Cancer-Related Fatigue in Lung Cancer

Introduction

The American Society of Clinical Oncology (ASCO) reports that the majority of cancer patients will experience some amount of fatigue during their treatment course. Fatigue can be due to the physical and psychological impacts of cancer and a consequence of cancer-associated treatments such as surgery, radiation, and chemotherapy. Prevalence is reported to range from 25% to 99%, with variability in reported numbers due to varying scales used to evaluate cancer-related fatigue (CRF), differences in quality of analysis and sampling strategies, and the inconsistencies in how fatigue may be experienced in different conditions. Fatigue has a strong association to health-related quality of life. Fatigue has a negative impact on patients' mood, sleep, and quality of life and unfortunately can persist beyond a few months. Approximately two-thirds of those with CRF report that it is severe for at least 6 months, and one-third of those with CRF report that it persists for years after treatment conclusion. In one telephone interview of cancer patients with a prior history of chemotherapy, fatigue was reported to be worse than pain, and disrupted day-to-day activity more than nausea, pain, or depression.

Lung cancer is the second most common cancer among both men and women and the leading cause of cancer death. The 5-year relative survival rate is estimated to only be 19%. Compared to other cancer populations, patients with lung cancer not only have the highest amount of health and existential concerns, but also the greatest number of symptoms. Despite the recent advances in lung cancer treatment, patients experience low quality of life, with fatigue continuing to be a distressing and frequent symptom in this group. A study in 2015 cited relief from fatigue as the most common unmet need in lung cancer patients.

Common treatments for lung cancer such as chemo-immunotherapy frequently lead to fatigue as a side effect. As disease advances, fatigue symptoms typically increase in frequency and intensity as well. Importantly, symptoms such as fatigue, pain, dyspnea, and sleep disturbance have been related to poor outcomes, ^, with symptom burden possibly leading to treatment changes and discontinuation. In addition, multiple studies have demonstrated fatigue to be significantly associated with physical functioning trajectory. Thus, it is vital that clinicians not only recognize the pervasive nature of CRF in lung cancer, but also understand its pathophysiology and treatment options, to help patients maintain a good quality of life and to reduce symptoms that may ultimately affect their ability to tolerate treatments.

Definitions

The National Comprehensive Cancer Network (NCCN) defines CRF as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.” Similarly, the International Statistical Classification of Diseases and Related Health Problems 10th edition (ICD-10) criteria define CRF by presence of diminished energy, increased need for rest beyond what is expected by activity level, and related physical, emotional, and cognitive symptoms. These symptoms must have affected function and/or caused distress to the patient. ^, Frustratingly for patients, CRF does not simply resolve with sleep or rest.

When discussing fatigue, it is also worth noting the distinction between two types: peripheral and central fatigue. Peripheral fatigue is independent of the central nervous system and refers to the exhaustion of the neuromuscular and cardiopulmonary systems. Peripheral fatigue is believed to be due to reduction in glycogen stores, sarcolemmal excitability, or cardiopulmonary endurance. Central fatigue refers to deficits in performance that is independent of muscle function, such as problems in memory, concentration, attention, and motivation. Patients may describe themselves as having “brain fog” or “chemobrain,” lacking the energy or motivation to begin or sustain tasks. Identifying the types of fatigue a patient suffers from can allow the clinician to develop a more specific treatment plan for the patient.

Mechanisms

Various mechanisms have been proposed to explain the etiology of CRF, and the development and persistence of CRF. Early and current research supports the idea that there are biological, psychosocial, and medical factors at play. Biological factors include cytokine dysregulation, hypothalamic–pituitary–adrenal (HPA) axis dysfunction, mitochondrial dysfunction, and genetic components.

Cytokine Dysregulation and Inflammation

Inflammation can be triggered in a variety of ways in the lung cancer patient. Common treatments for lung cancer, including surgery, radiation, and chemotherapy, can result in inflammation due to the result of direct damage to tissues. Psychological stress can also increase inflammatory markers. In addition, cancer cells along with stromal and immune cells in the nearby tumor microenvironment, release proinflammatory cytokines. These proinflammatory cytokines include IL-6, TNF-alpha, INF-gamma, and IL-1, the important players in peripheral immune activation. Altogether, these systemic inflammation changes can alter the body's protein and energy homeostasis.

