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Chronic Systemic Symptoms in Head and Neck Cancer Patients

Chronic Systemic Symptoms in Head and Neck Cancer Patients Abstract The systemic effects and manifestations of disease and treatment have been of interest for millennium. Until recently, basic and clinical research is just now reaching a watershed. Systemic symptoms usually do not occur in isolation but rather in clusters; however, much of the cutting-edge research pertaining to the etiology, mechanism, manifestations, and moderators of systemic symptoms in humans has been directed at individual symptoms, thus creating silos of knowledge. Breaching these silos and bridging the knowledge from disparate arenas of investigation to build a comprehensive depiction of acute and chronic systemic symptoms has been a challenge. In addition, much of the recent work in systemic symptoms has been conducted in the setting of nonmalignant disease. The degree to which the findings from other chronic disease processes can be translated into the oncologic realm is unknown. This article will explore inflammation as a major contributing factor to systemic symptoms and sickness behavior, discuss the most common manifestations in cancer survivors, and, where available, discuss specific data pertaining to head and neck cancer survivors. Systemic Symptoms and Sickness Behavior Disease processes including cancer, infection, or clinically significant trauma evoke a stereotypic neurohumoral response intended to aid the body in its recovery (1). Activation of these same biological processes results in general symptoms as well as adaptive behaviors (2, 3). In the short run, this may be physiologically beneficial; however, in the long term these same processes may be maladaptive and harmful to the host. The systemic effects and manifestations of disease and treatment have been of interest for millennium; however, basic and clinical research are just now reaching a watershed. The taxonomy that governs this area of research has yet to be solidified and terminology continues to evolve as data become available. For the purposes of this review, we will use the terms “systemic symptoms” and “sickness behavior” to describe patient-reported symptoms and observable behavioral changes, respectively. Systemic symptoms frequently described in the oncologic population include weakness, fatigue, sleep disturbance, temperature dysregulation, pain, gastrointestinal symptoms such as nausea and vomiting, and neurocognitive dysfunction and mood disorders such as depression and anxiety. Adaptive sickness behaviors include hypersomnia, depressed activity, lethargy, and altered dietary intake. Additional systemic physiological effects of cancer and its treatment, such as cachexia and sarcopenia, although not usually considered under the sickness syndrome umbrella, will be incorporated into our discussion. Before discussing individual symptoms, several observations should be made. First, systemic symptoms usually do not occur in isolation but rather in clusters. This suggests a shared underlying pathophysiologic mechanism. The results of symptom clustering are a marked increase in overall symptom burden, a decline in functionality, and decrease in quality of life. Second, much of the cutting-edge research pertaining to the etiology, mechanism, manifestations, and moderators of systemic symptoms in humans has been directed at individual symptoms, thus creating silos of knowledge. Breaching these silos and bridging the knowledge from disparate arenas of investigation to build a comprehensive depiction of acute and chronic systemic symptoms has been a challenge. Third, much of the recent work in systemic symptoms has been conducted in the setting of nonmalignant disease. For example, much of our knowledge regarding central widespread pain was generated in patients with fibromyalgia. The degree to which the findings from other chronic disease processes can be translated into the oncologic realm is unknown. Fourth, although symptoms within a cluster may have overlapping etiologies and mechanisms, they are nonetheless distinct. Clearly defining the commonalities and distinctions may be helpful in unraveling this complex network. Fifth, as molecular technologies evolve, large volumes of data are generated. Computation methods must be developed that allow interpretation of these large data sets. Computational biology is a molecular systems biology approach to model a robust population of molecular data. It represents a powerful tool that will allow interpretation and understanding of complex biological processes. For instance, in molecularly complex processes such as oral mucositis, computational strategies to identity the critical molecular network hubs and downstream pathways involved in the pathogenesis must be utilized. Finally, it is likely that genetic variability influences the type of late effects experienced by any individual patient. Understanding these genetic influences may help inform methodology as well as our interpretation and understanding of study outcomes. The disease-associated neurohumoral response may be exacerbated by treatment, including surgery, radiation therapy (RT), and chemotherapy. This may lead to or escalate symptom burden (4). It would be hypothesized that after treatment has ceased and the tumor is eradicated that the neurohumoral effects would subside, symptoms would resolve, and normal functionality would return. It is, however, becoming increasingly recognized that adaptive physiologic responses may result in permanent biological changes, resulting in long-term systemic symptoms and behavioral changes (5). This creates a challenge for investigators, because the transience of these neurohumoral insults will impede investigators’ ability to capture important causal associations. Consequently, cross-sectional studies have significant limitations, so animal models and/or prospective trials may be needed. Unfortunately, long-term, prospective human studies in the oncologic population are challenging due to issues of cost and feasibility. In this article, we will explore inflammation as a major contributing factor to systemic symptoms and sickness behavior, discuss the most common manifestations in cancer survivors, and, where available, discuss specific data pertaining to head and neck cancer (HNC) survivors. Neurohumoral Communication and Neuroinflammation To coordinate the physiologic and behavioral responses to disease, the body has created a complex communication system (Figure 1) that includes the immune system, the endocrine system, and the central and peripheral nervous systems. These systems communicate through a shared signaling system of common molecules and receptors (6). The role of circulating inflammatory mediators on the development and maintenance of acute and chronic systemic symptoms has been an area of intense investigation over the past decade. Of particular interest is the critical interplay between inflammatory mediators and the central nervous system (CNS; neuroinflammation) (7). Although the endocrine system plays a critical physiological role in disease states, due to space limitations this topic will not be discussed. Figure 1. View largeDownload slide Sickness behavior symptoms. HPA = hippocampal pituitary axis; Interleukin-1β (IL-1b); IL-6 = Interleukin-6; NO = nitrogen oxide; ROS = reactive oxygen species; SNS = sympathetic nervous system; TNF-α = Tumor Necrosis Factor α. Carissa A. Low et al., “Neurocognitive Impairment as One Facet of Cancer-Related Sickness Behavior Symptoms.” Journal of the National Cancer Institute, 2015. volume 107, issue 8, pages 1–3. By permission of Oxford University Press. Figure 1. View largeDownload slide Sickness behavior symptoms. HPA = hippocampal pituitary axis; Interleukin-1β (IL-1b); IL-6 = Interleukin-6; NO = nitrogen oxide; ROS = reactive oxygen species; SNS = sympathetic nervous system; TNF-α = Tumor Necrosis Factor α. Carissa A. Low et al., “Neurocognitive Impairment as One Facet of Cancer-Related Sickness Behavior Symptoms.” Journal of the National Cancer Institute, 2015. volume 107, issue 8, pages 1–3. By permission of Oxford University Press. Peripheral pro-inflammatory cytokines (eg, Inteleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF)-α) produced by the host in response to cancer or cancer therapy can function as immune-to-CNS signaling molecules. Although they cannot passively cross the blood brain barriers, cytokines signal the CNS through a variety of mechanisms, including (1) active transport, (2) crossing at circumventricular organs, (3) binding to receptors in the cerebral blood vessels, and (4) through interaction with the vagus nerve (8). Once inflammatory mediators have entered the CNS, they activate microglia cells and astrocytes. These in turn cause production of central pro-inflammatory cytokines and other neurotoxins. Overall, this creates a neuroinflammatory milieu that may cause alterations in neural function. After prolonged exposure, neural pathways may be permanently altered, leading to aberrant signals. Thus, peripheral pro-inflammatory cytokines are capable of indirectly modulating cytokine levels in the CNS. An abundance of data demonstrate that peripheral and CNS cytokines induce symptoms classically described as sickness symptoms, including fatigue, widespread pain, temperature dysregulation, reduced appetite, and depression (9, 10). This is pertinent to the oncologic patient population because tumor and treatment are associated with elevation of peripheral pro-inflammatory cytokines. It may therefore be hypothesized that peripheral cytokines produced by cancer and its therapy may alter CNS cytokine levels, thereby inducing systemic symptoms. Although neuroinflammation is thought to be a critical mediator of systemic symptoms and sickness behavior, other mechanisms contribute as well and will be discussed briefly where pertinent (11). Inflammation and HNC Both HNC and its treatment have been associated with elevated levels of pro-inflammatory cytokines, putting patients at high risk for adverse systemic effects. Preclinical models with HNC cell lines demonstrate elevated levels of inflammatory mediators such as chemokines, cytokines, and growth factors that play a critical role in tumorigenesis, metastasis, and angiogenesis (12). Studies in the HNC population confirm the association between treatment (radiation and/or chemotherapy) and changes in the level of inflammatory mediators. In a study of 34 HNC patients who received RT, there was a statistically significant rise in TNF-α and IL-6 levels posttreatment (13) Studies also demonstrate a correlation between the serum concentration of inflammatory mediators and toxicity grade. For example, mucositis is one of the most visible and impactful inflammatory complications of radiation to the head and neck region. In a 58-patient prospective phase II study of chemoradiation, the severity of mucositis correlated with levels of TNF-α, IL-1, IL-6, and IL-13 (14). In a second, larger prospective study of lymphedema and fibrosis, the systemic levels of select proinflammatory cytokines correlated with the presence and severity of acute and chronic soft tissue toxicities (15). It should be noted that cytokine levels and/or trajectory have been associated with treatment outcome. In a prospective trial of 30 patients, both the pretreatment levels of and change over time in IL-6, IL-8, VEGF, HGF, and GRO-1 were associated with treatment response and overall survival (16). Common Systemic Symptoms in Cancer Pain Pain is a ubiquitous problem in the HNC population: up to 57% (95% confidence interval = 43% to 70%) of patients have tumor-related pain at the time of presentation, effectively all patients have treatment-related pain, and up to 42% (95% confidence interval = 33% to 50%) have chronic posttreatment pain (17). Acute tumor- and treatment-related pain has been well described and will not be further discussed. Long term, HNC survivors describe distinct pain syndromes including neck and shoulder pain due to musculoskeletal impairment, chronic oral mucosal sensitivity due to RT, and chemotherapy-associated peripheral neuropathy. In addition, a subset of HNC survivors develops widespread joint and muscle pain due to alterations in pain and sensory processing (18), a phenomenon commonly referred to as central pain. Historically, the term “central pain syndromes” referred to rare syndromes associated with discrete CNS pathology such as thalamic stroke. Currently, central pain refers to “immune-related pain syndromes.” Central Pain: Pathobiology Central pain results from changes in central processing due to persistent noxious stimuli. This results in central sensitization (CS), a well-recognized component of central sensitivity syndromes (CSS) such as fibromyalgia, irritable bowel disease, and temporomandibular joint disorder (19–21). Central sensitization is a state of CNS hyper-excitability that results in marked amplification of peripheral pain stimuli and decreased central pain inhibitory signals. The clinical manifestations include hyperalgesia, allodynia, expansion of receptive fields with widespread musculoskeletal pain, and exaggerated pain well after withdrawal of a painful stimulus (2, 20). Pro-inflammatory mediators (Figure 2), particularly cytokines, play a direct role in the development and maintenance of CS through their interaction with the peripheral nervous system and CNS (20, 22–24). After neural injury, pro-inflammatory cytokines are recruited to or secreted by immune cells near the site of injury and aid in axonal regeneration (25). However, in the setting of a chronic inflammatory process, long-term exposure to pro-inflammatory cytokines can be neurotoxic. Pro-inflammatory cytokines can disrupt the blood-nerve barrier near the site of the damaged peripheral nerve, resulting in recruitment of additional neutrophils and macrophages (26). Thus, cytokines directly alter neural excitability and demyelinate the axons leading to degeneration of peripheral nerves as well as development of neuropathic pain (26). During this period, the repetitive nociceptive input from the peripherally inflamed neural tissue can lead to neuroplastic changes in pain processing within the CNS, resulting in long-term CS. Figure 2. View largeDownload slide Chronic pain, which includes neuropathic pain induced by nerve injury and spinal cord injury, arthritis-induced inflammatory pain, cancer pain, and pain induced by drug treatment, results from neuroinflammation in the spinal cord. This neuroinflammation is triggered by activity-dependent release of glial activators (ie, neurotransmitters, chemokines, and proteases as well as WNT ligands) from the central terminals of primary afferent neurons and/or by disruption of the blood-brain barrier (BBB). Neuroinflammation is characterized by the activation of microglia and astrocytes, the infiltration of immune cells to the peripheral nervous system eg, the dorsal root ganglia [DRG]) and the central nervous system eg, the spinal cord), and the production of inflammatory and glial mediators such as pro-inflammatory cytokines and chemokines as well as growth factors and gliotransmitters ie, glutamate and ATP). These glial mediators can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Glial mediators can further act on glial and immune cells to facilitate neuroinflammation via autocrine and paracrine routes. Furthermore, neuroinflammation generates anti-inflammatory cytokines and pro-resolution lipid mediators (PRLMs) to normalize neuroinflammation, synaptic plasticity, and abnormal chronic pain. AMPAR = AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor; BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; CCL2 = CC-chemokine ligand 2; CX3CL1 = CX3C-chemokine ligand 1; CXCL1 = CXC-chemokine ligand 1; ERK = extracellular signal-regulated kinase; GABAR = GABA (γ-aminobutyric acid) receptor; GlyR = glycine receptor; IFNγ = interferon-γ; IL-1β = interleukin-1β; JNK = JUN N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP9 = matrix metalloproteinase 9; NMDAR = NMDA (N-methyl-D-aspartate) receptor; TGFβ = transforming growth factor-β; TNF = tumor necrosis factor; tPA = tissue-type plasminogen activator. Reprinted by permission from Springer Nature. Nature Reviews Drug Discovery (Emerging targets in neuroinflammation-driven chronic pain, Ru-Rong Ji et al.), ©2014. Figure 2. View largeDownload slide Chronic pain, which includes neuropathic pain induced by nerve injury and spinal cord