Several conditions can induce fatigue in cancer patients including anemia, mood, and sleep disorders; patient’s symptoms such as pain, nausea and vomiting, diarrhea and electrolyte disturbances, cardiopulmonary, hepatic renal or endocrine dysfunction, infection, and poor nutritional status; and the side effects of drugs such as opioid analgesics or anticonvulsants [3].

Some of these variables may be produced by the tumor itself or treatment with radiation or chemotherapy.

It has been proposed that anemia induced by radiation can cause fatigue due to decreased oxygen delivery to tissue and a negative energy balance [3–5]. Irradiation of different parts of the body may induce fatigue by different mechanisms. Severe diarrhea during pelvic radiation therapy [6], hypothyroidism as a consequence of neck radiation therapy [7], psychological effect in women receiving radiation therapy for early breast cancer [8], direct effects on normal brain parenchyma related to cranial radiation therapy [9], or a decline in neuromuscular efficiency in prostate cancer radiation therapy [10] may be related to fatigue etiology in patients treated with radiation therapy.

Available data suggest that activation of the pro-inflammatory cytokine network and inflammatory response may be responsible for radiation-induced fatigue. In particular, increased levels of the interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1ra), and C-reactive protein (CRP) are associated with a higher frequency and severity of fatigue [11–15]. Excessive nuclear factor (NF)-κB pathway activation has been seen in fatigued patients who have a key role in controlling expression of pro-inflammatory genes [16, 17].

Pro-inflammatory cytokines can also be produced in the central nervous system in response to radiation and generate fatigue [11, 12, 18].

Persistent posttreatment fatigue is associated with elevated markers of pro-inflammatory cytokine activity and alterations in the cellular immune system along with subtle dysregulation in hypothalamic-pituitary-adrenal axis function [11, 19–21].

Some investigators have not validated these relationships, so further evaluation is needed [22].

Other mechanism proposed for radiation-induced fatigue is mitochondrial dysfunction. A defect in mitochondrial oxidative phosphorylation is induced by radiation and causes genetic instability and cellular damage. Mitochondrial synthesis of ATP is disrupted and fatigue develops [23].

Fatigue may be developed or increased from baseline levels during radiation therapy. Fatigue usually begins during the second or third week of radiation therapy. Symptoms of fatigue become more severe over the course of treatment (cumulative fatigue) [24]. More than three-fourths of fatigue occurs by the third to fifth weeks of treatment. Fatigue is usually reduced gradually after treatment completion to the pretreatment levels within 4–8 weeks following the completion of treatment [25] but in some patients is protracted over many weeks (may last from 3–4 weeks to 2–3 months after treatment stops) [20, 26–31].

It has been observed that the radiation therapy-free weekends are associated with a lesser fatigue [32].

There are inconsistent data across studies evaluating fatigue-related factors, and additional research is warranted to determinate the predictor factors of radiation-induced fatigue. We discuss some of these factors here.

One of the uniformly reported predictive factors for fatigue during radiation therapy is higher than the baseline fatigue level. The presence of fatigue at the initiation of irradiation is associated with more fatigue experienced by patients during radiation therapy [33, 34].

Both fatigue and psychological disorders (like anxiety and mood disorders) are prevalent in cancer patients and have overlapping symptoms that produce some ambiguity for conclusion. There are conflicting data regarding to relationship between fatigue severity and psychological distress [7, 22, 35, 36]. Some have reported no significant relationship [37], and others have shown predictability of mood disorders for fatigue [36].

Some researchers have found differences in fatigue levels by radiation therapy sites. High frequency of radiation-induced fatigue was seen in breast cancer patients receiving radiation therapy rather than other common cancers including lung or prostate cancer [38–44], although some reported that patients with lung, gastrointestinal, and head and neck cancers experience more severe fatigue and that their fatigue increases more intensely over the course of radiation than does that of patients with breast cancer [45].

There are sparse data about the treatment parameter for radiation-induced fatigue. Radiation field sizes seem to be positively associated with maximum radiation-induced fatigue [46, 47]. Total dose might also be expected to influence the severity of fatigue although linear increase in fatigue with cumulative radiation dose over time is not seen [48].

Correlation between immune serum markers and fatigued patients has been proposed [49]. An analysis of different variables showed that higher baseline neutrophil counts have more consistent relation with fatigue than circulating cytokines, coagulation factors, peripheral blood indices, and biochemical factors [33]; however, more studies are needed to assess the relation of different immune markers and fatigue level.

Data about the role of chemotherapy as a predictor of radiation therapy-induced fatigue is also inconclusive. Some studies have shown that pretreatment with chemotherapy may increase fatigue severity, although others have reported that fatigue severity scores are not associated with chemotherapy [50, 51].

Other clinical variables including disease stage, previous surgery, weight [51, 52], and demographic variables such as race, gender, age, marital status, personality characteristics, and employment status [2, 3, 48, 53, 54] have not been consistently reported to be related with fatigue induced during radiation therapy.

Cancer-related fatigue is defined as a sensation of tiredness or lack of energy that is associated with functional limitations and impaired quality of life [34, 53, 55–60]. Unlike simple tiredness, it is more debilitating and not relieved by sleep or rest. It interferes with activities of daily living like preparing food or cleaning the house and leads to withdrawal from enjoyable activities like social activities with friends and family and even discontinuation of cancer treatment [26, 61]. Objective physical function (performance status) [62–64] and psychological status (mental/emotional aspects) [65–67] are also affected by fatigue.