The cytokine hypothesis of CRF has received the most attention and is based on research indicating that proinflammatory cytokines can elicit a change in the brain called the “sickness behavior.” The sickness behavior includes changes such as decreased motor activity, social withdrawal, reduced oral intake, and cognitive alterations. Treatment of cancer with cytokines has resulted in increase in fatigue, depressed mood, and sleep disturbances in human studies. There is a strong association among inflammation and lung cancer. In NSCLC patients, high levels of Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) cytokine at diagnosis have been associated with greater severity of fatigue. Those with lower levels of plasma RANTES were associated with long-term survival, suggesting that those with higher levels of RANTES may experience more intense fatigue and have shorter survival time. In a separate study of nonsmall cell lung cancer (NSCLC) patients undergoing combined radiation and chemotherapy, there was a simultaneous increase in symptom burden and in serum levels of IL-6, sTNF-R1, and IL-10 at week 8. In addition, there was an association between worsening treatment-related symptoms and the amount of circulating proinflammatory cytokines.

The increase in inflammation in cancer that then leads to CRF is a potential target for treatment. In fact, exercise and physical activity is believed to have a positive effect on chronic low-grade inflammation. Exercise as a treatment will be further discussed later in this chapter.

Mitochondrial Dysfunction and Muscle Fatigue

ATP dysregulation due to impaired mitochondrial mechanisms is hypothesized to be another reason for fatigue in cancer patients. Skeletal muscle requires high levels of ATP for metabolism, and thus, there is an intricate relationship between mitochondrial function and muscle function, strength, and endurance. Chemotherapies are known to target skeletal muscle, with particular predilection for mitochondria, leading to high oxidative stress and lower energy supplies. Muscle fatigue leads to the classic peripheral fatigue symptoms of weakness, reduced endurance, and decreased muscle power.

Proposed mechanisms for the long-term effects on skeletal muscle include damage to DNA that then hinders protein synthesis and cell processes; creation of free radicals that cause cell damage; reduced nuclear DNA transcription; and activation of mitochondrial death. For example, doxorubicin, a chemotherapy used in lung cancer, increases radical oxygen species. Platinum-derived chemotherapy agents, also used in lung cancer, may induce mutations in mitochondrial DNA that can lead to dysfunction and energy imbalances in skeletal muscle. In a study of patients with NSCLC or gastrointestinal cancer, fatigue levels were negatively associated with skeletal muscle mass index.

ATP infusion in patients with NSCLC demonstrated temporary improvements in fatigue and muscle strength. Studies of exercise, including resistance training, found that physical activity is a significant modulator of skeletal muscle and may offset the detrimental effects of lung cancer and cancer treatment. In addition, physical activity may modulate oxidative stress.

Hypothalamic–Pituitary–Adrenal Axis Disruption

Disruption of the HPA axis has also been implicated in CRF. The HPA axis regulates the release of cortisol in response to stress. Cortisol plays a critical role in mediating energy and inflammation, inhibiting cytokine production. Proinflammatory cytokines are stimulators of the HPA axis, and the HPA axis regulates cytokine production via a negative feedback loop. Chronic cytokine exposure results in decreased HPA axis stimulation. This can result in lower cortisol levels; studies have demonstrated the presence of hypocortisolemia in cancer and other chronic inflammatory conditions like rheumatoid arthritis and chronic fatigue syndrome. In addition, lower cortisol levels can disrupt the circadian rhythm, which regulates behaviors such as sleep, body temperature, hormone secretion, and arousal. In addition, cancer and its treatments can also directly alter endocrine pathways.

Genetic Factors

Studies have shown an association between fatigue and various genotypes. In various cancer types, including lung cancer, patterns of fatigue have been associated with a variety of genetic findings. In lung cancer survivors, single nucleotide polymorphisms of IL-1β, IL-1RN, and IL-10 were significantly associated with fatigue levels. In a separate study of NSCLC patients, the IL-8-T251A genotype was found to be associated with pain, depression, and fatigue. In early-stage NSCLC, genetic variants in the IL-10 receptor were significant for fatigue in women.

Risk Factors

Psychosocial, behavioral, and medical factors may put patients at risk for development of CRF. Though much of the research on psychosocial and behavioral risk factors is in nonlung cancer populations, some of the information can likely be extrapolated to lung cancer patients.

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