injury, arthritis-induced inflammatory pain, cancer pain, and pain induced by drug treatment, results from neuroinflammation in the spinal cord. This neuroinflammation is triggered by activity-dependent release of glial activators (ie, neurotransmitters, chemokines, and proteases as well as WNT ligands) from the central terminals of primary afferent neurons and/or by disruption of the blood-brain barrier (BBB). Neuroinflammation is characterized by the activation of microglia and astrocytes, the infiltration of immune cells to the peripheral nervous system eg, the dorsal root ganglia [DRG]) and the central nervous system eg, the spinal cord), and the production of inflammatory and glial mediators such as pro-inflammatory cytokines and chemokines as well as growth factors and gliotransmitters ie, glutamate and ATP). These glial mediators can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Glial mediators can further act on glial and immune cells to facilitate neuroinflammation via autocrine and paracrine routes. Furthermore, neuroinflammation generates anti-inflammatory cytokines and pro-resolution lipid mediators (PRLMs) to normalize neuroinflammation, synaptic plasticity, and abnormal chronic pain. AMPAR = AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor; BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; CCL2 = CC-chemokine ligand 2; CX3CL1 = CX3C-chemokine ligand 1; CXCL1 = CXC-chemokine ligand 1; ERK = extracellular signal-regulated kinase; GABAR = GABA (γ-aminobutyric acid) receptor; GlyR = glycine receptor; IFNγ = interferon-γ; IL-1β = interleukin-1β; JNK = JUN N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP9 = matrix metalloproteinase 9; NMDAR = NMDA (N-methyl-D-aspartate) receptor; TGFβ = transforming growth factor-β; TNF = tumor necrosis factor; tPA = tissue-type plasminogen activator. Reprinted by permission from Springer Nature. Nature Reviews Drug Discovery (Emerging targets in neuroinflammation-driven chronic pain, Ru-Rong Ji et al.), ©2014. Studies have shown that there are elevated levels of pro-inflammatory cytokines such as IL-1RA, IL-6, and IL-8 in many of the CSS conditions such as fibromyalgia and irritable bowel disease (27, 28). Peripheral pro-inflammatory cytokines can lead to elevated levels within the CNS as noted above. Activation of spinal cord glial cells with release of pro-inflammatory molecules, such as IL-1β, can modulate the pain response at the level of the spinal cord (8, 29). In support of this theory, inhibition of spinal cord glial cells and blockage of IL-1R in the spinal cord have been associated with decreased pain (8). Additionally, intrathecal administration of IL-10, an anti-inflammatory cytokine, was successful in attenuating neuropathic pain (30). Thus, peripheral cytokines induce changes in central cytokines that can then modulate the pain pathway. Cancers often develop within an inflammatory milieu. This same environment may lead to increased pain. In a rat model of tongue cancer, squamous cell carcinoma-inoculated rats had increased background activity and mechanically evoked responses compared with sham-inoculated mice. Presentation and Symptoms Central pain is characterized by widespread pain in the muscles and joints with no identifiable nociceptive cause. It is considered a chronic condition; thus, pain must be present for at least 3 months. Central pain is usually a component of a symptom complex that includes fatigue, neurocognitive changes, and waking unrefreshed. Widespread pain in HNC patients has been reported in up to 50% of patients (31, 32). Altered Neurocognitive Function Although a long-accepted risk and consequence of CNS neoplasms and treatment, the development of neurocognitive deficits in survivors of non-CNS malignancies garnered attention in the 1980s and 1990s. Early cross-sectional studies uncovered a minority of survivors whose neurocognitive function, as measured by directed neurocognitive testing, was below that of normative control subjects (33). Initially, neurocognitive abnormalities were attributed to the effects of chemotherapy. However, it was subsequently uncovered that a substantial proportion of patients present with measurable neurocognitive deficits at diagnosis, thus highlighting the potential impact of cancer itself on neurocognitive function (34, 35). The proposed pathobiology of these neurocognitive changes has evolved since this phenomenon was first recognized. Although the etiology of neurocognitive disorders in cancer patients is multifactorial, the cytokine-mediated model of neurocognitive impairment has garnered a great deal of traction. As previously outlined, numerous malignancies are associated with elevated levels of pro-inflammatory cytokines before, during, and after treatment (36). Experimental conditions stimulating pro-inflammatory cytokine production in both humans and animals, namely administration of endotoxin, result in the development of sickness behaviors similar to those experienced by cancer patients, including neurocognitive dysfunction (37–39). Animal data demonstrate that pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α exert multiple physiologic functions in the CNS and that these functions vary in part according to the presence or absence of concomitant physiologic stress (10, 40). Specifically, IL-1β, IL-6, and TNF-α have all been shown to exert both neuroprotective and neurodegenerative effects (40). In addition, each seems to facilitate synaptic plasticity at physiological levels and inhibit it at elevated levels. In the oncology population, prospective studies assessing neurocognitive function have revealed that memory, particularly verbal memory, is the most commonly affected neurocognitive domain (39, 41–44). This is particularly relevant because recent studies employing neuroimaging in conjunction with neurocognitive testing have demonstrated aberrations in hippocampal volume and memory in cancer patients (42). These findings align with the current understanding of the structures and processes involved with memory consolidation. Specifically, neuroimaging studies have supported the widely held belief that hippocampal activation is key to memory consolidation (45, 46). Initial studies of neurocognitive function in patients with HNC examined the late effects of RT in patients with nasopharyngeal cancer (NPC) and base of skull tumors (47–50), diseases for which RT frequently results in incidental irradiation of heathy brain tissue. Lee et al. found that patients with NPC (n = 19) treated with RT had significantly lower neurocognitive scores compared with untreated patients with newly diagnosed NPC (n = 21) (47). Hua et al. examined neurocognitive function in 27 patients with NPC who had received RT a median of 1.7 years (range: 7 days to 9 years) earlier (48). Compared with untreated NPC patients (n = 28) and normal adult control subjects (n = 35), patients who received RT had impairments in multiple neurocognitive domains, including auditory attention/concentration, immediate and delayed verbal recall, immediate visual recall, recent memory, visuospatial abilities, and bimanual dexterity. Meyers et al. found that 80% of patients who received paranasal sinus irradiation at least 20 months and up to 20 years (M = 73.4 months) previously had memory impairments and 33% had impairments in visual motor speed, executive function, and fine motor coordination (50). Lam et al. studied neurocognitive function in patients with NPC who had been treated with RT (n = 60) more than 2 years earlier (49). Forty patients had radiographic evidence of temporal lobe injury (TLI). Compared with healthy control subjects (n = 19), patients with and without TLI performed worse on most memory tests. Patients with TLI did not differ significantly from those without TLI. Two studies have also examined the effect of intensity-modulated radiation therapy (IMRT) on neurocognitive function. Hsiao et al. conducted a prospective longitudinal study in 30 patients with NPC. Patients were assessed 1 day before starting RT and at least 12 months after completing RT (51). Posttreatment, 76.7% of patients had significantly lower scores on neurocognitive tests compared with pretreatment scores. Gan et al. examined neurocognitive function in 10 patients with non-NPC head and neck tumors on average 20 months posttreatment (range: 9–41 months) (52). Five patients had been treated with IMRT alone and five received cisplatin concurrently with IMRT. All but one demonstrated impairment in neurocognitive function with memory being most severely affected. To date, studies suggest that a subset of HNC survivors exhibit posttreatment impairments in neurocognitive function. However, these studies have significant methodological limitations. Most included small samples, used retrospective and cross-sectional designs, had widely varying posttreatment assessment timeframes, and did not account for potential confounders. Additionally, the studies do not address the vast majority of HNC patients (including those with tumors of the oral cavity, oropharynx, and larynx) that do not receive incidental direct radiation to the brain. Furthermore, treatments in the studies do not reflect current treatment regimens for HNC. To address these limitations, Bond et al. conducted a prospective study of neurocognitive function in 70 patients with HNC patients undergoing primary or adjuvant chemoradiation therapy. He found that 47% of patients exhibited pretreatment neurocognitive impairment based on global deficit score. Varying degrees of impairment were noted in the following neurocognitive domains: verbal learning (35.7%), executive function (31.8%), verbal memory (30.3%), processing speed (27.1%), verbal fluency (24.3%), and attention/concentration (23.0%) (41). During treatment, 9% of patients experienced syndromal delirium as documented on clinical exam (53). In addition, 31% of patients and 43.5% of caregivers reported symptoms of delirium. Three months posttreatment, 21.8% of patients demonstrated a decline in neurocognitive function in at least one tested domain. Of note, 13% had a decline in language function. Although commonly studied in the dementia population, neuropsychiatric symptoms have garnered less attention in the oncologic population. In one report, 23 caregivers reported their observation of neuropsychiatric symptoms in HNC patients undergoing treatment as well as its emotional impact. Neuropsychiatric symptoms were reported to be common, severe, and potentially impactful. Symptoms such as altered nighttime behaviors (82.6%) and irritability/lability (52.5%) caused substantial caregiver distress. Decreased alertness (69.6%), apathy or lack of motivation (56.5%), and slowed behavior (43.5%) can affect treatment compliance and self-care capacity. Unfortunately, neuropsychiatric symptoms may persist long term. In a report of 100 HNC patients who completed therapy a minimum of 12 months before study entry, restlessness, lack of motivation, distractibility, irritability, and slowed movement were common (31). Chronic Fatigue The sensation of fatigue is a physiological indicator of disease that signals the body to conserve resources by resting. Similar to other systemic symptoms, fatigue is associated with decreased quality of life and shortened overall survival (54). Fatigue may be categorized as peripheral or central. Peripheral fatigue relates to a sense of physical exhaustion and is often related to decreased energy and muscle fatigue, and central fatigue relates to central processes that direct the thoughts and behaviors associated with fatigue including lack of motivation (55). The diagnosis of chronic fatigue (CF) and associated syndromes remains a topic of debate, and diagnostic criteria continue to evolve as our knowledge base broadens. Currently, several distinct but clinically overlapping syndromes have been postulated: CF, chronic fatigue syndrome (CFS), and myalgic encephalomyelitis (ME). Maes et al. underscored the distinct nature of these symptoms by applying Fukuda’s criteria to a cohort of 144 patients with fatigue; results of the study demonstrated that CF, CFS, and ME were distinct clinical syndromes with distinct biomarkers (56). Unlike CF, both CFS and ME are inflammatory in etiology and associated with symptoms such as neurocognitive impairment, sleep disturbance, and weakness. In addition, ME is associated with postexertional malaise, a defining characteristic of this syndrome. Factor analysis demonstrated two distinct subsets of patients with postexertional malaise: malaise illness (fatigue-neurocognitive-depression) or malaise-hyperalgesia (fatigue-pain) (56). As data accumulate, the complexity of fatigue unfolds. Many of our currently available self-report measures are too blunt to characterize these distinct syndromes and subsyndromes. However, it is becoming evident that defining the subsets of patients is critical. For example, using a hierarchical cluster analysis, patients with CFS could be divided into four distinct clusters, once again underscoring the heterogeneity of the population and the need to clearly define subsets of patients. Conflicting results from fatigue studies may be in part related to the failure to distinguishing biologically and clinically distinct sub-populations within studies. It has been argued that objective tests may be useful and more reliable (57). For example, loss of energy or weakness can be assessed by cardiopulmonary exercise test, muscle weakness can be evaluated by testing muscle power and endurance test, and sleep disturbance can be tested by polysomnographic investigations. The degree to which work in CFS and ME is applicable to the oncological population is unknown. Nonetheless, results from these studies provide a cautionary note for investigators. To generate meaningful results, thoughtful consideration of eligibility requirements and a clearly defined study population is critical. Over time, it has been recognized that fatigue is the result of a complex network of biological processes including the following. Peripheral pro-inflammatory cytokines modulate central inflammatory mediators, which in turn affect the function of neural tissue including astrocytes and oligodendrocytes (Figure 3). Inflammation results in oxidative and nitrosative stress, which in turn may result in mitochondrial dysfunction (58). This is supported by the fact that fatigue is a hallmark of mitochondrial diseases (59). This is further underscored by data demonstrating that both oxidative stress and mitochondrial dysfunction have been demonstrated in patients with CFS (58). Autonomic dysfunction, as characterized by increased sympathetic and decreased parasympathetic activation, is seen in CFS and other central sensitivity syndromes. A central autonomic network is responsible for control of the sympathoexcitatory response. Patients with CFS demonstrate decreased grey matter volume in the prefrontal cortex, which is a critical component of the autonomic regulatory network. Sleep disturbance, with longer bedtime sleep and decreased sleep efficiency, has been described in patients with CFS. Alterations in circadian patterns and biological clock modulation have been reported in association with fatigue. Figure 3. View largeDownload slide Peripheral and central mechanisms of inflammation-associated central fatigue. Systemic inflammation, which can be caused by several factors, involves both innate immune cells and T lymphocytes. The proinflammatory cytokines that are produced de novo by these cells affect the bioavailability of amino acid precursors of neurotransmitters. Specifically, peripheral proinflammatory cytokines activate GTP cyclohydrolase 1 (GTP-CH1), which mediates synthesis of neopterin by macrophages. This results in a relative deficit in tetrahydrobiopterin (BH4), an essential cofactor of aromatic amino acid hydroxylase enzymes used in the synthesis of dopamine, norepinephrine, and serotonin. BH4 is also a cofactor for the synthesis of nitric oxide by inducible nitric oxide synthase. Proinflammatory cytokines also activate indoleamine 2, 3-dioxygenase (IDO) in macrophages and dendritic cells, which degrades tryptophan (TRP) along the kynurenine (KYN) pathway. KYN competes with TRP for entry into the brain. KYN is further metabolized by activated microglia into 3-hydroxy KYN and quinolinic acid, which are both potent radical donors. Quinolinic acid acts also as an agonist of N-methyl-D-aspartate (NMDA) receptors and promotes neurotoxicity. The conversion of KYN into kynurenic acid, which acts as an