There are a few common features that may connect cancer to CFS/ME.There are similarities and differences in the type of fatigue experienced by CFS/ME patients and cancer patients. CFS/ME patients experience post-exertional malaise (PEM), which is defined as the worsening of symptoms upon minimal physical or mental exertion ^[1][119]. In contrast to CFS/ME-related fatigue, cancer-related fatigue is not typically associated with post-exertional malaise ^[2][120]. This difference could point to differences in the mechanisms underlying the diseases, or potentially a differential systemic response to external stressors. For some time, researchers have questioned whether CFS/ME or similar syndromes could predispose individuals to or indicate carcinogenesis. Since the advent of cancer therapy, cancer-related fatigue is a syndrome that has been observed in many neoplastic diseases and affects most of those with cancer ^[3][121]. This fatigue is often associated with symptomatology that mirrors CFS/ME, including other symptoms like chronic pain, sleep disturbances, cognitive dysfunction, and emotional distress. This fatigue and related symptoms may be associated with the burden of radiation and/or chemotherapy treatment on the body. However, fatigue is also common in those not undergoing treatment, when a cancer is in remission, and even prior to diagnosis. The pathophysiology of cancer-related fatigue is poorly understood, but sometimes it is possible to determine whether the fatigue is related to the treatment or disease alone; if fatigue symptoms are exacerbated following treatment but subside upon suspension of the regime, then it may be concluded that the fatigue results from treatment ^[4][5][6][122,123,124]. As stated previously, both chemotherapy and radiation therapy are known to induce fatigue in patients, and the onset and severity of fatigue typically follow a reproducible course if treatment is suspended and resumed at a later period ^[7][8][9][43,46,125]. There is also evidence that changes induced by cancer, such as increased energy and metabolite demand, may be responsible for cancer-related fatigue. Some proposed mechanisms that may underpin CRF include inflammation and induction of cytokine signaling, disruption of sleep cycles and the circadian rhythm, disruption of the hypothalamic-pituitary-adrenal (HPA) axis, muscle loss, and nutritional deficit ^[4][122]. One systematic review of the literature found that cancer-related fatigue was consistently linked to immune and inflammatory responses, metabolic changes, neuroendocrine changes, and changes in genetic biomarkers ^[5][123]. Idiopathic fatigue can be distinguished from secondary fatigue caused by cancer-induced changes; for example, fatigue can also be a symptom indicative of anemia, and leukemias may cause anemia due to the destruction of bone marrow ^[10][126]. If the underlying problem can be addressed, such as nutritional deficiencies or side effects from medications, then the fatigue symptom can likely be effectively treated.

Even though CRF and CFS/ME share some common features, along with differences, the connection between the two has not been conclusively established. While there are reports that attempt to refute any relationship between the syndromes, there are several studies that investigate whether CRF and CFS/ME are coincident and etiologically linked. Based on one reviewed study, there is a general increased risk of earlier mortality in CFS/ME patients compared to the general US population. Interestingly, CFS/ME patients showed a lower age of death for suicide and cancer (cancer: M = 66.3 years; 71.1 years), indicating that CFS/ME patients with cancer tended towards poorer outcomes over the general public ^[11][127]. Another study discusses an increased incidence of brain tumors and non-Hodgkin lymphoma in those with CFS/ME, including analyses of two outbreaks of fatigue-related illnesses and the frequency of cancers in those involved. However, the authors of this report state that further research is needed because a causative factor for carcinogenesis and manifestation of fatigue could not be determined ^[12][128]. Another study found an increased incidence of brain tumors in CFS/ME patients, but not non-Hodgkin Lymphoma (NHL) ^[13][129]. Moreover, there are subgroups of cancer therapy patients where severe fatigue may be connected to CFS/ME ^[14][130]. A recent study indicated that CFS/ME is associated with an increased risk of various subtypes of NHL ^[15][131] which was found in another study mentioned previously. The same study also found that CFS/ME was associated with cancers of the pancreas, breast, oral cavity, and pharynx, although not after correcting for the multiple comparisons used in statistical analysis. One comparative study looked at prostate cancer patients and CFS/ME patients for evidence of common biomarkers. The authors found that both prostate cancer patients and CFS/ME patients showed modulation of the expression of P2Rx7, a metabolite-detecting transmembrane receptor, and HSPA2, a heat shock protein implicated in a wide range of cellular processes, compared to controls. Expression of DBI, a GABA-A receptor modulator, was also correlated with the severity of fatigue in both prostate cancer fatigue (PCF) and CFS/ME patients ^[16][132]. Another study found differences in the “psychophysiology” of patients with cancer-related fatigue and CFS/ME. They found that patients with cancer-related fatigue showed higher hs-CRP levels, an inflammatory marker, and reduced HRV-index scores, a measure of heart rate variability, compared to the CFS/ME group, and that the CFS/ME group could be distinguished by EEG.

Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis has been suggested as a contributing factor in the underlying etiology of both CFS/ME and CRF. Currently, there is controversy concerning whether the HPA axis plays a role in the genesis of fatigue symptoms in general ^[17][133]. One study reported detectable dysfunction in CFS/ME patients; the authors proposed that administration of cortisol at physiologic levels may be tried as a putative therapy for CFS/ME where there is evidence of adrenal dysfunction ^[18][134]. Another report corroborated these findings and discussed that low cortisol levels are more likely to be present in women than in men, that a multidimensional etiological model for CFS/ME is likely, that cognitive-behavioral therapy may be useful in addressing the deficiency in cortisol levels, and finally that further research is needed to fully understand the involvement of HPA axis dysfunction in CFS/ME ^[19][135]. Several other reports discussed this feature of CFS/ME, connections to genetic changes, inflammatory responses, and neuroendocrine changes, and similarly suggested that further research is needed to elucidate these connections ^{[20][21][22][23]}[136,137,138,139].

In terms of CRF, the involvement of HPA axis dysfunction also remains somewhat contentious. One review of the literature suggested that multiple factors likely contribute to CRF, with correlated symptoms of depression, anxiety, and chronic pain ^[24][25][26][140,141,142]; some of these symptoms also fall in the diagnostic criteria of CFS/ME. Additional factors were also identified, such as comorbid medical conditions and different distribution depending on demographic factors ^[26][27][142,143]. Numerous studies on a myriad of biological parameters that could potentially induce fatigue—including hemoglobin, albumin, and thyroid hormone levels—have been mostly fruitless in explaining the fatigue syndrome in cancer patients ^[28][144]. This could also reflect a heterogenous etiology in CRF. The authors note that treatment with pro-inflammatory cytokines, such as interleukin-8, interleukin-6, and tumor necrosis factor-alpha, at physiologic doses, appears to facilitate HPA axis dysfunction and promote fatigue-like symptoms. As with CFS/ME, further research is needed to establish a causal relationship between CRF and HPA axis dysfunction.

Another study noted similarities between CFS/ME and cancer-related fatigue and described some proposed mechanisms ^[29][145]. The author noted that 5-HT metabolism and neurotransmission could potentially be implicated in both CFS/ME and CRF, as another study found increased free tryptophan in the blood of CFS/ME patients ^[30][146]. While some investigators showed that administration of 5-HT or selective serotonin reuptake inhibitors reduced the capacity for exercise in humans, others investigating CRF in specific cancers found no connection ^[31][32][33][147,148,149]. In some types of lung cancer, the metabolism of tryptophan to kynurenine may result in further conversion to neurotoxic metabolites that are associated with fatigue ^[34][35][36][150,151,152]. Currently, the link between CRF and 5-HT metabolism remains a controversial but very interesting area of ongoing research. Another study examining a chronic fatigue model in rats found that the quantity of serotonin increased following exercise and this was associated with the induction of chronic fatigue ^[37][153].

