RIF has been noted to increase slightly beginning at week 3 of treatment, then worsen significantly in severity by week 6 of RT, remaining elevated following the completion of treatment [14,19–21]. RIF is a distressing and highly prevalent symptom experienced by cancer patients during RT. Unfortunately, the etiology of RIF remains elusive. This may be related to the lack of a widely accepted RIF phenotype that can drive the RIF biomarker discovery forward. This gap may be related to the lack of consensus on the standardized measure of RIF that can define its phenotype.

Proposed mechanisms of RIF

Recent evidence suggests that RIF may be related to mitochondrial dysfunction [19,22]. Downregulation of mitochondrial markers involved in cell death that are responsible for maintaining mitochondrial membrane integrity and regulating apoptosis (e.g. BCL2, AIFM2) may influence the worsening of fatigue symptoms during RT [19]. Further evidence also suggests that genes that are related to regulation of the production of reactive oxygen species (ROS) and release of cytochrome c may be involved in the worsening of fatigue symptoms during RT [22]. It is specifically proposed that RIF could be due to attenuated physiological and cellular energy caused by a reduction in the capacity of mitochondria to utilize oxygen and synthesize adenosine triphosphate (ATP) [23]. These self-preservation physiological processes, such as apoptosis and autophagy, are activated in response to RT and may play significant roles in the worsening of fatigue symptoms during RIF. Other experts believe that impairment in these physiological processes to counter the toxic effects of RT, as well as bystander tissue damage from RT, may lead to the persistence and chronicity of symptoms through an altered immune response [24].

Other factors have been proposed in the literature to cause RIF including genetic factors, anemia, pro-inflammatory cytokine production, hypothalamic–pituitary–adrenal axis dysfunction, and neuromuscular abnormality [25,26]. We will discuss three of these major mechanisms.

Inflammation and immune response

The individual’s inflammatory response is a main mechanism that is proposed to contribute to the experience of RIF. An increased serum level of IL-6sR was significantly associated with fatigue symptoms in women with stage 0-IIA breast cancer receiving 40 Gy of RT for 15 sessions [27]. Increased serum concentrations of IL6 were significantly associated with fatigue symptoms in individuals with unresectable non-small-cell lung cancer receiving curative conventional external beam RT with concurrent chemotherapy [28]. RIF was significantly associated with serum sTNF-R1and IL-6 levels after controlling for numerous covariates in locally advanced colorectal and esophageal cancer receiving concurrent chemoradiation therapy [29]. Homozygous (AA) alleles of IL-6 were associated with higher levels of evening and morning fatigue symptoms among cancer patients before, during, and those actively receiving RT [30].

Microglial and glial cells in the central nervous system (CNS) also produce cytokines especially in response to stressful conditions caused by RT [31]. The inflammatory cytokines (e.g. IL-1, IL-6, TNF-α) from these cells are thought to communicate with CNS structures causing fatigue by altering neurotransmission in the CNS through the afferent vagus nerve root [32]. For example, the neurons of the preoptic nucleus that synthesize IL-1β have processes that have ramifications for other CNS structures, including the limbic system and the brainstem causing modulation of the neural response leading to significant fatigue [31].

We recently proposed the biological underpinnings of RIF, based on the biomarkers and biological pathways we observed from our investigations, which indicated that cancer and cancer treatment induce a cascade of biological changes causing RIF [33–37]. These biomarkers and biological pathways include alpha-synuclein [34], neurotrophic factors (BDNF, GDNF, and SNAPIN) [35], para-inflammatory bystander markers (the interferon alpha-inducible protein 27, IFI27) [36], and immunespecific response markers (e.g. MS4A1) [37], mitochondrial associated genes (BCL2L1, FIS2, BCS1L, and SCL25A37) as well as RIF-associated biological pathways (glutathione biosynthesis, γ-glutamyl cycle, and antigen presentation pathways) [37].