antagonist of NMDA receptors, occurs in astrocytes. However, in conditions of inflammation, this potentially neuroprotective pathway is less effective than the pathway leading to quinolinic acid. Peripheral inflammatory mediators activate immune-to-brain communication pathways, including afferent nerves. This leads to the local synthesis of inflammatory mediators that affect neuronal function and structure directly or via impairment of the neuronal environment, reduction of the synthesis of neurotrophic factors, and oxidative stress. These effects are rarely sufficient to cause neurotoxicity, but they can easily potentiate the neurotoxic activity of several other factors. Activation of the pituitary-adrenal axis by proinflammatory cytokines under the combined effect of corticotrophin-releasing hormone and vasopressin (not shown in the figure) should normally contribute to downregulation of the inflammatory response both at the periphery and in the central nervous system via the production of cortisol and the anti-inflammatory properties of vasopressin. However, this effect can be compromised by the development of cortisol resistance during inflammation. Adverse behavioral responses are the ultimate consequence of activation of these pathways. Red arrows signify the direction of change in a specific inflammatory mediator, enzyme, or molecule following systemic inflammation; processes at similar levels (eg, both peripheral and central causes of inflammation) are highlighted with a common color. Reprinted from Trends in Neurosciences, Vol. 37, issue 1, Robert Danzer et al., The neuroimmune basis of fatigue, pages 39–46, Copyright 2014, with permission from Elsevier. Figure 3. View largeDownload slide Peripheral and central mechanisms of inflammation-associated central fatigue. Systemic inflammation, which can be caused by several factors, involves both innate immune cells and T lymphocytes. The proinflammatory cytokines that are produced de novo by these cells affect the bioavailability of amino acid precursors of neurotransmitters. Specifically, peripheral proinflammatory cytokines activate GTP cyclohydrolase 1 (GTP-CH1), which mediates synthesis of neopterin by macrophages. This results in a relative deficit in tetrahydrobiopterin (BH4), an essential cofactor of aromatic amino acid hydroxylase enzymes used in the synthesis of dopamine, norepinephrine, and serotonin. BH4 is also a cofactor for the synthesis of nitric oxide by inducible nitric oxide synthase. Proinflammatory cytokines also activate indoleamine 2, 3-dioxygenase (IDO) in macrophages and dendritic cells, which degrades tryptophan (TRP) along the kynurenine (KYN) pathway. KYN competes with TRP for entry into the brain. KYN is further metabolized by activated microglia into 3-hydroxy KYN and quinolinic acid, which are both potent radical donors. Quinolinic acid acts also as an agonist of N-methyl-D-aspartate (NMDA) receptors and promotes neurotoxicity. The conversion of KYN into kynurenic acid, which acts as an antagonist of NMDA receptors, occurs in astrocytes. However, in conditions of inflammation, this potentially neuroprotective pathway is less effective than the pathway leading to quinolinic acid. Peripheral inflammatory mediators activate immune-to-brain communication pathways, including afferent nerves. This leads to the local synthesis of inflammatory mediators that affect neuronal function and structure directly or via impairment of the neuronal environment, reduction of the synthesis of neurotrophic factors, and oxidative stress. These effects are rarely sufficient to cause neurotoxicity, but they can easily potentiate the neurotoxic activity of several other factors. Activation of the pituitary-adrenal axis by proinflammatory cytokines under the combined effect of corticotrophin-releasing hormone and vasopressin (not shown in the figure) should normally contribute to downregulation of the inflammatory response both at the periphery and in the central nervous system via the production of cortisol and the anti-inflammatory properties of vasopressin. However, this effect can be compromised by the development of cortisol resistance during inflammation. Adverse behavioral responses are the ultimate consequence of activation of these pathways. Red arrows signify the direction of change in a specific inflammatory mediator, enzyme, or molecule following systemic inflammation; processes at similar levels (eg, both peripheral and central causes of inflammation) are highlighted with a common color. Reprinted from Trends in Neurosciences, Vol. 37, issue 1, Robert Danzer et al., The neuroimmune basis of fatigue, pages 39–46, Copyright 2014, with permission from Elsevier. Clinically, fatigue is one of the most pervasive symptoms experienced by HNC patients across the trajectory of treatment, recovery, and survivorship. Although fatigue is common in patients postoperatively and when undergoing chemotherapy, RT-associated fatigue has garnered particular attention due to its severity, duration, and impact (60). RT to the head and neck region induces a robust pan-tissue inflammatory reaction that is manifested by mucositis, soft tissue swelling due to acute edema, and dermatitis. In a prospective study of 46 HNC patients undergoing RT, there were correlations between self-reported fatigue and levels of both IL-6 and CRP, with increasing fatigue positively associated with increasing levels of IL-6 and CRP (61). Because inflammatory mediators contribute to fatigue, it may be hypothesized that there should be a correlation between severity of fatigue and severity of treatment-related toxicities involving the mucosa, soft tissues, and skin. This hypothesis is supported by data from a retrospective review of 684 patients treated on RTOG 0129, which demonstrated that fatigue clustered with dermatitis, mucositis, dysphagia (surrogate for edema), and pain (62). Predictors for higher levels of fatigue in HNC patients include younger age, history of RT, fewer months since cancer diagnosis, and depression. Fatigue interference, a measure of the degree to which fatigue affects daily activity, is associated with younger age and depression (63). The incidence of CF in HNC survivors is high. In one report, 52% of patients more than 1 year posttreatment reported unexplained fatigue and 50% reported fatigue that limited activity (31). Qualitative data from the same study indicated that CF results in disability, decreased general function, and decreased quality of life. Patients continued to complain of fatigue for years after therapy had been completed. It is important to note that although investigators have made considerable advances unraveling the inciting events of acute fatigue, the processes that maintain and potentiate a state of CF remain obscure. Mood Disorders HNC patients are at high risk for developing mood disorders such as depression and anxiety. Depression is common in HNC patients across the cancer trajectory. In a recent systematic review, the prevalence of depression ranged from 13% to 40% at diagnosis, to 25% to 54% during treatment, and 11% to 45% at 6 months posttreatment (64). Depression and Cytokines Derangements in catecholamines (eg, serotonin and norepinephrine) have historically been accepted as central to the pathogenesis of depression, directing the pharmacological development and use of anti-depressants. However, alternative theories suggest that immune dysregulation and pro-inflammatory cytokines are involved in the pathogenesis of depression (65). First, many studies have shown significant elevations in pro-inflammatory cytokines such as IL-6 (66–71), TNF-α (71–74), IL-1β (70–72, 75, 76), and IFN-γ in patients with depression (70, 71). Second, in a recent meta-analysis, patients with major depression had significant elevations of TNF-α and IL-6 compared with nondepressed control subjects (77). Finally, depression can precede the diagnosis of cancer, suggesting that the pretreatment pro-inflammatory state may contribute to the increased prevalence of mood disorders (78). Additional neurohumoral mechanisms that may serve in the pathogenesis of depression include the complex interaction between inflammatory cytokines and their effects on brain monoamines, the glutamate system, and the brain-derived neurotropic factor neurotransmitter (65). Depression and Genetic Predisposition There is an increasing understanding in the role of genetics in the development of depression and its response to treatment. Of particular interest are polymorphisms in the 5-HTTLPR-serotonin transport gene. One study by Caspi et al. found that individuals who had the short, or “S,” allele had higher rates of depression and depressive symptoms in relation to stressful life events (79), such as a cancer diagnosis. Other studies have shown that the acquisition of the S allele is strongly associated with alcohol (80) and nicotine (81) dependence, both of which are synergistic risk factors for the development of HNC. Furthermore, one study found a significantly higher incidence of the S allele in HNC patients with depression vs HNC patients without depression (85.7% vs 68.4%, P < .04) (82). Studies have also shown that polymorphisms in 5-HTTLPR, serotonin receptor 2 A, and tryptophan hydroxylase 1 may also play a role in therapeutic response to anti-depressant therapy (83, 84). For example, the presence of the long, or “L,” allele in 5-HTTLPR appears to be protective in that it has been found to be associated with better treatment efficacy (85, 86) and reduced rates of adverse drug reactions (84). Taken together, these data suggest that 5-HTTLPR polymorphisms may contribute to the increased risk of depression in patients with HNC and also affect their response to therapy. Temperature Dysregulation Vasomotor symptoms are commonly acknowledged sequelae of cancer treatment, particularly in patients receiving endocrine therapy for hormonally driven cancers. However, survivors across multiple tumor types describe a related, although seemingly distinct, experience of thermal discomfort while under ambient temperature conditions. Unlike true vasomotor episodes, which are acute events, these are often described as protracted interludes where the sufferer feels uncomfortably hot or cold. Some authors have described this as “thermal discomfort,” and although there is a paucity of data on this subject in the medical literature, this is a prominent chronic symptom described among networks of cancer survivors, including breast and testicular cancer (87, 88). Patients with hot thermal discomfort may be clinically managed with agents targeting vasomotor symptoms, although the efficacy is unknown. Patients who experience primarily cold thermal discomfort typically go untreated (87). As with the breast and testicular cancer populations, this phenomenon has been anecdotally noted in the HNC population during and after treatment with chemoradiation. In a recent report, 54% of head and neck patients report unexplained cold, 38% unexplained warmth, and 20% report sweating episodes (31). Qualitative data revealed that temperature discomfort could substantially affect activities and function for patients. Thus, further investigations are needed to determine the frequency, severity, and impact of thermal discomfort in HNC cancer survivors. Several theories have been proposed regarding the mechanisms at play in this phenomenon. Endothelin-1, a vasoactive peptide, is an established growth factor for multiple malignancies, including breast, ovarian, colorectal, and prostate cancers. In addition to its role as a growth factor, endothelin-1 has been shown to induce thermal hyperalgesia in humans (89). Therefore, alterations in endothelin-1 signaling could play a role in thermal discomfort in cancer patients (87). It has also been noted that many of the same pro-inflammatory cytokines noted to be elevated in malignant states, including IL-1, IL-6, and TNF-α, are those known to have a role in thermoregulation as well as sickness behavior. It has therefore been proposed that cancer and treatment-associated systemic inflammation as propagated by the aforementioned pro-inflammatory cytokines may result in central changes to thermoregulatory mechanisms manifesting as thermal discomfort (87). Investigation into the biological underpinnings of temperature dysregulation is needed. Metabolic Alterations: Cachexia and Sarcopenia Cachexia Cachexia is a pervasive paraneoplastic syndrome manifested primarily by unintentional weight loss. It is seen in many malignancies including HNC, upper gastrointestinal, lung, and prostate cancers (90). Cancer cachexia is a unique entity and can be differentiated from other causes of weight loss such as anorexia or starvation (91). In cachexia, skeletal muscle loss is out of proportion to fat loss, whereas starvation produces primarily fat loss followed by muscle loss in late stages (92). In addition to muscle wasting and weight loss, the overarching cachexia syndrome includes a cluster of symptoms, including fatigue, anemia, neurocognitive deficits, mood disorders, and others. Although classically described in end-stage disease, data have demonstrated widespread development of cachexia early in the course of cancer, with a portion of patients experiencing loss of weight and muscle mass before diagnosis (93). HNC patients commonly experience profound weight loss. This has traditionally been attributed to decreased oral intake secondary to cancer-related obstruction and treatment-related toxicity. However, accumulating data support the contributory role of cachexia in this population. In a recent metanalysis, where cachexia was defined as a weight loss of greater than 5% in less than 12 months with three of five additional cachexia criteria (decreased muscle strength, fatigue, anorexia, low fat-free mass or abnormal labs such as increased CRP, anemia or decreased albumin), 20.2% of patients at diagnosis and 32.2% of patients at time of treatment initiation met the criteria for cachexia (94). In a small prospective study, cachexia (42%) and pre-cachexia (15%) were noted in pretreated HNC patients (95). Thus, tumor-associated cachexia contributes substantially to weight loss in the HNC population. In addition, treatment with RT is associated with profound weight loss. Although this may be due in part to inadequate caloric intake, a prospective trial conducted in patients undergoing chemoradiation demonstrated that treatment-associated weight was largely composed of fat-free mass (96). This supports the hypothesis that radiation-induced soft tissue inflammation may cause or exacerbate the metabolic abnormalities associated with cachexia. Sarcopenia Sarcopenia is defined as a depletion of skeletal muscle mass. Some apply this terminology exclusively to muscle mass loss due to normal aging (97). Others use the term to describe skeletal muscle depletion of any cause. The recent use of CT and MRI imaging techniques to assess body composition have provided a unique opportunity to evaluate the role of lean body mass and fat mass on disease outcome (98). Studies in the lung and colon cancer population demonstrate pretreatment sarcopenia is associated with poorer outcomes even in the obese patient population (99). A similar study conducted in the HNC patient population evaluated 175 patients who underwent pre- and posttreatment PET or CT scans. Using CT images at L3 to derive a skeletal muscle index, investigators determined the impact of pre- and posttreatment sarcopenia on survival (100). Sarcopenia was present in 65 patients (37.1%) before radiation and developed in an additional 42.7% of patient’s postradiation for a posttreatment total of 79.7%. For patients receiving postoperative RT, pretreatment sarcopenia did not predict outcome. For patients receiving primary RT who had preradiation sarcopenia, there was a significant decrease in local disease control, disease-specific survival, and overall survival. All patients who developed sarcopenia during RT demonstrated significant decrease in local disease control, disease-specific survival, and overall survival. Similarly, results were reported in a retrospective analysis of 190 HNC patients treated with curative intent RT (101). Skeletal muscle depletion was found in 35% of patients before and 65.8% at the completion of treatment. Both pre- and posttreatment skeletal muscle depletion was associated with decreased overall survival. Weight loss without skeletal muscle depletion did not correlate with survival. Cisplatin, a commonly used chemotherapy agent for treatment of HNC, has