It is very interesting to people that serotonin may be involved in CFS/ME and CRF. If a common link is found, it may explain the underlying mechanisms behind the disease in at least some of the affected populations. The involvement of serotonin in radiation-induced bystander effects has been extensively documented in the literature by a group and others ^{[2][11][38][39][40][41]}[120,127,154,155,156,157]. Serotonin was demonstrated to be required for bystander effects in one study ^[40][156], and this was proposed as a potential explanation for the inter-laboratory variation in bystander effects; this was concluded because the commercially available fetal calf serum batches that were used in cell culture were found to contain variable quantities of serotonin. Another group found that there appeared to be an interaction between serum serotonin levels and p53 status with respect to cells’ ability to respond to bystander effects ^[42][158]. Supplementing serotonin in culture medium produced “a modest but significant increase in (micronuclei) formation”, while low serotonin levels again abrogated bystander effects in the p53 wild-type cell line. However, the addition of serotonin to the p53-null cell line appeared to allow the cells to respond to bystander signals.

These findings are very interesting and should be investigated further. This could be diagnosed as CFS/ME, however, depending on the context of symptom onset, may be diagnosed as CRF. Predisposing factors could include bacterial or viral infection, genetic background, or serotonin imbalance. There may be some connection between excess serotonin, a permissive environment for the reduction of oxidative metabolism, radiation exposure, and bystander effects. These are excellent avenues of research for prospective epidemiological studies, and hopefully, future research will be able to tease out the connection between these phenomena.

It should first be noted that the suprachiasmatic nucleus in the brain controls the mammalian circadian clock, and some studies have found that serotonin is a direct regulator of the phase of this clock. Recent studies have also suggested that serotonin is involved in regulating the circadian clock in mammals by directly modulating the expression of specific genes in the brain ^[43][159]. The circadian clock is also regulated by external, environmental factors, such as day and night cycles.

There are a few studies that investigate a link between the circadian clock and CFS/ME. The rationale behind these studies is that CFS/ME presents with symptoms that are associated with trouble falling, staying asleep, or otherwise unrestful sleep. Insomnia is comorbid with a panel of mental health disorders, including anxiety, depression, and substance abuse disorders ^[44][160]. A systematic review of the literature by Shan et al. ^[45][161] found that reduced serotonin transporters were found in several studies examining CNS abnormalities in CFS/ME patients. One study examining eight patients with CFS/ME concluded that the patients exhibited lower daytime activity and less regular activity-rest cycles due to the illness, noting that “some of the symptoms of chronic fatigue syndrome (CFS) are the same as for disrupted circadian rhythm” ^[46][162].

Alterations to circadian function are present in some patients with cancer; associated changes include disruptions to endocrine rhythms, metabolic processes, and the immune system ^{[4][47][48][49][50][51][52]}[122,163,164,165,166,167,168]. Researchers have determined that cortisol levels are different between breast cancer patients experiencing fatigue and those not experiencing fatigue ^[53][169]. As in CFS/ME, sleep disturbances and disorders are common in patients with cancer ^[54][55][170,171]. Several groups reported that fatigue in cancer patients is associated with altered activity-rest activity patterns ^[6][51][56][124,167,172]. The causes of these disturbances in cancer patients are not fully understood. However, it is suspected that a combination of genetic, psychosocial, environmental, behavioral, and metabolic causes are to blame ^[4][122]. It is also likely that tumors have a direct effect on the regulation of host rest/wake cycles through the tumor microenvironment and influence immune responses ^[4][122]. This provides a connection to potential neuroimmune involvement. Changes in cortisol levels can change the function of immune cells, which in turn promotes proinflammatory cytokine production ^[4][57][58][122,173,174]. Moreover, altered immune function is coincident with flattened cortisol rhythms in patients with breast cancer ^[4][59][60][122,175,176].