Anemia and radiation-induced fatigue

The pathological process of radiation injury begins immediately after radiation exposure, but the clinical features may not present for weeks, months, or even years after treatment completion [2,6]. Fatigue induced by RT may be the body’s response to a toxic insult [38]. Several studies have indicated that RIF is associated with anemia and functional iron deficiency [39–44]. Heme levels (red blood cells, hemoglobin, hematocrit) are found to be correlated with fatigue severity at completion of external beam radiation therapy (EBRT) suggesting that stabilizing heme levels may prevent worsening of fatigue symptoms during EBRT [41]. A longitudinal study observed that the most predictive biologic factor for RIF is red blood cell count, after controlling for covariates [41,43]. Anemia, caused by cancer or cancer treatment, leads to decrease oxygen delivery to tissue and eventually a negative energy balance [40], causing fatigue in cancer patients.

Mitochondria bioenergetics and radiation-induced fatigue

In addition to the evidence that inflammation, immune, and anemia-modulated processes contribute to RIF, it is likely that mitochondrial energetics also play a role in the pathobiology of RIF. There is evidence that an increase in ROS formation from RT will cause cellular damage resulting in dysfunction to the mitochondria [45]. ROS are considered one of the major direct causes of ionizing radiation-induced damage [46], resulting in a number of adverse effects (e.g. fatigue, nausea, vomiting, diarrhea, peripheral neuropathy, and cognitive function impairment) that reduce the efficacy of treatment [47]. It is known that radiation-induced damage alters mitochondrial metabolism, inhibits the mitochondrial respiratory chain, and forms highly reactive peroxynitrite (ONO₂⁻) [48]. Once mitochondrial proteins are damaged, the affinity of substrates or enzymes is decreased resulting in mitochondrial dysfunction [45].

The mitochondrial respiratory chain is essential to produce and to maintain effective cell content of ATP [45,49]. Our previous study has shown that changes in mitochondrial-related gene expression (e.g. downregulation of BCS1L and upregulation of SLC25A37) in lymphocytes were associated with fatigue symptoms experienced by men with nonmetastatic prostate cancer during RT [19,22]. Decreased BCS1L protein has been shown to lead to decreased incorporation of the Rieske iron–sulfur protein into complex III and decreased activity of complex III [50]. A defect in complex III will impair ATP production through a decrease in oxidative phosphorylation [51,52]. Additionally, decreased complex III activity is associated with increased superoxide (O₂⁻) production and dismutation to hydrogen peroxide (H₂O₂) [53,54]. Furthermore, upregulation of SLC25A37 increases the mitochondrial inner membrane mitoferrin-1 protein [19,22]. Increased mitoferrin-1 protein leads to increased iron uptake into mitochondria and promotes heme synthesis [55], and this increased matrix-free iron potentially can increase hydroxyl radical formation from H₂O₂. A physiological model of RIF proposes that radiation causes genetic instability and cellular damage, triggers a defect in mitochondrial oxidative phosphorylation, causes ATP depletion and ROS production, thus results in debilitating fatigue [56]. The proposed physiological mechanism of RIF is linked to ATP depletion and impairment of mitochondrial bioenergetics, triggered by radiation-induced genetic instability and cellular damage. These hypotheses-testing and translational researches will provide pharmacologic therapy and potential nutraceutical strategies related to molecular-genetic targets, for example, coenzyme Q and ascorbate to bypass the complex III or energy-enhanced diet to increase ATP level.

Current treatment of RIF

There is no optimal pharmacologic therapy for RIF. NCCN Practice Guidelines in Oncology currently recommend five non-pharmacological interventions to manage fatigue related to cancer and/or cancer therapy, which include activity enhancement, psychosocial improvement, attention-restoring therapy, nutrition, and sleep [57]. For pharmacologic interventions, the NCCN guidelines recommend that after ruling out other causes of fatigue, the use of psychostimulants should be considered. Methylphenidate has been recommended, but available literature reports conflicting results in methylphenidate’s ability to improve fatigue in two small, randomized clinical trials [57,58]. Recent studies have shown that another psychostimulant, modafinil, does not significantly improve fatigue or HRQoL of glioma patients undergoing RT [59,60].