been shown to induce loss of muscle mass that may persist after discontinuation of drug. In 26 bladder cancer patients treated with platinum-based induction chemotherapy, there was a significant decrease in skeletal muscle index (49.1 vs 44.5 cm2/m2, P > .001) and increase in sarcopenia (69% vs 81%, P = .02) between pre- and posttreatment measures. In mouse models, this has been shown to be at least in part related to induction of nuclear factor-kappa B (NF-kB) activity (102). Catabolism and Anabolism Clearly, it is critical to understand the impact of cancer, cancer therapy, and nutritional support on the metabolic processes that govern muscle and metabolism. Several lines of research are ongoing to try to understand the mechanism of sarcopenia in the oncologic population. When considering skeletal muscle metabolism in the larger context of cachexia, it can be instructive to consider this as two interdependent pathways: muscle anabolism and muscle catabolism. As previously established, HNC and its treatment are associated with significant elevations in pro-inflammatory cytokines, a cytokine profile notably similar to that association with cachexia (103). The current literature indicates that inflammation promotes skeletal muscle catabolism while simultaneously inhibiting anabolism (104–107). The inhibition of anabolism is believed to occur due to decreases in testosterone, insulin-like growth factor 1, and other anabolic factors (105). Insulin-like growth factor 1 is an anabolic factor that stimulates skeletal muscle protein synthesis and may also inhibit proteolysis by the ubiquitin-proteasome system (UPS) (108, 109). Muscle wasting in cancer cachexia likely has an even larger contribution from increased catabolism than it does from depressed anabolism. Muscle homeostasis includes at least four central proteolytic pathways—autophagy (ie, lysosome-endosome), calcium dependent, caspase dependent, and UPS dependent—but it is the UPS that appears to be primarily responsible for degradation of skeletal muscle (105). Multiple laboratory models of cancer cachexia, including Lewis lung carcinoma, colon 26, and AH-130, have demonstrated upregulation of atrogin-1 and MuRF-1, positive regulators of the UPS (110–112). There is also evidence that mediators of inflammation upregulate UPS degradation of skeletal muscle. TNF-α signaling has also been shown to regulate expression of MuRF-1, an E3 ubiquitin ligase and trigger of ubiquitination (105). Symptom Clustering: Additive or Synergistic Impact on Quality of Life and Functionality Thus far we have primarily described individual systemic symptoms. As previously discussed, systemic symptoms share common underlying biologic mechanisms, resulting in the concurrent development and/or persistence of multiple symptoms simultaneously (Figure 4). Thus, the concept of symptom clusters has arisen and remained an area of investigation in the general and oncologic populations. Symptom clustering was originally thought to represent a psychogenic process, but the literature refutes this claim. For example, neuroimaging studies confirm sensory augmentation in nonmalignant CSS (113). Numerous syndromes have now been added to the list of CSS such as fibromyalgia, CFS, and irritable bowel syndrome. Cancer and cancer treatments result in symptom complexes that mirror those seen in CSS. More formal and systematic comparison of cancer-related systemic symptoms with known CSS is warranted. By understanding the similarities and differences between cancer-associated systemic symptoms and established CSS, we can direct research efforts in the oncology realm more efficiently and effectively. Figure 4. View largeDownload slide Symptom complexes: shared biology with variable manifestations. GI = gastrointestinal. Figure 4. View largeDownload slide Symptom complexes: shared biology with variable manifestations. GI = gastrointestinal. Within the HNC population, analyses have been conducted in attempts to define general symptom clusters across the broad spectrum of symptoms and functional abnormalities experienced by patients (62). This can be further refined to specifically assess systemic symptoms clusters. Preclinical and clinical data regarding the frequency, severity, and cluster patterns of sickness symptoms in the head and neck patient population are limited. Nonetheless, existing data support the existence of systemic symptom clusters in this cohort. In one preclinical study, mice implanted with Human Papillomavirus (HPV)-positive cancer cell lines were observed for sickness behavior before and after chemoradiation (114). Tumor-bearing mice demonstrated decreased burrowing time, body weight, and nutrition intake. Both brain and liver inflammatory cytokine levels were elevated as well as alterations in mitochondrial function. In humans, there are few studies assessing chronic systemic symptom burden in HNC patients. In a recent report at ASCO, investigators reported the results of a cross-sectional study of symptom burden in 167 patients treated with either IMRT or 3-dimensional conformal RT (115). Patients were a median of 5.32 years posttreatment with over 70% of patients over 3 years. Eight patients were postoperative, and 99 received chemotherapy plus RT. The patients were administered the MDASI-HN and the Brief Fatigue Inventory. The results demonstrated that 11% of patients had fatigue that was “unusual,” 6% had fatigue at the time of completing the patient-reported outcome measures, 9% were experiencing their usual level of fatigue, and 10% were experiencing their worst level of fatigue. Fatigue did not correlate with patient, tumor, or treatment characteristics but did cluster with derangements in sleep, memory, level of consciousness, mood (upset or sad), and appetite. Thus, the results indicate that a small but clinically significant cohort of patients had a significant cluster of systemic symptoms. A cluster analysis of 95 HNC survivors demonstrated two unique groups: a low systemic symptom group and a high systemic symptom group. The most common systemic symptoms in the high symptom burden cohort were fatigue (79%), difficulty staying asleep (69%), cold (62.2%), problems with memory or concentration (45%), and joint/muscle pain (45%) (31). Patients with multiple systemic symptoms had decreased overall quality of life as well as decreased physical, emotional, and intellectual domains. It may also be hypothesized that systemic symptoms may interact in a synergistic manner at a biological and behavioral level. For example, patients with central fatigue may fail to comply with an exercise regimen to prevent muscle mass loss, or patients with memory loss may fail to comply with complex supportive care regimens. Further work is needed to understand the relationship between individual symptoms, how symptoms cluster, and the relative impact of distinct clusters in the HNC population. The Impact of HPV Status The epidemiology of HNC has changed dramatically over the past two decades with a dramatic rise in the number of HPV-associated oropharyngeal cancers. HPV-associated cancers decrease the acute inflammatory responses in the mucosal epithelium (116). The question arises as to whether this will affect the acute and chronic systemic symptoms experienced by patients. Unfortunately, most studies pay scant attention to acute and chronic symptoms. However, other outcome measures such as quality of life and general function may at least suggest the potential for adverse impact by systemic symptoms, thus providing direction for future research efforts. A study examined the most common initial symptoms in patients with HPV-positive (n = 71) and HPV-negative (n = 17) oropharyngeal cancer (117). It was found that patients with HPV-positive disease presented more commonly with a neck mass whereas HPV-negative patients often presented with sore throat, dysphagia, and/or odynophagia (all P < .05). There was no difference in weight loss (P = .09), fatigue (P = .99), or nonspecific pain (P = .32). A second study comparing 21 patients with HPV-associated oropharynx cancers vs 17 patients with smoking-associated oral cavity cancers demonstrated that patients with HPV-associated cancers experience lower symptom severity, depression, and cancer worry pretreatment than patients with non-HPV–associated tumors (118). Furthermore, depression decreased significantly over time in patients with HPV-associated cancers. In a prospective study of fatigue in 94 HNC patients undergoing RT, patients with HPV-associated tumors reported less pretreatment fatigue than patients with non-HPV–associated cancers (119). At 1 month post radiation, fatigue levels were significantly elevated in both groups and the difference in fatigue levels had disappeared. At 3 months posttreatment, fatigue levels continued to rise in the non-HPV–associated cancer and had dropped significantly in the HPV-associated tumors. Patients with non-HPV-associated tumors had higher levels of C-reactive protein (P < .001), sTNFR2 (P = .0369), and IL-6c (P = .021). These findings indicate that patients with HPV-associated cancers experience lower than average levels of fatigue and lower levels of circulating inflammatory proteins than those with non-HPV–associated tumors. To understand the potential molecular mechanism of underlying these differences in circulating inflammatory biomarkers, a study examined the activity of the NF-kB family of pro-inflammatory transcription factors and activity of the interferon regulatory factor family of antiviral transcription factors in patients with HPV-associated cancers (120). The study found that patients with HPV-associated tumors had lower activity of NF-kB (P = .005) and higher activity of interferon regulatory factor family factors (P = .017) relative to patients with non-HPV–associated cancers. These findings support lower levels of fatigue and inflammation in patients with HPV-associated cancers at pretreatment and the acute recovery phase. Data on long-term systemic symptoms are lacking. Conversely, a recent retrospective study examined the impact of HPV status on functional outcomes and quality of life after surgical treatment of oropharyngeal carcinoma with free-flap reconstruction (121). The study found that there was no statistically or clinically significant difference in speech, swallowing ability, swallowing safety, and quality of life outcomes between p16 positive and negative oropharyngeal cancer. These data imply that p16 status may not be predictive of functional outcomes or quality of life in surgically treated oropharyngeal cancer. However, once again, data on systemic symptoms was limited. Patients with HNC have a high rate of long-term disability due at least in part to the late effects of therapy, most notably fatigue. In a study of 129 patients with HPV-associated oropharynx cancer who were longer than 1 year post primary chemoradiation, 9% of patients stopped working permanently, 69% stopped working temporarily but were able to return to work, 19% continued to work through treatment with reduced work responsivities, and 3% continued to work. Median time to return to work was 14 weeks (122). Early randomized trials indicate that deintensification treatment strategies using lower doses of radiation, small radiation fields, or omission of concurrent chemotherapy may lead to decreased local toxicities (123). It is therefore reasonable to expect that deintensification strategies would result in a reduction of acute and chronic systemic symptoms. Directions for Future Research Research in central sensitivity syndromes such as CFS and FM is robust and can help inform future work evaluating systemic symptoms and sickness behavior in the Oncologic setting. Collaborative efforts that bridge the syndrome- and symptom-related silos should be developed and fostered. Basic research delineating the pathobiology of chronic systemic symptoms is essential. Of particular importance are statistical methods that allow use of large data sets to identify subpopulations of patients with common pathophysiologic underpinnings. Individual symptoms may be manifestations of numerous discrete clinical syndromes with distinct etiologies, pathobiology, and clinical courses. These syndromes need to be clearly defined and nomenclature must be standardized using clinical, laboratory, and imaging methods. Cross-study comparison of cytokine data is fraught with difficulty due to variability in important factors such as assay selection; time of day when the sample is collected; identification of co-morbid disease; patient characteristics such as age, sex, and BMI; and concomitant medications (such as antidepressants). Thus, standardization of methodologies may help limit variability and minimize confounding factors. Continued investigation of cytokine polymorphisms may help better our understanding of genetic influences on inflammatory processes and associated symptoms in the HNC population. Prospective, longitudinal studies are needed to understand the relationship between the physiologic stress, the host response, and systemic symptom development and evolution over time. This is important because clinical symptoms may not manifest until after the physiological insult, and by that time peripheral levels of inflammatory mediators may have returned to normal. Human studies largely measure peripheral cytokine levels, which may not reflect central cytokine levels. Continued efforts must be directed at the development of methods for noninvasive assessment of neuroinflammation. New strategies need to be developed to prevent and treat acute and chronic systemic symptoms. This should include both pharmacologic and nonpharmacologic strategies that decrease inflammation. Well-conducted clinical trials that test novel preventive and treatment strategies to ameliorate acute and chronic systemic symptoms must be conducted in the oncological population. Establishing a consensus on outcome measures as well as trial designs to promote harmonization across studies is needed to ensure successful development of a body of literature that can inform clinical practice. There is need to further evaluate the impact of chronic systemic symptoms on patients, caregivers, and treatment-related outcomes. HNC and its treatment are associated with profound systemic symptomatology. Although it is generally recognized that patients experience systemic symptoms due to the acute effects of therapy, chronic systemic symptomatology often goes unrecognized and underappreciated. Patients often feel that their systemic symptoms are both minimized and marginalized, leading to conflict with medical providers. Thus, the first step is to recognize and legitimize symptom complaints. When systemic symptom burden is recognized, pharmacological and nonpharmacological interventional strategies may be implemented. Unfortunately, for many chronic systemic symptoms, the therapeutic impact is often modest at best. Patients, caregivers, and providers who work diligently to identify and implement measures to improve symptoms and functionality may experience significant frustration and burnout. For caregivers and providers, burnout is a noteworthy problem when patients suffer from central fatigue and associated motivational impairment. Because patients are likely to suffer long term, emotional support for both the patient and their caregivers is critical to help them manage expectations. Finally, further study of the trajectory of systemic symptomatology, symptoms clustering, and underlying mechanisms is needed to identify potential therapeutic interventions designed to improve functionality and quality of life. Notes Affiliations of authors: Department of Medicine (BAM, EWB) and Division of Hematology-Oncology (EWB), Vanderbilt University Medical Center, Nashville, TN; Vanderbilt University School of Medicine, Nashville, TN (MG); William F. Connell School of Nursing, Boston College, Boston, MA (SMB); School of Nursing, University of Pennsylvania, Philadelphia PA (JD). The authors declare that they have no conflicts of interest. For support see Funding Acknowledgement section of Monograph. References 1 Dantzer R , Kelley KW. Twenty years of research in cytokine-induced sickness behavior . Brain Behav Immun . 2007 ; 21 2 : 153 – 160 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Yunus MB. 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Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Chronic Systemic Symptoms in Head and Neck Cancer Patients

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