CFS/ME has been observed to develop the following infection and has been reported following cases of Epstein-Barr viral infection ^[61][177]. Interestingly, a report published in the early nineties demonstrated the presence of retroviral sequences related to T-lymphotropic virus type II in CFS/ME patients ^[61][177]. These viruses can cause a specific type of cancer in humans known as adult T-cell lymphoma/leukemia. Additionally, they can cause a demyelinating disease. Infection with HTLV-2 is associated with neurological abnormalities, including sensory neuropathies, abnormal gait, cognitive impairment, and erectile dysfunction ^[62][63][64][178,179,180]. Even though these studies can still be found in the literature, several groups could not replicate these findings; therefore, this hypothesis is no longer supported ^[65][66][67][181,182,183]. Another recent review notes the immunological similarities between CFS/ME and cancer and proposed common links to fatigue symptoms ^[68][184].

A review by Noda et al. ^[69][185] reported that CFS/ME is a disease that may be linked to neuroinflammation, which is discussed in further detail above. One study found that decreased natural killer cell activity was positively correlated with the severity of CFS/ME ^[70][186]. Several studies have examined the role of cytokines in CFS/ME, which is also described above. One report noted that the cytokine profile in the plasma of female CFS/ME patients appeared to be consistent with “processes active in latent viral infection” ^[71][187]. Another paper by Broderick et al. ^[72][188] showed significant differences in IL-8 and IL-23 concentrations in adolescents with post-infection CFS/ME. However, a critical review of the methods used in the literature cautioned that the potential variance in cytokine responses between individuals will make it difficult for future studies to replicate findings.

It is known that oncogenesis and cancer therapies—including surgery, chemotherapy, radiotherapy, and targeted therapy—are associated with increased levels of plasma cytokines and inflammation ^{[73][74][75][76][77]}[189,190,191,192,193]. Some proinflammatory cytokines have also been implicated in CRF. In particular, TNF-alpha and IL-1beta are implicated in many mechanisms believed to be responsible for fatigue. Supplementation of TNF-alpha is known to provoke behavioral changes, including lethargy, and when used in immunotherapy, a common side effect is fatigue ^[78][79][194,195]. Therefore, it is suspected that cytokine signaling networks coordinate biological responses following exposure to some injurious, cytotoxic factor—such as ionizing radiation chemotherapy, et cetera—resulting in inflammation and cytokine signaling.

With respect to ionizing radiation exposure, cytokines have been shown to be involved in bystander signaling as well. An analysis of cytokine secretions was found to be cell line-specific in one study, with a smaller increase in overall concentration after fractionated rather than acute doses ^[80][196]. The highest level of cytokine secretion was also associated with the poorest survival in A549, a human adenocarcinoma cell line. In glioblastoma cells, gamma irradiation caused the release of IL-8 and IL-6, resulting in bystander effects in reporter cells ^[81][197]. Interleukin-8 (IL-8) is released into extracellular space following irradiation of T98G cells in vitro in a time-dependent and dose-independent manner ^[82][198]. IL-6 is also known to be released from irradiated cells and has been implicated in bystander responses ^[83][199]. These changes to inflammatory responses are expected with ionizing radiation exposure, however, it is noteworthy that these responses do not exhibit a clear dose-dependent relationship.

Since the recognition of CFS/ME as a debilitating disease, researchers have suspected that the symptomatology of the disease does not simply result from psychological or neurological causes. It was believed that a lack of energy to perform routine tasks, which were previously performed without difficulties, could stem from a lack of energy in skeletal muscle or the tissues supporting it. Researchers suspected that ATP deficiencies could account for the lack of this energy. An analysis of blood samples from 74 CFS/ME patients found significant evidence of mitochondrial dysfunction, and specifically deficiencies in ATP production. A report by Naviaux et al. ^[84][22] found that CFS/ME appears to be “a highly concerted hypometabolic response to environmental stress that traces to mitochondria”. The researchers utilized broad-spectrum metabolomics and assessed 84 CFS/ME patients; 612 metabolites in plasma were analyzed that were involved in 63 biochemical pathways. Patients showed significant abnormalities in approximately one-third of the metabolites examined. Abnormalities were related to branched amino acid synthesis, phospholipid metabolism, cholesterol metabolism, and mitochondrial metabolism. The researchers demonstrated a relatively homogenous metabolic response in the cohort that was examined. Another report using the metabolic profiling of blood and urine samples from CFS/ME patients showed elevated blood glucose and reduced blood lactate, urine pyruvate, and urine alanine ^[85][200]. The researchers stated that the dysfunction of glycolysis could explain these results, with fewer metabolites available for reactions in the citric acid cycle. Additionally, the researchers presented evidence for oxidative stress in these patients. However, another report found normal lactate metabolism and oxygen uptake in CFS/ME patients ^[86][201]. Another study showed abnormalities in fatty acid and lipid metabolism. A systematic review of the literature by Shan et al. ^[45][161] found that regional hypometabolism was observed by several groups of researchers. These are just a few of the studies that have examined metabolic changes in CFS/ME patients. Much of the current research focuses on these potential biomarkers and explains discrepancies in results between different research groups ^[87][202].

