, Ahmad Ameri1 and Mona Malekzadeh2
Department of Clinical Oncology, Imam Hossein Educational Hospital, Shahid Beheshti University of Medical Sciences (SBMU), Shahid Madani Street, Tehran, Iran
Department of Radiotherapy and Oncology, Shohadaye Tajrish Educational Hospital Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
Radiotherapy-induced fatigue is a common early and long-lasting side effect of radiation therapy, which, despite its negative effect on patient quality of life, is often underestimated and undertreated in daily practice. Patients usually do not consider fatigue as a treatment side effect. Indeed only in one-fourth of cases are any intervention proposed to the patient, and only about 50% of patients discuss it with a physician .
Hickok et al. reported on the radiation-induced fatigue incidence in 372 patients with various types of cancer who had received radiation therapy without concurrent chemotherapy. They found that of the 160 patients who did not have any fatigue at the start of irradiation, 70% (112 patients) developed the symptoms during radiation therapy, and approximately 84% of patients that reported fatigue at the initiation of therapy also reported fatigue over the course of treatment .
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 .
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 , hypothyroidism as a consequence of neck radiation therapy , psychological effect in women receiving radiation therapy for early breast cancer , direct effects on normal brain parenchyma related to cranial radiation therapy , or a decline in neuromuscular efficiency in prostate cancer radiation therapy  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 .
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 .
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) . 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  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 .
18.3 Risk Factors
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 , and others have shown predictability of mood disorders for fatigue .
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 .
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 .
Correlation between immune serum markers and fatigued patients has been proposed . 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 ; 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 .
18.5 Diagnosis and Scoring
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” .
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 .
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 .
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 , the Piper Fatigue Scale , the Fatigue Symptom Inventory [84, 85], the Lee Fatigue Scale [86, 87], the revised Schwartz Cancer Fatigue Scale , and the Cancer Fatigue Scale .
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 , the Rotterdam Symptoms Checklist , the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality-of-life measure , the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) , the MD Anderson Symptoms Inventory , the Zung Self-Rating Depression Scale , the Visual Analog Fatigue Scale , or multi-item scales such as the Brief Fatigue Inventory .
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 .
Proposed (1998 draft) ICD-10 criteria for cancer-related fatigue is shown in Table 18.1.
Proposed (1998 draft) ICD-10 criteria for cancer-related fatigue
Six (or more) of the following symptoms have been present every day or nearly every day during the same 2-week period in the past month, and at least one of the symptoms is (A1) significant fatigue (A1)
A1. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level
A2. Complaints of generalized weakness or limb heaviness
A3. Diminished concentration or attention
A4. Decreased motivation or interest to engage in usual activities
A5. Insomnia or hypersomnia
A6. Experience of sleep as unrefreshing or nonrestorative
A7. Perceived need to struggle to overcome inactivity
A8. Marked emotional reactivity (e.g., sadness, frustration, or irritability) to feeling fatigued
A9. Difficulty completing daily tasks attributed to feeling fatigued
A10. Perceived problems with short-term memory
A11. Post-exertional malaise lasting several hours
B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
C. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy
D. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium
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:
History and physical examination (disease status and treatment, review of systems, social support status/availability of caregivers, economic status, onset, pattern, duration change over time) 
Assessment of: Treatable contributing factors (pain, anemia, nutritional deficits/imbalance, sleep disturbance/poor sleep hygiene, decreased functional status, emotional distress, drug induced sedation comorbidities (alcohol/substance abuse, cardiac dysfunction, hot flashes, hypothyroidism, hypogonadism, adrenal insufficiency, gastrointestinal dysfunction, hepatic dysfunction, infection, neurologic dysfunction, pulmonary dysfunction, renal dysfunction) 
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 .
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 .
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.
18.6.1 Non-pharmacologic Interventions
There are various non-pharmacologic interventions including exercises (e.g., home-based exercise, supervised exercise), education and counseling, sleep therapy, and complementary therapy. These non-pharmacologic interventions alone or in combination with pharmacologic approaches may be implemented for the effective management of cancer-related fatigue .
Exercise can be helpful for individuals with cancer-related fatigue during and post-cancer therapy [103–108]. Exercise improves patient function during radiation therapy, which is attributed to reduce radiation fatigue and the improvement of quality of life [109–111]. The proposed mechanism of exercise in reducing cancer-related fatigue is balancing in energy resources, attenuation of the progressive muscle wasting, and disruptions in muscle metabolism that occur with cancer and prescribed treatments .
Both home-based exercise and supervised exercise can improve fatigue. Home-based exercise program is a potentially effective, low-cost, and safe intervention , and supervised exercise allows individualizing the exercise regimen to the specific condition of the patient and type of cancer by professional therapists and offers greater motivation. Therefore, supervised exercise might be more effective than home-based exercise in improvement in physical and psychological functioning especially in patients that have cancer or treatment-related morbidity [110, 113–116].
Exercise contraindications (such as extensive lytic bone metastases, extreme thrombocytopenia) should be regarded. Neutropenic patients must avoid environments where the risk of exposure to infectious agents is high (e.g., public swimming pools) ).
Home-based physical activity interventions usually consist of at least 10–30 min per day for at least 2–5 days per week .
Supervised exercise interventions consist of combined aerobic, resistance, and stretching exercises .
18.6.3 Counseling and Education
Education and counseling about cancer-related fatigue, its adverse effects, and strategies to deal with it by telephone or online support programs, comprehensive coping strategy programs or other programs, or organizations have been reported to greatly benefit cancer-related fatigue management [119, 120].