A broad range of non-pharmacological interventions to alleviate fatigue have been evaluated. These include psychosocial interventions (e.g. mindfulness-based stress reduction [61], cognitive-behavioral therapy [62], and relaxation [63]), complementary and alternative therapies (e.g. acupuncture [64], acupressure [65,66], Chinese medicine [67], energy conservation [68]), physical exercise interventions (e.g. aerobics, resistance, and home-based exercise [69–75], and nutraceutical supplements (e.g. lipid replacement therapy [76,77], molecular replacement therapy [47], and l-carnitine and coenzyme Q10 [78]). However, even if non-pharmacological interventions reduced RIF, the mechanism behind the effect of these interventions on CRF remains unclear and the effect sizes of these treatments on CRF are small.

Of all these interventions suggested to manage RIF, only aerobic exercise has been shown to consistently reduce RIF [79]. There is growing body of evidence that increasing physical activity during and following RT can reduce RIF [80]. The NCCN guidelines recommend a combination of endurance and resistance exercises to manage RIF [57]. Most of these exercises to manage RIF are at least twice weekly and involves range of motion/flexibility, muscle strength, aerobic training, and mind/body fitness [79]. Early non-randomized trials of nutraceutical supplements such as levocarnitine or vitamins offer an intriguing possible avenue [81]. Nevertheless, there remains a critical need to develop a better understanding of the biologic mechanisms of RIF to identify therapeutic targets to develop precise interventions.

Expert commentary

In order to understand the etiology of RIF, it is critical that we start by addressing the challenges that is limiting our biomarker discovery investigations. First, we need to come to a consensus for a case definition of RIF. Second, we need a standardized assessment tool and scoring criteria to define the RIF phenotype [82]. These gaps are needed to be addressed before we can move the discovery of RIF biomarker forward. Once those challenges are addressed, translational investigations can provide opportunities to gain new insights into the etiology of RIF.

This is not a systematic review, but a narrative of updated findings of studies that used molecular–genetic approaches to propose the biologic underpinnings of RIF. We also reviewed evidence to proposed interventions to manage RIF. The key issues are listed chronologically, based on the definition, trajectory, proposed etiology, and management of RIF.

Five-year view

Recent efforts are directed at predicting individuals who are at risk to develop RT-related side effects [35,41,83]. One study proposed specific gene signatures to classify and identify individuals who are at risk to develop severe adverse effects from RT [43]. These efforts not only allow identification of at-risk individuals, but also provide relevant information to understand the biologic underpinnings of RT-related side effects and can identify potential markers to reduce these toxicities.

A multimodal, multidisciplinary approach may be necessary to manage RIF including physical exercise, psychosocial intervention, and medications to address the contributing factors of RIF (e.g. anemia, inflammation). Other interventional modalities, such as such as mind–body medicine intervention, the use of cognitive behavioral therapy [84], or complementary therapies such as relaxation [65] can provide the greatest possibility of success to treat and prevent the development and intensification of RIF. Capturing the interplay of peripheral and central domains of RIF is essential in understanding its etiology and optimizing its management.

Key issues.

• ●Fatigue is one of the debilitating symptoms most often reported by cancer patients receiving radiation therapy.
• ●RIF is a pervasive, subjective sense of tiredness persisting over time, interferes with activities of daily living, and is not relieved by rest or sleep.
• ●RIF increase significantly in severity during the course of radiation therapy, remaining elevated following the completion of treatment.
• ●The interactions of several mechanisms have been proposed to influence the individual’s RIF experience, including genetic factors, energy expenditure, metabolism, aerobic capacity, and the patients’ immune response to inflammation.
• ●No optimal pharmacologic therapy for RIF; however, the NCCN guidelines recommend that after ruling out other causes of fatigue, the use of psychostimulants should be considered.
• ●A multimodal, multidisciplinary approach may be necessary to manage and further prevent RIF, including physical exercise, psychosocial intervention, and medications to address the contributing factors of RIF.