Further, the presence of a tumor microenvironment promotes these changes even in the presence of oxygen. CRF has been hypothesized to result from changes to energy demands in the body following the development of a tumor. It may be anticipated that a tumor will use a considerable portion of available nutrients to accumulate biomass, thereby leading to metabolic deficiencies in the patient. This results in a multitude of symptoms, however, an energy deficit may be explained partly through a lack of metabolites or other reorganization of the metabolism at the molecular level.

Alteration of ATP production is known to be involved in responses to ionizing radiation as well ^[88][89][61,101]. While there is a dearth of research on the ability of bystander effects to promote oncogenesis, it is known that radiation responses can create conditions that are conducive to the formation of cancer. For example, the release of ROS promotes an oncogenic state because it leads to the damage of healthy tissue, and at the molecular level, oxidative or reductive damage to DNA; this is also known to result in genomic instability, in theory promoting carcinogenesis ^{[90][91][92][93][94]}[114,203,204,205,206]. In CFS/ME or CRF, attenuation of oxidative metabolism by bystander effects ^[88][89][61,101] after exposure to ionizing radiation or another environmental stressor could cause fatigue symptoms in theory. This is a very exciting area of research that may be promising in elucidating the etiology of both diseases.

Cancer-related fatigue and associated symptoms are often present in cancer patients—even those not undergoing treatment—however, the underlying pathophysiology is not well understood. Researchers discussed several mechanisms that could be behind these symptoms, including increased cytokines, dysregulation of the HPA axis in the brain, disruption of sleep and circadian rhythms, muscle loss, nutrient deficiency, and genetic changes. Fatigue can sometimes be associated with a separate condition like anemia due to cancer, however, the fatigue is usually idiopathic. Additionally, many patients who recover from cancer continue to report fatigue long after remission, indicating that these changes may become chronic in some cases. On a cellular level, it may be that these changes are transferred to cell progeny, either through inheritance or maintenance of some tissue microenvironment.

It is widely appreciated that CFS/ME and cancer are very different diseases. Cancer is known to promote drastic changes to cellular metabolism, which causes proliferation and growth under anaerobic conditions. It is suspected, based on numerous previously published articles, that CFS/ME also produces changes to cellular metabolism and may cause the downregulation of energy production. The underlying causative agent(s) for the instance of cancer and CFS/ME may dictate this response. Given this consideration, the development of a neoplasm versus maintenance of a fatigued state could depend on genetic background, nutritional availability and microenvironment, presence of other toxins, or even the dose of the injurious agent. These toxins could include heavy metals or radioisotopes, for example. Alternatively, the response may be dependent on the individual, with previous exposures “tempering” or sensitizing organs and tissues to additional uptake. A potential example of something that could cause the initiation of SIPI (stress-induced phenotype instability) is exposure to very low doses of ionizing radiation. When a person is exposed to one of these stressors, multiple outcomes are possible, and different dose relationships may be inferred. For example, hormetic responses, a biphasic response, tolerance, or hypersensitivity. It will likely be very difficult to determine how cancer fatigue and CFS/ME are linked unless additional research is conducted. Furthermore, it is important to note that this hypothesis is yet to be proven or refuted.