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10.1093/jncimonographs/lgz004
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Abstract

Abstract The systemic effects and manifestations of disease and treatment have been of interest for millennium. Until recently, basic and clinical research is just now reaching a watershed. Systemic symptoms usually do not occur in isolation but rather in clusters; however, much of the cutting-edge research pertaining to the etiology, mechanism, manifestations, and moderators of systemic symptoms in humans has been directed at individual symptoms, thus creating silos of knowledge. Breaching these silos and bridging the knowledge from disparate arenas of investigation to build a comprehensive depiction of acute and chronic systemic symptoms has been a challenge. In addition, much of the recent work in systemic symptoms has been conducted in the setting of nonmalignant disease. The degree to which the findings from other chronic disease processes can be translated into the oncologic realm is unknown. This article will explore inflammation as a major contributing factor to systemic symptoms and sickness behavior, discuss the most common manifestations in cancer survivors, and, where available, discuss specific data pertaining to head and neck cancer survivors. Systemic Symptoms and Sickness Behavior Disease processes including cancer, infection, or clinically significant trauma evoke a stereotypic neurohumoral response intended to aid the body in its recovery (1). Activation of these same biological processes results in general symptoms as well as adaptive behaviors (2, 3). In the short run, this may be physiologically beneficial; however, in the long term these same processes may be maladaptive and harmful to the host. The systemic effects and manifestations of disease and treatment have been of interest for millennium; however, basic and clinical research are just now reaching a watershed. The taxonomy that governs this area of research has yet to be solidified and terminology continues to evolve as data become available. For the purposes of this review, we will use the terms “systemic symptoms” and “sickness behavior” to describe patient-reported symptoms and observable behavioral changes, respectively. Systemic symptoms frequently described in the oncologic population include weakness, fatigue, sleep disturbance, temperature dysregulation, pain, gastrointestinal symptoms such as nausea and vomiting, and neurocognitive dysfunction and mood disorders such as depression and anxiety. Adaptive sickness behaviors include hypersomnia, depressed activity, lethargy, and altered dietary intake. Additional systemic physiological effects of cancer and its treatment, such as cachexia and sarcopenia, although not usually considered under the sickness syndrome umbrella, will be incorporated into our discussion. Before discussing individual symptoms, several observations should be made. First, systemic symptoms usually do not occur in isolation but rather in clusters. This suggests a shared underlying pathophysiologic mechanism. The results of symptom clustering are a marked increase in overall symptom burden, a decline in functionality, and decrease in quality of life. Second, much of the cutting-edge research pertaining to the etiology, mechanism, manifestations, and moderators of systemic symptoms in humans has been directed at individual symptoms, thus creating silos of knowledge. Breaching these silos and bridging the knowledge from disparate arenas of investigation to build a comprehensive depiction of acute and chronic systemic symptoms has been a challenge. Third, much of the recent work in systemic symptoms has been conducted in the setting of nonmalignant disease. For example, much of our knowledge regarding central widespread pain was generated in patients with fibromyalgia. The degree to which the findings from other chronic disease processes can be translated into the oncologic realm is unknown. Fourth, although symptoms within a cluster may have overlapping etiologies and mechanisms, they are nonetheless distinct. Clearly defining the commonalities and distinctions may be helpful in unraveling this complex network. Fifth, as molecular technologies evolve, large volumes of data are generated. Computation methods must be developed that allow interpretation of these large data sets. Computational biology is a molecular systems biology approach to model a robust population of molecular data. It represents a powerful tool that will allow interpretation and understanding of complex biological processes. For instance, in molecularly complex processes such as oral mucositis, computational strategies to identity the critical molecular network hubs and downstream pathways involved in the pathogenesis must be utilized. Finally, it is likely that genetic variability influences the type of late effects experienced by any individual patient. Understanding these genetic influences may help inform methodology as well as our interpretation and understanding of study outcomes. The disease-associated neurohumoral response may be exacerbated by treatment, including surgery, radiation therapy (RT), and chemotherapy. This may lead to or escalate symptom burden (4). It would be hypothesized that after treatment has ceased and the tumor is eradicated that the neurohumoral effects would subside, symptoms would resolve, and normal functionality would return. It is, however, becoming increasingly recognized that adaptive physiologic responses may result in permanent biological changes, resulting in long-term systemic symptoms and behavioral changes (5). This creates a challenge for investigators, because the transience of these neurohumoral insults will impede investigators’ ability to capture important causal associations. Consequently, cross-sectional studies have significant limitations, so animal models and/or prospective trials may be needed. Unfortunately, long-term, prospective human studies in the oncologic population are challenging due to issues of cost and feasibility. In this article, we will explore inflammation as a major contributing factor to systemic symptoms and sickness behavior, discuss the most common manifestations in cancer survivors, and, where available, discuss specific data pertaining to head and neck cancer (HNC) survivors. Neurohumoral Communication and Neuroinflammation To coordinate the physiologic and behavioral responses to disease, the body has created a complex communication system (Figure 1) that includes the immune system, the endocrine system, and the central and peripheral nervous systems. These systems communicate through a shared signaling system of common molecules and receptors (6). The role of circulating inflammatory mediators on the development and maintenance of acute and chronic systemic symptoms has been an area of intense investigation over the past decade. Of particular interest is the critical interplay between inflammatory mediators and the central nervous system (CNS; neuroinflammation) (7). Although the endocrine system plays a critical physiological role in disease states, due to space limitations this topic will not be discussed. Figure 1. View largeDownload slide Sickness behavior symptoms. HPA = hippocampal pituitary axis; Interleukin-1β (IL-1b); IL-6 = Interleukin-6; NO = nitrogen oxide; ROS = reactive oxygen species; SNS = sympathetic nervous system; TNF-α = Tumor Necrosis Factor α. Carissa A. Low et al., “Neurocognitive Impairment as One Facet of Cancer-Related Sickness Behavior Symptoms.” Journal of the National Cancer Institute, 2015. volume 107, issue 8, pages 1–3. By permission of Oxford University Press. Figure 1. View largeDownload slide Sickness behavior symptoms. HPA = hippocampal pituitary axis; Interleukin-1β (IL-1b); IL-6 = Interleukin-6; NO = nitrogen oxide; ROS = reactive oxygen species; SNS = sympathetic nervous system; TNF-α = Tumor Necrosis Factor α. Carissa A. Low et al., “Neurocognitive Impairment as One Facet of Cancer-Related Sickness Behavior Symptoms.” Journal of the National Cancer Institute, 2015. volume 107, issue 8, pages 1–3. By permission of Oxford University Press. Peripheral pro-inflammatory cytokines (eg, Inteleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF)-α) produced by the host in response to cancer or cancer therapy can function as immune-to-CNS signaling molecules. Although they cannot passively cross the blood brain barriers, cytokines signal the CNS through a variety of mechanisms, including (1) active transport, (2) crossing at circumventricular organs, (3) binding to receptors in the cerebral blood vessels, and (4) through interaction with the vagus nerve (8). Once inflammatory mediators have entered the CNS, they activate microglia cells and astrocytes. These in turn cause production of central pro-inflammatory cytokines and other neurotoxins. Overall, this creates a neuroinflammatory milieu that may cause alterations in neural function. After prolonged exposure, neural pathways may be permanently altered, leading to aberrant signals. Thus, peripheral pro-inflammatory cytokines are capable of indirectly modulating cytokine levels in the CNS. An abundance of data demonstrate that peripheral and CNS cytokines induce symptoms classically described as sickness symptoms, including fatigue, widespread pain, temperature dysregulation, reduced appetite, and depression (9, 10). This is pertinent to the oncologic patient population because tumor and treatment are associated with elevation of peripheral pro-inflammatory cytokines. It may therefore be hypothesized that peripheral cytokines produced by cancer and its therapy may alter CNS cytokine levels, thereby inducing systemic symptoms. Although neuroinflammation is thought to be a critical mediator of systemic symptoms and sickness behavior, other mechanisms contribute as well and will be discussed briefly where pertinent (11). Inflammation and HNC Both HNC and its treatment have been associated with elevated levels of pro-inflammatory cytokines, putting patients at high risk for adverse systemic effects. Preclinical models with HNC cell lines demonstrate elevated levels of inflammatory mediators such as chemokines, cytokines, and growth factors that play a critical role in tumorigenesis, metastasis, and angiogenesis (12). Studies in the HNC population confirm the association between treatment (radiation and/or chemotherapy) and changes in the level of inflammatory mediators. In a study of 34 HNC patients who received RT, there was a statistically significant rise in TNF-α and IL-6 levels posttreatment (13) Studies also demonstrate a correlation between the serum concentration of inflammatory mediators and toxicity grade. For example, mucositis is one of the most visible and impactful inflammatory complications of radiation to the head and neck region. In a 58-patient prospective phase II study of chemoradiation, the severity of mucositis correlated with levels of TNF-α, IL-1, IL-6, and IL-13 (14). In a second, larger prospective study of lymphedema and fibrosis, the systemic levels of select proinflammatory cytokines correlated with the presence and severity of acute and chronic soft tissue toxicities (15). It should be noted that cytokine levels and/or trajectory have been associated with treatment outcome. In a prospective trial of 30 patients, both the pretreatment levels of and change over time in IL-6, IL-8, VEGF, HGF, and GRO-1 were associated with treatment response and overall survival (16). Common Systemic Symptoms in Cancer Pain Pain is a ubiquitous problem in the HNC population: up to 57% (95% confidence interval = 43% to 70%) of patients have tumor-related pain at the time of presentation, effectively all patients have treatment-related pain, and up to 42% (95% confidence interval = 33% to 50%) have chronic posttreatment pain (17). Acute tumor- and treatment-related pain has been well described and will not be further discussed. Long term, HNC survivors describe distinct pain syndromes including neck and shoulder pain due to musculoskeletal impairment, chronic oral mucosal sensitivity due to RT, and chemotherapy-associated peripheral neuropathy. In addition, a subset of HNC survivors develops widespread joint and muscle pain due to alterations in pain and sensory processing (18), a phenomenon commonly referred to as central pain. Historically, the term “central pain syndromes” referred to rare syndromes associated with discrete CNS pathology such as thalamic stroke. Currently, central pain refers to “immune-related pain syndromes.” Central Pain: Pathobiology Central pain results from changes in central processing due to persistent noxious stimuli. This results in central sensitization (CS), a well-recognized component of central sensitivity syndromes (CSS) such as fibromyalgia, irritable bowel disease, and temporomandibular joint disorder (19–21). Central sensitization is a state of CNS hyper-excitability that results in marked amplification of peripheral pain stimuli and decreased central pain inhibitory signals. The clinical manifestations include hyperalgesia, allodynia, expansion of receptive fields with widespread musculoskeletal pain, and exaggerated pain well after withdrawal of a painful stimulus (2, 20). Pro-inflammatory mediators (Figure 2), particularly cytokines, play a direct role in the development and maintenance of CS through their interaction with the peripheral nervous system and CNS (20, 22–24). After neural injury, pro-inflammatory cytokines are recruited to or secreted by immune cells near the site of injury and aid in axonal regeneration (25). However, in the setting of a chronic inflammatory process, long-term exposure to pro-inflammatory cytokines can be neurotoxic. Pro-inflammatory cytokines can disrupt the blood-nerve barrier near the site of the damaged peripheral nerve, resulting in recruitment of additional neutrophils and macrophages (26). Thus, cytokines directly alter neural excitability and demyelinate the axons leading to degeneration of peripheral nerves as well as development of neuropathic pain (26). During this period, the repetitive nociceptive input from the peripherally inflamed neural tissue can lead to neuroplastic changes in pain processing within the CNS, resulting in long-term CS. Figure 2. View largeDownload slide Chronic pain, which includes neuropathic pain induced by nerve injury and spinal cord injury, arthritis-induced inflammatory pain, cancer pain, and pain induced by drug treatment, results from neuroinflammation in the spinal cord. This neuroinflammation is triggered by activity-dependent release of glial activators (ie, neurotransmitters, chemokines, and proteases as well as WNT ligands) from the central terminals of primary afferent neurons and/or by disruption of the blood-brain barrier (BBB). Neuroinflammation is characterized by the activation of microglia and astrocytes, the infiltration of immune cells to the peripheral nervous system eg, the dorsal root ganglia [DRG]) and the central nervous system eg, the spinal cord), and the production of inflammatory and glial mediators such as pro-inflammatory cytokines and chemokines as well as growth factors and gliotransmitters ie, glutamate and ATP). These glial mediators can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Glial mediators can further act on glial and immune cells to facilitate neuroinflammation via autocrine and paracrine routes. Furthermore, neuroinflammation generates anti-inflammatory cytokines and pro-resolution lipid mediators (PRLMs) to normalize neuroinflammation, synaptic plasticity, and abnormal chronic pain. AMPAR = AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor; BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; CCL2 = CC-chemokine ligand 2; CX3CL1 = CX3C-chemokine ligand 1; CXCL1 = CXC-chemokine ligand 1; ERK = extracellular signal-regulated kinase; GABAR = GABA (γ-aminobutyric acid) receptor; GlyR = glycine receptor; IFNγ = interferon-γ; IL-1β = interleukin-1β; JNK = JUN N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP9 = matrix metalloproteinase 9; NMDAR = NMDA (N-methyl-D-aspartate) receptor; TGFβ = transforming growth factor-β; TNF = tumor necrosis factor; tPA = tissue-type plasminogen activator. Reprinted by permission from Springer Nature. Nature Reviews Drug Discovery (Emerging targets in neuroinflammation-driven chronic pain, Ru-Rong Ji et al.), ©2014. Figure 2. View largeDownload slide Chronic pain, which includes neuropathic pain induced by nerve injury and spinal cord injury, arthritis-induced