There is a diurnal variation in radiation-induced fatigue, with increasing levels in the evening, which is consistent with the diurnal pattern of fatigue in the general population [68–71]. The severity of both evening and morning fatigue increases during radiation therapy and then decreases following the completion of radiation therapy [72].

Fatigue is a sensation with multidimensional components including sensory, cognitive, affective, behavioral, and physiologic aspects.

Based on NCCN guidelines “Cancer-related fatigue is defined as a persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that significantly interferes with usual functioning” [73].

Numerous assessment measures (including unidimensional and multidimensional scales) have been developed for screening and diagnosis of cancer-related fatigue. Most of them are based on patient self-report; however, there is no consensus about the best method for assessment.

Multidimensional measures examine several domains of sensory, cognitive, affective, behavioral, and physiologic function that is affected by cancer-related fatigue. Therefore, a multidimensional measurement may seem to be a more specific and refined diagnostic tool but may be too long to complete and not be suitable for screening or scoring in practice [9, 74].

Unidimensional measures (single-item or multi-item) are often single-question scales that are rapid and sensitive and can be applied efficiently for screening of the occurrence and measuring the severity of cancer-related fatigue but may lose the multiple dimensions of fatigue [3, 75]. Moreover, some argue that the extent of overlap between fatigue and depression is reduced with using a single item than a multi-item measure for fatigue [76].

Consideration of the measurement properties, strengths, and limitations of these instruments, including reliability, validity, specificity, sensitivity, recall period, respondent burden, translation in multiple languages, and the availability of normed values to aid interpretation, should be used to guide decisions about the utility of a measure for specific clinical or research purposes [3].

Specific diagnostic criteria have been proposed for defining cancer-related fatigue as an independent entity in the International Classification of Diseases, 10th revision (ICD-10) [77–79].

Some of the other multidimensional scales for cancer-related fatigue have been proposed including the Multidimensional Fatigue Inventory [80, 81], the Functional Assessment of Cancer Therapy-Fatigue Scale [82], the Piper Fatigue Scale [83], the Fatigue Symptom Inventory [84, 85], the Lee Fatigue Scale [86, 87], the revised Schwartz Cancer Fatigue Scale [88], and the Cancer Fatigue Scale [89].

The Lee Fatigue Scale has established internal consistency reliability in a variety of populations including cancer patients [86, 87, 90, 91]. In this scale, fatigue severity is measured using 13 items. Each item has a 0–10 numeric rating scale with higher scores indicating higher levels of fatigue severity. Respondents are asked to rate each item based on how they felt “right now,” within 30 min of awakening (i.e., morning fatigue), and before going to bed (i.e., evening fatigue) for two consecutive days and nights. The fatigue scale score is calculated as the mean of the 13 fatigue items. It has established that cutoff scores for clinically significant levels of fatigue (i.e., ≥3.2 for morning fatigue, ≥5.6 for evening fatigue) [86, 91].

There are several unidimensional single-item scales such as the Symptom Distress Scale [92], the Rotterdam Symptoms Checklist [93], the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality-of-life measure [94], the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) [95], the MD Anderson Symptoms Inventory [96], the Zung Self-Rating Depression Scale [97], the Visual Analog Fatigue Scale [98], or multi-item scales such as the Brief Fatigue Inventory [99].

Based on National Comprehensive Cancer Network (NCCN) guidelines, fatigue should be assessed quantitatively on a 0–l0 scale (where 0 means no fatigue and 10 means the worst fatigue imaginable, how would you rate your fatigue at its worst over the past 7 days?); A score of 0 indicates an absence of fatigue, a score of 1–3 indicates the presence of mild fatigue that does not require clinical intervention, and scores of 4–6 and 7–10 indicate moderate and severe fatigue, respectively, which require further evaluation and clinical intervention [73].

Proposed (1998 draft) ICD-10 criteria for cancer-related fatigue is shown in Table 18.1.

All cancer patients should be screened by a certain fatigue scale at their initial and follow-up visits.

Patients with significant fatigue scale should be further evaluated by history and physical examination. Cutoff for significant fatigue varies based on different fatigue scale tools (see Sect. 18.5).

Based on NCCN guidelines, primary patient evaluation includes:

In context with medical assessment of treatable factors, laboratory tests may be ordered as clinically indicated including complete blood count (CBC), electrolyte profile (sodium, potassium, chloride, bicarbonate), chemistry panel (creatinine, blood urea nitrogen, glucose, magnesium, calcium, phosphorus, bilirubin, serum transaminases, alkaline phosphatase, lactate dehydrogenase, albumin, total protein), transferrin, total iron-binding capacity, ferritin, iron levels, folic acid, B12 level, and thyroid function tests [100].

After primary patient evaluation, if there are any treatable contributing factors, it should be managed, and if fatigue persists with clinical management of these conditions, additional therapeutic modalities may be required [101].

There are both pharmacologic interventions and integrative non-pharmacologic behavioral interventions to alleviate fatigue symptoms that physicians can consider in the setting of no specific causal factors. Patients should be managed by multidisciplinary teams (oncologist, psychologist, physical therapist, exercise specialist, oncologist nurse, and nutritionist) for the best treatment approach.