Efforts to educate should be directed at patient’s educational level. Open communication between patient, family, and caregiving team can facilitate discussions about the experience of fatigue and its effects on daily life.
18.6.4 Optimize Sleep Quality
One approach of non-pharmacologic supportive interventions to optimize sleep quality and also decrease cancer-related fatigue is cognitive behavioral therapy, which is a form of psychotherapy that treats problems and boosts happiness by modifying dysfunctional emotions, behaviors, and thoughts.
Cognitive behavioral therapy for insomnia (stimulus control instructions, sleep restriction therapy, and sleep hygiene counseling) seems to improve cancer-related fatigue [120–122].
Due to some inconsistent results, additional research is needed to explore the impact of this intervention on patients with different degrees of insomnia and fatigue.
The aim of stimulus control is to limit the amount of time that patients spend awake in bed. The recommendations consist of going to bed at the same time each night or when sleepy, waking up at the same time every morning, and leaving the bed after 20 min if unable to fall sleep .
The aim of sleep restriction is to limit the amount of time that patients spend in bed to the amount of actual total sleep time to increase sleep consolidation. The protocol includes avoiding afternoon naps and limiting total time in bed .
The sleep hygiene principle consists of a variety of behaviors and environmental factors; it can be implemented by educating patients to avoid heavy meal closest to bed time, avoiding caffeine in the afternoon, and establishing an environment that can promote sleep, such as preparing a dark, quiet, and comfortable bedroom .
18.6.5 Complementary Therapies
Energy conservation such as tai chi (energy arts from China) [122, 123], polarity therapy (energy therapy) , pranayama (control of breath) , and yoga [126, 127] may be effective interventions for managing cancer-related fatigue. Further confirmatory studies are warranted.
The general consideration of energy conservation should be provided to patients like balancing activities with rest, pacing slowly and steadily, selecting the tasks based on priority and eliminating unnecessary tasks, and avoiding poor body posture .
18.6.6 Other Psychosocial Interventions
Cognitive behavior therapy has a clinically relevant effect in reducing fatigue and functional impairments in cancer survivors . Although a variety of cognitive behavioral and psychosocial interventions can be beneficial, discovering what patients benefit from what type of psychosocial intervention is an unresolved issue .
Whether all patients require formal cognitive behavioral therapy by a psychologist or psychiatrist in addition of general counseling is unclear .
Group therapy (approximately six patients per group) may be effective in both emotional and physical symptoms and enhance quality of life for cancer patients undergoing radiation therapy .
The results suggest that relaxation training  and hypnosis  may improve several psychological parameters such as fatigue in ambulatory patients who are undergoing radiation therapy .
Mindfulness-based stress reduction may be a useful therapeutic intervention for improving cancer-related fatigue, although the evidence is preliminary .
18.6.7 Nutrition Counseling
Patients should be encouraged to have adequate intake of fluid* (e.g., 8–12 cups of fluid throughout the day) and adequate nutrition (e.g., high-protein diet) .
Caution should be taken in patients with comorbidities that affect fluid balance (e.g., congestive heart failure).
18.6.8 Pharmacologic Intervention
Methylphenidate (Ritalin®) is a central nervous system (CNS) stimulant that is structurally related to amphetamines with a short half-life and a rapid onset of action.
The results suggest that methylphenidate could be considered in patients with severe cancer-related fatigue [135–138].
Prescribing strategy: start methylphenidate at 5 mg in the morning and 5 mg at noon, titrating as necessary. The maximal dose with the potential for benefit in cancer-related fatigue is 40 mg daily .
Contraindications: hypersensitivity, glaucoma, family history of Tourette’s syndrome or motor tics, marked anxiety, tension, agitation, taking MAOIs within 2 weeks, and risk of severe hypertensive reaction.
Modafinil, a non-amphetamine wake-promoting agent, is used for the treatment of narcolepsy. As compared with other psychostimulants such as methylphenidate, it has a relatively selective site of action in the brain, with resultant fewer adverse effects and lower potential for abuse.
There is insufficient evidence to prescribe modafinil for patients with cancer-related fatigue outside of a clinical trial context [139, 140].
Steroids (e.g., dexamethasone , methylprednisolone , megestrol acetate ) may be effective in cancer-related fatigue in patients with advanced cancer [144, 145]. The possibility of steroid-induced secondary fatigue in terminally ill cancer patients should be taken into consideration .
Antidepressants (e.g., paroxetine) have failed to demonstrate any improvements in fatigue [145, 147]. There are some positive results about bupropion sustained-release efficacy in cancer-related fatigue. Further studies would be necessary to establish the efficacy of this intervention [147, 148].
Guarana (Paullinia cupana) is a plant native to the Amazon basin. Guarana was shown to be effective for fatigue in breast cancer patients receiving systemic chemotherapy. Further studies are needed to confirm its efficacy and its use in radiation therapy-related fatigue .
High doses of American ginseng (Panax quinquefolius) have been shown to be an effective and safe natural supplement for helping manage the fatigue associated with cancer treatment. While data seem promising, additional studies are needed to confirm these findings before ginseng can be recommended as a treatment for cancer-related fatigue .
Multivitamins do not improve radiation-related fatigue .
IV vitamin C administration appears to reduce cancer-related fatigue. Additional well-designed placebo-controlled studies investigating the effects of IV vitamin C on cancer-related fatigue appear warranted .
Donepezil is an inhibitor of acetylcholinesterase used for Alzheimer’s, and dementia was not significantly superior to placebo in the treatment of cancer-related fatigue .
Jereczek-Fossa BA, Marsiglia HR, Orecchia R (2002) Radiotherapy-related fatigue. Crit Rev Oncol Hematol 41(3):317–325PubMed
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