inflammatory pain, cancer pain, and pain induced by drug treatment, results from neuroinflammation in the spinal cord. This neuroinflammation is triggered by activity-dependent release of glial activators (ie, neurotransmitters, chemokines, and proteases as well as WNT ligands) from the central terminals of primary afferent neurons and/or by disruption of the blood-brain barrier (BBB). Neuroinflammation is characterized by the activation of microglia and astrocytes, the infiltration of immune cells to the peripheral nervous system eg, the dorsal root ganglia [DRG]) and the central nervous system eg, the spinal cord), and the production of inflammatory and glial mediators such as pro-inflammatory cytokines and chemokines as well as growth factors and gliotransmitters ie, glutamate and ATP). These glial mediators can powerfully modulate excitatory and inhibitory synaptic transmission, leading to central sensitization and enhanced chronic pain states. Glial mediators can further act on glial and immune cells to facilitate neuroinflammation via autocrine and paracrine routes. Furthermore, neuroinflammation generates anti-inflammatory cytokines and pro-resolution lipid mediators (PRLMs) to normalize neuroinflammation, synaptic plasticity, and abnormal chronic pain. AMPAR = AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor; BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; CCL2 = CC-chemokine ligand 2; CX3CL1 = CX3C-chemokine ligand 1; CXCL1 = CXC-chemokine ligand 1; ERK = extracellular signal-regulated kinase; GABAR = GABA (γ-aminobutyric acid) receptor; GlyR = glycine receptor; IFNγ = interferon-γ; IL-1β = interleukin-1β; JNK = JUN N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP9 = matrix metalloproteinase 9; NMDAR = NMDA (N-methyl-D-aspartate) receptor; TGFβ = transforming growth factor-β; TNF = tumor necrosis factor; tPA = tissue-type plasminogen activator. Reprinted by permission from Springer Nature. Nature Reviews Drug Discovery (Emerging targets in neuroinflammation-driven chronic pain, Ru-Rong Ji et al.), ©2014. Studies have shown that there are elevated levels of pro-inflammatory cytokines such as IL-1RA, IL-6, and IL-8 in many of the CSS conditions such as fibromyalgia and irritable bowel disease (27, 28). Peripheral pro-inflammatory cytokines can lead to elevated levels within the CNS as noted above. Activation of spinal cord glial cells with release of pro-inflammatory molecules, such as IL-1β, can modulate the pain response at the level of the spinal cord (8, 29). In support of this theory, inhibition of spinal cord glial cells and blockage of IL-1R in the spinal cord have been associated with decreased pain (8). Additionally, intrathecal administration of IL-10, an anti-inflammatory cytokine, was successful in attenuating neuropathic pain (30). Thus, peripheral cytokines induce changes in central cytokines that can then modulate the pain pathway. Cancers often develop within an inflammatory milieu. This same environment may lead to increased pain. In a rat model of tongue cancer, squamous cell carcinoma-inoculated rats had increased background activity and mechanically evoked responses compared with sham-inoculated mice. Presentation and Symptoms Central pain is characterized by widespread pain in the muscles and joints with no identifiable nociceptive cause. It is considered a chronic condition; thus, pain must be present for at least 3 months. Central pain is usually a component of a symptom complex that includes fatigue, neurocognitive changes, and waking unrefreshed. Widespread pain in HNC patients has been reported in up to 50% of patients (31, 32). Altered Neurocognitive Function Although a long-accepted risk and consequence of CNS neoplasms and treatment, the development of neurocognitive deficits in survivors of non-CNS malignancies garnered attention in the 1980s and 1990s. Early cross-sectional studies uncovered a minority of survivors whose neurocognitive function, as measured by directed neurocognitive testing, was below that of normative control subjects (33). Initially, neurocognitive abnormalities were attributed to the effects of chemotherapy. However, it was subsequently uncovered that a substantial proportion of patients present with measurable neurocognitive deficits at diagnosis, thus highlighting the potential impact of cancer itself on neurocognitive function (34, 35). The proposed pathobiology of these neurocognitive changes has evolved since this phenomenon was first recognized. Although the etiology of neurocognitive disorders in cancer patients is multifactorial, the cytokine-mediated model of neurocognitive impairment has garnered a great deal of traction. As previously outlined, numerous malignancies are associated with elevated levels of pro-inflammatory cytokines before, during, and after treatment (36). Experimental conditions stimulating pro-inflammatory cytokine production in both humans and animals, namely administration of endotoxin, result in the development of sickness behaviors similar to those experienced by cancer patients, including neurocognitive dysfunction (37–39). Animal data demonstrate that pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α exert multiple physiologic functions in the CNS and that these functions vary in part according to the presence or absence of concomitant physiologic stress (10, 40). Specifically, IL-1β, IL-6, and TNF-α have all been shown to exert both neuroprotective and neurodegenerative effects (40). In addition, each seems to facilitate synaptic plasticity at physiological levels and inhibit it at elevated levels. In the oncology population, prospective studies assessing neurocognitive function have revealed that memory, particularly verbal memory, is the most commonly affected neurocognitive domain (39, 41–44). This is particularly relevant because recent studies employing neuroimaging in conjunction with neurocognitive testing have demonstrated aberrations in hippocampal volume and memory in cancer patients (42). These findings align with the current understanding of the structures and processes involved with memory consolidation. Specifically, neuroimaging studies have supported the widely held belief that hippocampal activation is key to memory consolidation (45, 46). Initial studies of neurocognitive function in patients with HNC examined the late effects of RT in patients with nasopharyngeal cancer (NPC) and base of skull tumors (47–50), diseases for which RT frequently results in incidental irradiation of heathy brain tissue. Lee et al. found that patients with NPC (n = 19) treated with RT had significantly lower neurocognitive scores compared with untreated patients with newly diagnosed NPC (n = 21) (47). Hua et al. examined neurocognitive function in 27 patients with NPC who had received RT a median of 1.7 years (range: 7 days to 9 years) earlier (48). Compared with untreated NPC patients (n = 28) and normal adult control subjects (n = 35), patients who received RT had impairments in multiple neurocognitive domains, including auditory attention/concentration, immediate and delayed verbal recall, immediate visual recall, recent memory, visuospatial abilities, and bimanual dexterity. Meyers et al. found that 80% of patients who received paranasal sinus irradiation at least 20 months and up to 20 years (M = 73.4 months) previously had memory impairments and 33% had impairments in visual motor speed, executive function, and fine motor coordination (50). Lam et al. studied neurocognitive function in patients with NPC who had been treated with RT (n = 60) more than 2 years earlier (49). Forty patients had radiographic evidence of temporal lobe injury (TLI). Compared with healthy control subjects (n = 19), patients with and without TLI performed worse on most memory tests. Patients with TLI did not differ significantly from those without TLI. Two studies have also examined the effect of intensity-modulated radiation therapy (IMRT) on neurocognitive function. Hsiao et al. conducted a prospective longitudinal study in 30 patients with NPC. Patients were assessed 1 day before starting RT and at least 12 months after completing RT (51). Posttreatment, 76.7% of patients had significantly lower scores on neurocognitive tests compared with pretreatment scores. Gan et al. examined neurocognitive function in 10 patients with non-NPC head and neck tumors on average 20 months posttreatment (range: 9–41 months) (52). Five patients had been treated with IMRT alone and five received cisplatin concurrently with IMRT. All but one demonstrated impairment in neurocognitive function with memory being most severely affected. To date, studies suggest that a subset of HNC survivors exhibit posttreatment impairments in neurocognitive function. However, these studies have significant methodological limitations. Most included small samples, used retrospective and cross-sectional designs, had widely varying posttreatment assessment timeframes, and did not account for potential confounders. Additionally, the studies do not address the vast majority of HNC patients (including those with tumors of the oral cavity, oropharynx, and larynx) that do not receive incidental direct radiation to the brain. Furthermore, treatments in the studies do not reflect current treatment regimens for HNC. To address these limitations, Bond et al. conducted a prospective study of neurocognitive function in 70 patients with HNC patients undergoing primary or adjuvant chemoradiation therapy. He found that 47% of patients exhibited pretreatment neurocognitive impairment based on global deficit score. Varying degrees of impairment were noted in the following neurocognitive domains: verbal learning (35.7%), executive function (31.8%), verbal memory (30.3%), processing speed (27.1%), verbal fluency (24.3%), and attention/concentration (23.0%) (41). During treatment, 9% of patients experienced syndromal delirium as documented on clinical exam (53). In addition, 31% of patients and 43.5% of caregivers reported symptoms of delirium. Three months posttreatment, 21.8% of patients demonstrated a decline in neurocognitive function in at least one tested domain. Of note, 13% had a decline in language function. Although commonly studied in the dementia population, neuropsychiatric symptoms have garnered less attention in the oncologic population. In one report, 23 caregivers reported their observation of neuropsychiatric symptoms in HNC patients undergoing treatment as well as its emotional impact. Neuropsychiatric symptoms were reported to be common, severe, and potentially impactful. Symptoms such as altered nighttime behaviors (82.6%) and irritability/lability (52.5%) caused substantial caregiver distress. Decreased alertness (69.6%), apathy or lack of motivation (56.5%), and slowed behavior (43.5%) can affect treatment compliance and self-care capacity. Unfortunately, neuropsychiatric symptoms may persist long term. In a report of 100 HNC patients who completed therapy a minimum of 12 months before study entry, restlessness, lack of motivation, distractibility, irritability, and slowed movement were common (31). Chronic Fatigue The sensation of fatigue is a physiological indicator of disease that signals the body to conserve resources by resting. Similar to other systemic symptoms, fatigue is associated with decreased quality of life and shortened overall survival (54). Fatigue may be categorized as peripheral or central. Peripheral fatigue relates to a sense of physical exhaustion and is often related to decreased energy and muscle fatigue, and central fatigue relates to central processes that direct the thoughts and behaviors associated with fatigue including lack of motivation (55). The diagnosis of chronic fatigue (CF) and associated syndromes remains a topic of debate, and diagnostic criteria continue to evolve as our knowledge base broadens. Currently, several distinct but clinically overlapping syndromes have been postulated: CF, chronic fatigue syndrome (CFS), and myalgic encephalomyelitis (ME). Maes et al. underscored the distinct nature of these symptoms by applying Fukuda’s criteria to a cohort of 144 patients with fatigue; results of the study demonstrated that CF, CFS, and ME were distinct clinical syndromes with distinct biomarkers (56). Unlike CF, both CFS and ME are inflammatory in etiology and associated with symptoms such as neurocognitive impairment, sleep disturbance, and weakness. In addition, ME is associated with postexertional malaise, a defining characteristic of this syndrome. Factor analysis demonstrated two distinct subsets of patients with postexertional malaise: malaise illness (fatigue-neurocognitive-depression) or malaise-hyperalgesia (fatigue-pain) (56). As data accumulate, the complexity of fatigue unfolds. Many of our currently available self-report measures are too blunt to characterize these distinct syndromes and subsyndromes. However, it is becoming evident that defining the subsets of patients is critical. For example, using a hierarchical cluster analysis, patients with CFS could be divided into four distinct clusters, once again underscoring the heterogeneity of the population and the need to clearly define subsets of patients. Conflicting results from fatigue studies may be in part related to the failure to distinguishing biologically and clinically distinct sub-populations within studies. It has been argued that objective tests may be useful and more reliable (57). For example, loss of energy or weakness can be assessed by cardiopulmonary exercise test, muscle weakness can be evaluated by testing muscle power and endurance test, and sleep disturbance can be tested by polysomnographic investigations. The degree to which work in CFS and ME is applicable to the oncological population is unknown. Nonetheless, results from these studies provide a cautionary note for investigators. To generate meaningful results, thoughtful consideration of eligibility requirements and a clearly defined study population is critical. Over time, it has been recognized that fatigue is the result of a complex network of biological processes including the following. Peripheral pro-inflammatory cytokines modulate central inflammatory mediators, which in turn affect the function of neural tissue including astrocytes and oligodendrocytes (Figure 3). Inflammation results in oxidative and nitrosative stress, which in turn may result in mitochondrial dysfunction (58). This is supported by the fact that fatigue is a hallmark of mitochondrial diseases (59). This is further underscored by data demonstrating that both oxidative stress and mitochondrial dysfunction have been demonstrated in patients with CFS (58). Autonomic dysfunction, as characterized by increased sympathetic and decreased parasympathetic activation, is seen in CFS and other central sensitivity syndromes. A central autonomic network is responsible for control of the sympathoexcitatory response. Patients with CFS demonstrate decreased grey matter volume in the prefrontal cortex, which is a critical component of the autonomic regulatory network. Sleep disturbance, with longer bedtime sleep and decreased sleep efficiency, has been described in patients with CFS. Alterations in circadian patterns and biological clock modulation have been reported in association with fatigue. Figure 3. View largeDownload slide Peripheral and central mechanisms of inflammation-associated central fatigue. Systemic inflammation, which can be caused by several factors, involves both innate immune cells and T lymphocytes. The proinflammatory cytokines that are produced de novo by these cells affect the bioavailability of amino acid precursors of neurotransmitters. Specifically, peripheral proinflammatory cytokines activate GTP cyclohydrolase 1 (GTP-CH1), which mediates synthesis of neopterin by macrophages. This results in a relative deficit in tetrahydrobiopterin (BH4), an essential cofactor of aromatic amino acid hydroxylase enzymes used in the synthesis of dopamine, norepinephrine, and serotonin. BH4 is also a cofactor for the synthesis of nitric oxide by inducible nitric oxide synthase. Proinflammatory cytokines also activate indoleamine 2, 3-dioxygenase (IDO) in macrophages and dendritic cells, which degrades tryptophan (TRP) along the kynurenine (KYN) pathway. KYN competes with TRP for entry into the brain. KYN is further metabolized by activated microglia into 3-hydroxy KYN and quinolinic acid, which are both potent radical donors. Quinolinic acid acts also as an agonist of N-methyl-D-aspartate (NMDA) receptors and promotes neurotoxicity. The conversion of KYN into kynurenic acid, which acts as an antagonist of NMDA receptors, occurs in astrocytes. However, in conditions of inflammation, this potentially neuroprotective pathway is less effective than the pathway leading to quinolinic acid. Peripheral inflammatory mediators activate immune-to-brain communication pathways, including afferent nerves. This leads to the local synthesis of inflammatory mediators that affect neuronal function and structure directly or via impairment of the neuronal environment, reduction of the synthesis of neurotrophic factors, and oxidative stress. These effects are rarely sufficient to cause neurotoxicity, but they can easily potentiate the neurotoxic activity of several other factors. Activation of the pituitary-adrenal axis by proinflammatory cytokines under the combined effect of corticotrophin-releasing hormone and vasopressin (not shown in the figure) should normally contribute to downregulation of the inflammatory response both at the periphery and in the central nervous system via the production of cortisol and the anti-inflammatory properties of vasopressin. However, this effect can be compromised by the development of cortisol resistance during inflammation. Adverse behavioral responses are the ultimate consequence of activation of these pathways. Red arrows signify the direction of change in a specific inflammatory mediator, enzyme, or molecule following systemic inflammation; processes at similar levels (eg, both peripheral and central causes of inflammation) are highlighted with a common color. Reprinted from Trends in Neurosciences, Vol. 37, issue 1, Robert Danzer et al., The neuroimmune basis of fatigue, pages 39–46, Copyright 2014, with permission from Elsevier. Figure 3. View largeDownload slide Peripheral and central mechanisms of inflammation-associated central fatigue. Systemic inflammation, which can be caused by several factors, involves both innate immune cells and T lymphocytes. The proinflammatory cytokines that are produced de novo by these cells affect the bioavailability of amino acid precursors of neurotransmitters. Specifically, peripheral proinflammatory cytokines activate GTP cyclohydrolase 1 (GTP-CH1), which mediates synthesis of neopterin by macrophages. This results in a relative deficit in tetrahydrobiopterin (BH4), an essential cofactor of aromatic amino acid hydroxylase enzymes used in the synthesis of dopamine, norepinephrine, and serotonin. BH4 is also a cofactor for the synthesis of nitric oxide by inducible nitric oxide synthase. Proinflammatory cytokines also activate indoleamine 2, 3-dioxygenase (IDO) in macrophages and dendritic cells, which degrades tryptophan (TRP) along the kynurenine (KYN) pathway. KYN competes with TRP for entry into the brain. KYN is further metabolized by activated microglia into 3-hydroxy KYN and quinolinic acid, which are both potent radical donors. Quinolinic acid acts also as an agonist of N-methyl-D-aspartate (NMDA) receptors and promotes neurotoxicity. The conversion of KYN into kynurenic acid, which acts as an antagonist of NMDA receptors, occurs in astrocytes. However, in conditions of inflammation, this potentially neuroprotective pathway is less effective than the pathway leading to quinolinic acid. Peripheral inflammatory mediators activate immune-to-brain communication pathways, including afferent nerves. This leads to the local synthesis of inflammatory mediators that affect neuronal function and structure directly or via impairment of the neuronal environment, reduction of the synthesis of neurotrophic factors, and oxidative stress. These effects are rarely sufficient to cause neurotoxicity, but they can easily potentiate the neurotoxic activity of several other factors. Activation of the pituitary-adrenal axis by proinflammatory cytokines under the combined effect of corticotrophin-releasing hormone and vasopressin (not shown in the figure) should normally contribute to downregulation of the inflammatory response both at the periphery and in the central nervous system via the production of cortisol and the anti-inflammatory properties of vasopressin. However, this effect can be compromised by the development of cortisol resistance during inflammation. Adverse behavioral responses are the ultimate consequence of activation of these pathways. Red arrows signify the direction of change in a specific inflammatory mediator, enzyme, or molecule following systemic inflammation; processes at similar levels (eg, both peripheral and central causes of inflammation) are highlighted with a common color. Reprinted from Trends in Neurosciences, Vol. 37, issue 1, Robert Danzer et al., The neuroimmune basis of fatigue, pages 39–46, Copyright 2014, with permission from Elsevier. Clinically, fatigue is one of the most pervasive symptoms experienced by HNC patients across the trajectory of treatment, recovery, and survivorship. Although fatigue is common in patients postoperatively and when undergoing chemotherapy, RT-associated fatigue has garnered particular attention due to its severity, duration, and impact (60). RT to the head and neck region induces a robust pan-tissue inflammatory reaction that is manifested by mucositis, soft tissue swelling due to acute edema, and dermatitis. In a prospective study of 46 HNC patients undergoing RT, there were correlations between self-reported fatigue and levels of both IL-6 and CRP, with increasing fatigue positively associated with increasing levels of IL-6 and CRP (61). Because inflammatory mediators contribute to fatigue, it may be hypothesized that there should be a correlation between severity of fatigue and severity of treatment-related toxicities involving the mucosa, soft tissues, and skin. This hypothesis is supported by data from a retrospective review of 684 patients treated on RTOG 0129, which demonstrated that fatigue clustered with dermatitis, mucositis, dysphagia (surrogate for edema), and pain (62). Predictors for higher levels of fatigue in HNC patients include younger age, history of RT, fewer months since cancer diagnosis, and depression. Fatigue interference, a measure of the degree to which fatigue affects daily activity, is associated with younger age and depression (63). The incidence of CF in HNC survivors is high. In one report, 52% of patients more than 1 year posttreatment reported unexplained fatigue and 50% reported fatigue that limited activity (31). Qualitative data from the same study indicated that CF results in disability, decreased general function, and decreased quality of life. Patients continued to complain of fatigue for years after therapy had been completed. It is important to note that although investigators have made considerable advances unraveling the inciting events of acute fatigue, the processes that maintain and potentiate a state of CF remain obscure. Mood Disorders HNC patients are at high risk for developing mood disorders such as depression and anxiety. Depression is common in HNC patients across the cancer trajectory. In a recent systematic review, the prevalence of depression ranged from 13% to 40% at diagnosis, to 25% to 54% during treatment, and 11% to 45% at 6 months posttreatment (64). Depression and Cytokines Derangements in catecholamines (eg, serotonin and norepinephrine) have historically been accepted as central to the pathogenesis of depression, directing the pharmacological development and use of anti-depressants. However, alternative theories suggest that immune dysregulation and pro-inflammatory cytokines are involved in the pathogenesis of depression (65). First, many studies have shown significant elevations in pro-inflammatory cytokines such as IL-6 (66–71), TNF-α (71–74), IL-1β (70–72, 75, 76), and IFN-γ in patients with depression (70, 71). Second, in a recent meta-analysis, patients with major depression had significant elevations of TNF-α and IL-6 compared with nondepressed control subjects (77). Finally, depression can precede the diagnosis of cancer, suggesting that the pretreatment pro-inflammatory state may contribute to the increased prevalence of mood disorders (78). Additional neurohumoral mechanisms that may serve in the pathogenesis of depression include the complex interaction between inflammatory cytokines and their effects on brain monoamines, the glutamate system, and the brain-derived neurotropic factor neurotransmitter (65). Depression and Genetic Predisposition There is an increasing understanding in the role of genetics in the development of depression and its response to treatment. Of particular interest are polymorphisms in the 5-HTTLPR-serotonin transport gene. One study by Caspi et al. found that individuals who had the short, or “S,” allele had higher rates of depression and depressive symptoms in relation to stressful life events (79), such as a cancer diagnosis. Other studies have shown that the acquisition of the S allele is strongly associated with alcohol (80) and nicotine (81) dependence, both of which are synergistic risk factors for the development of HNC. Furthermore, one study found a significantly higher incidence of the S allele in HNC patients with depression vs HNC patients without depression (85.7% vs 68.4%, P < .04) (82). Studies have also shown that polymorphisms in 5-HTTLPR, serotonin receptor 2 A, and tryptophan hydroxylase 1 may also play a role in therapeutic response to anti-depressant therapy (83, 84). For example, the presence of the long, or “L,” allele in 5-HTTLPR appears to be protective in that it has been found to be associated with better treatment efficacy (85, 86) and reduced rates of adverse drug reactions (84). Taken together, these data suggest that 5-HTTLPR polymorphisms may contribute to the increased risk of depression in patients with HNC and also affect their response to therapy. Temperature Dysregulation Vasomotor symptoms are commonly acknowledged sequelae of cancer treatment, particularly in patients receiving endocrine therapy for hormonally driven cancers. However, survivors across multiple tumor types describe a related, although seemingly distinct, experience of thermal discomfort while under ambient temperature conditions. Unlike true vasomotor episodes, which are acute events, these are often described as protracted interludes where the sufferer feels uncomfortably hot or cold. Some authors have described this as “thermal discomfort,” and although there is a paucity of data on this subject in the medical literature, this is a prominent chronic symptom described among networks of cancer survivors, including breast and testicular cancer (87, 88). Patients with hot thermal discomfort may be clinically managed with agents targeting vasomotor symptoms, although the efficacy is unknown. Patients who experience primarily cold thermal discomfort typically go untreated (87). As with the breast and testicular cancer populations, this phenomenon has been anecdotally noted in the HNC population during and after treatment with chemoradiation. In a recent report, 54% of head and neck patients report unexplained cold, 38% unexplained warmth, and 20% report sweating episodes (31). Qualitative data revealed that temperature discomfort could substantially affect activities and function for patients. Thus, further investigations are needed to determine the frequency, severity, and impact of thermal discomfort in HNC cancer survivors. Several theories have been proposed regarding the mechanisms at play in this phenomenon. Endothelin-1, a vasoactive peptide, is an established growth factor for multiple malignancies, including breast, ovarian, colorectal, and prostate cancers. In addition to its role as a growth factor, endothelin-1 has been shown to induce thermal hyperalgesia in humans (89). Therefore, alterations in endothelin-1 signaling could play a role in thermal discomfort in cancer patients (87). It has also been noted that many of the same pro-inflammatory cytokines noted to be elevated in malignant states, including IL-1, IL-6, and TNF-α, are those known to have a role in thermoregulation as well as sickness behavior. It has therefore been proposed that cancer and treatment-associated systemic inflammation as propagated by the aforementioned pro-inflammatory cytokines may result in central changes to thermoregulatory mechanisms manifesting as thermal discomfort (87). Investigation into the biological underpinnings of temperature dysregulation is needed. Metabolic Alterations: Cachexia and Sarcopenia Cachexia Cachexia is a pervasive paraneoplastic syndrome manifested primarily by unintentional weight loss. It is seen in many malignancies including HNC, upper gastrointestinal, lung, and prostate cancers (90). Cancer cachexia is a unique entity and can be differentiated from other causes of weight loss such as anorexia or starvation (91). In cachexia, skeletal muscle loss is out of proportion to fat loss, whereas starvation produces primarily fat loss followed by muscle loss in late stages (92). In addition to muscle wasting and weight loss, the overarching cachexia syndrome includes a cluster of symptoms, including fatigue, anemia, neurocognitive deficits, mood disorders, and others. Although classically described in end-stage disease, data have demonstrated widespread development of cachexia early in the course of cancer, with a portion of patients experiencing loss of weight and muscle mass before diagnosis (93). HNC patients commonly experience profound weight loss. This has traditionally been attributed to decreased oral intake secondary to cancer-related obstruction and treatment-related toxicity. However, accumulating data support the contributory role of cachexia in this population. In a recent metanalysis, where cachexia was defined as a weight loss of greater than 5% in less than 12 months with three of five additional cachexia criteria (decreased muscle strength, fatigue, anorexia, low fat-free mass or abnormal labs such as increased CRP, anemia or decreased albumin), 20.2% of patients at diagnosis and 32.2% of patients at time of treatment initiation met the criteria for cachexia (94). In a small prospective study, cachexia (42%) and pre-cachexia (15%) were noted in pretreated HNC patients (95). Thus, tumor-associated cachexia contributes substantially to weight loss in the HNC population. In addition, treatment with RT is associated with profound weight loss. Although this may be due in part to inadequate caloric intake, a prospective trial conducted in patients undergoing chemoradiation demonstrated that treatment-associated weight was largely composed of fat-free mass (96). This supports the hypothesis that radiation-induced soft tissue inflammation may cause or exacerbate the metabolic abnormalities associated with cachexia. Sarcopenia Sarcopenia is defined as a depletion of skeletal muscle mass. Some apply this terminology exclusively to muscle mass loss due to normal aging (97). Others use the term to describe skeletal muscle depletion of any cause. The recent use of CT and MRI imaging techniques to assess body composition have provided a unique opportunity to evaluate the role of lean body mass and fat mass on disease outcome (98). Studies in the lung and colon cancer population demonstrate pretreatment sarcopenia is associated with poorer outcomes even in the obese patient population (99). A similar study conducted in the HNC patient population evaluated 175 patients who underwent pre- and posttreatment PET or CT scans. Using CT images at L3 to derive a skeletal muscle index, investigators determined the impact of pre- and posttreatment sarcopenia on survival (100). Sarcopenia was present in 65 patients (37.1%) before radiation and developed in an additional 42.7% of patient’s postradiation for a posttreatment total of 79.7%. For patients receiving postoperative RT, pretreatment sarcopenia did not predict outcome. For patients receiving primary RT who had preradiation sarcopenia, there was a significant decrease in local disease control, disease-specific survival, and overall survival. All patients who developed sarcopenia during RT demonstrated significant decrease in local disease control, disease-specific survival, and overall survival. Similarly, results were reported in a retrospective analysis of 190 HNC patients treated with curative intent RT (101). Skeletal muscle depletion was found in 35% of patients before and 65.8% at the completion of treatment. Both pre- and posttreatment skeletal muscle depletion was associated with decreased overall survival. Weight loss without skeletal muscle depletion did not correlate with survival. Cisplatin, a commonly used chemotherapy agent for treatment of HNC, has been shown to induce loss of muscle mass that may persist after discontinuation of drug. In 26 bladder cancer patients treated with platinum-based induction chemotherapy, there was a significant decrease in skeletal muscle index (49.1 vs 44.5 cm2/m2, P > .001) and increase in sarcopenia (69% vs 81%, P = .02) between pre- and posttreatment measures. In mouse models, this has been shown to be at least in part related to induction of nuclear factor-kappa B (NF-kB) activity (102). Catabolism and Anabolism Clearly, it is critical to understand the impact of cancer, cancer therapy, and nutritional support on the metabolic processes that govern muscle and metabolism. Several lines of research are ongoing to try to understand the mechanism of sarcopenia in the oncologic population. When considering skeletal muscle metabolism in the larger context of cachexia, it can be instructive to consider this as two interdependent pathways: muscle anabolism and muscle catabolism. As previously established, HNC and its treatment are associated with significant elevations in pro-inflammatory cytokines, a cytokine profile notably similar to that association with cachexia (103). The current literature indicates that inflammation promotes skeletal muscle catabolism while simultaneously inhibiting anabolism (104–107). The inhibition of anabolism is believed to occur due to decreases in testosterone, insulin-like growth factor 1, and other anabolic factors (105). Insulin-like growth factor 1 is an anabolic factor that stimulates skeletal muscle protein synthesis and may also inhibit proteolysis by the ubiquitin-proteasome system (UPS) (108, 109). Muscle wasting in cancer cachexia likely has an even larger contribution from increased catabolism than it does from depressed anabolism. Muscle homeostasis includes at least four central proteolytic pathways—autophagy (ie, lysosome-endosome), calcium dependent, caspase dependent, and UPS dependent—but it is the UPS that appears to be primarily responsible for degradation of skeletal muscle (105). Multiple laboratory models of cancer cachexia, including Lewis lung carcinoma, colon 26, and AH-130, have demonstrated upregulation of atrogin-1 and MuRF-1, positive regulators of the UPS (110–112). There is also evidence that mediators of inflammation upregulate UPS degradation of skeletal muscle. TNF-α signaling has also been shown to regulate expression of MuRF-1, an E3 ubiquitin ligase and trigger of ubiquitination (105). Symptom Clustering: Additive or Synergistic Impact on Quality of Life and Functionality Thus far we have primarily described individual systemic symptoms. As previously discussed, systemic symptoms share common underlying biologic mechanisms, resulting in the concurrent development and/or persistence of multiple symptoms simultaneously (Figure 4). Thus, the concept of symptom clusters has arisen and remained an area of investigation in the general and oncologic populations. Symptom clustering was originally thought to represent a psychogenic process, but the literature refutes this claim. For example, neuroimaging studies confirm sensory augmentation in nonmalignant CSS (113). Numerous syndromes have now been added to the list of CSS such as fibromyalgia, CFS, and irritable bowel syndrome. Cancer and cancer treatments result in symptom complexes that mirror those seen in CSS. More formal and systematic comparison of cancer-related systemic symptoms with known CSS is warranted. By understanding the similarities and differences between cancer-associated systemic symptoms and established CSS, we can direct research efforts in the oncology realm more efficiently and effectively. Figure 4. View largeDownload slide Symptom complexes: shared biology with variable manifestations. GI = gastrointestinal. Figure 4. View largeDownload slide Symptom complexes: shared biology with variable manifestations. GI = gastrointestinal. Within the HNC population, analyses have been conducted in attempts to define general symptom clusters across the broad spectrum of symptoms and functional abnormalities experienced by patients (62). This can be further refined to specifically assess systemic symptoms clusters. Preclinical and clinical data regarding the frequency, severity, and cluster patterns of sickness symptoms in the head and neck patient population are limited. Nonetheless, existing data support the existence of systemic symptom clusters in this cohort. In one preclinical study, mice implanted with Human Papillomavirus (HPV)-positive cancer cell lines were observed for sickness behavior before and after chemoradiation (114). Tumor-bearing mice demonstrated decreased burrowing time, body weight, and nutrition intake. Both brain and liver inflammatory cytokine levels were elevated as well as alterations in mitochondrial function. In humans, there are few studies assessing chronic systemic symptom burden in HNC patients. In a recent report at ASCO, investigators reported the results of a cross-sectional study of symptom burden in 167 patients treated with either IMRT or 3-dimensional conformal RT (115). Patients were a median of 5.32 years posttreatment with over 70% of patients over 3 years. Eight patients were postoperative, and 99 received chemotherapy plus RT. The patients were administered the MDASI-HN and the Brief Fatigue Inventory. The results demonstrated that 11% of patients had fatigue that was “unusual,” 6% had fatigue at the time of completing the patient-reported outcome measures, 9% were experiencing their usual level of fatigue, and 10% were experiencing their worst level of fatigue. Fatigue did not correlate with patient, tumor, or treatment characteristics but did cluster with derangements in sleep, memory, level of consciousness, mood (upset or sad), and appetite. Thus, the results indicate that a small but clinically significant cohort of patients had a significant cluster of systemic symptoms. A cluster analysis of 95 HNC survivors demonstrated two unique groups: a low systemic symptom group and a high systemic symptom group. The most common systemic symptoms in the high symptom burden cohort were fatigue (79%), difficulty staying asleep (69%), cold (62.2%), problems with memory or concentration (45%), and joint/muscle pain (45%) (31). Patients with multiple systemic symptoms had decreased overall quality of life as well as decreased physical, emotional, and intellectual domains. It may also be hypothesized that systemic symptoms may interact in a synergistic manner at a biological and behavioral level. For example, patients with central fatigue may fail to comply with an exercise regimen to prevent muscle mass loss, or patients with memory loss may fail to comply with complex supportive care regimens. Further work is needed to understand the relationship between individual symptoms, how symptoms cluster, and the relative impact of distinct clusters in the HNC population. The Impact of HPV Status The epidemiology of HNC has changed dramatically over the past two decades with a dramatic rise in the number of HPV-associated oropharyngeal cancers. HPV-associated cancers decrease the acute inflammatory responses in the mucosal epithelium (116). The question arises as to whether this will affect the acute and chronic systemic symptoms experienced by patients. Unfortunately, most studies pay scant attention to acute and chronic symptoms. However, other outcome measures such as quality of life and general function may at least suggest the potential for adverse impact by systemic symptoms, thus providing direction for future research efforts. A study examined the most common initial symptoms in patients with HPV-positive (n = 71) and HPV-negative (n = 17) oropharyngeal cancer (117). It was found that patients with HPV-positive disease presented more commonly with a neck mass whereas HPV-negative patients often presented with sore throat, dysphagia, and/or odynophagia (all P < .05). There was no difference in weight loss (P = .09), fatigue (P = .99), or nonspecific pain (P = .32). A second study comparing 21 patients with HPV-associated oropharynx cancers vs 17 patients with smoking-associated oral cavity cancers demonstrated that patients with HPV-associated cancers experience lower symptom severity, depression, and cancer worry pretreatment than patients with non-HPV–associated tumors (118). Furthermore, depression decreased significantly over time in patients with HPV-associated cancers. In a prospective study of fatigue in 94 HNC patients undergoing RT, patients with HPV-associated tumors reported less pretreatment fatigue than patients with non-HPV–associated cancers (119). At 1 month post radiation, fatigue levels were significantly elevated in both groups and the difference in fatigue levels had disappeared. At 3 months posttreatment, fatigue levels continued to rise in the non-HPV–associated cancer and had dropped significantly in the HPV-associated tumors. Patients with non-HPV-associated tumors had higher levels of C-reactive protein (P < .001), sTNFR2 (P = .0369), and IL-6c (P = .021). These findings indicate that patients with HPV-associated cancers experience lower than average levels of fatigue and lower levels of circulating inflammatory proteins than those with non-HPV–associated tumors. To understand the potential molecular mechanism of underlying these differences in circulating inflammatory biomarkers, a study examined the activity of the NF-kB family of pro-inflammatory transcription factors and activity of the interferon regulatory factor family of antiviral transcription factors in patients with HPV-associated cancers (120). The study found that patients with HPV-associated tumors had lower activity of NF-kB (P = .005) and higher activity of interferon regulatory factor family factors (P = .017) relative to patients with non-HPV–associated cancers. These findings support lower levels of fatigue and inflammation in patients with HPV-associated cancers at pretreatment and the acute recovery phase. Data on long-term systemic symptoms are lacking. Conversely, a recent retrospective study examined the impact of HPV status on functional outcomes and quality of life after surgical treatment of oropharyngeal carcinoma with free-flap reconstruction (121). The study found that there was no statistically or clinically significant difference in speech, swallowing ability, swallowing safety, and quality of life outcomes between p16 positive and negative oropharyngeal cancer. These data imply that p16 status may not be predictive of functional outcomes or quality of life in surgically treated oropharyngeal cancer. However, once again, data on systemic symptoms was limited. Patients with HNC have a high rate of long-term disability due at least in part to the late effects of therapy, most notably fatigue. In a study of 129 patients with HPV-associated oropharynx cancer who were longer than 1 year post primary chemoradiation, 9% of patients stopped working permanently, 69% stopped working temporarily but were able to return to work, 19% continued to work through treatment with reduced work responsivities, and 3% continued to work. Median time to return to work was 14 weeks (122). Early randomized trials indicate that deintensification treatment strategies using lower doses of radiation, small radiation fields, or omission of concurrent chemotherapy may lead to decreased local toxicities (123). It is therefore reasonable to expect that deintensification strategies would result in a reduction of acute and chronic systemic symptoms. Directions for Future Research Research in central sensitivity syndromes such as CFS and FM is robust and can help inform future work evaluating systemic symptoms and sickness behavior in the Oncologic setting. Collaborative efforts that bridge the syndrome- and symptom-related silos should be developed and fostered. Basic research delineating the pathobiology of chronic systemic symptoms is essential. Of particular importance are statistical methods that allow use of large data sets to identify subpopulations of patients with common pathophysiologic underpinnings. Individual symptoms may be manifestations of numerous discrete clinical syndromes with distinct etiologies, pathobiology, and clinical courses. These syndromes need to be clearly defined and nomenclature must be standardized using clinical, laboratory, and imaging methods. Cross-study comparison of cytokine data is fraught with difficulty due to variability in important factors such as assay selection; time of day when the sample is collected; identification of co-morbid disease; patient characteristics such as age, sex, and BMI; and concomitant medications (such as antidepressants). Thus, standardization of methodologies may help limit variability and minimize confounding factors. Continued investigation of cytokine polymorphisms may help better our understanding of genetic influences on inflammatory processes and associated symptoms in the HNC population. Prospective, longitudinal studies are needed to understand the relationship between the physiologic stress, the host response, and systemic symptom development and evolution over time. This is important because clinical symptoms may not manifest until after the physiological insult, and by that time peripheral levels of inflammatory mediators may have returned to normal. Human studies largely measure peripheral cytokine levels, which may not reflect central cytokine levels. Continued efforts must be directed at the development of methods for noninvasive assessment of neuroinflammation. New strategies need to be developed to prevent and treat acute and chronic systemic symptoms. This should include both pharmacologic and nonpharmacologic strategies that decrease inflammation. Well-conducted clinical trials that test novel preventive and treatment strategies to ameliorate acute and chronic systemic symptoms must be conducted in the oncological population. Establishing a consensus on outcome measures as well as trial designs to promote harmonization across studies is needed to ensure successful development of a body of literature that can inform clinical practice. There is need to further evaluate the impact of chronic systemic symptoms on patients, caregivers, and treatment-related outcomes. HNC and its treatment are associated with profound systemic symptomatology. Although it is generally recognized that patients experience systemic symptoms due to the acute effects of therapy, chronic systemic symptomatology often goes unrecognized and underappreciated. Patients often feel that their systemic symptoms are both minimized and marginalized, leading to conflict with medical providers. Thus, the first step is to recognize and legitimize symptom complaints. When systemic symptom burden is recognized, pharmacological and nonpharmacological interventional strategies may be implemented. Unfortunately, for many chronic systemic symptoms, the therapeutic impact is often modest at best. Patients, caregivers, and providers who work diligently to identify and implement measures to improve symptoms and functionality may experience significant frustration and burnout. For caregivers and providers, burnout is a noteworthy problem when patients suffer from central fatigue and associated motivational impairment. Because patients are likely to suffer long term, emotional support for both the patient and their caregivers is critical to help them manage expectations. Finally, further study of the trajectory of systemic symptomatology, symptoms clustering, and underlying mechanisms is needed to identify potential therapeutic interventions designed to improve functionality and quality of life. Notes Affiliations of authors: Department of Medicine (BAM, EWB) and Division of Hematology-Oncology (EWB), Vanderbilt University Medical Center, Nashville, TN; Vanderbilt University School of Medicine, Nashville, TN (MG); William F. Connell School of Nursing, Boston College, Boston, MA (SMB); School of Nursing, University of Pennsylvania, Philadelphia PA (JD). The authors declare that they have no conflicts of interest. For support see Funding Acknowledgement section of Monograph. References 1 Dantzer R , Kelley KW. Twenty years of research in cytokine-induced sickness behavior . Brain Behav Immun . 2007 ; 21 2 : 153 – 160 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Yunus MB. 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JNCI MonographsOxford University Press

Published: Aug 1, 2019

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