Recent research has expanded our understanding of possible causes of CRF including inflammatory and immune responses from the cancer and/or its treatment. Inflammation is present at all stages of cancer, before treatment, during treatment, and even persisting up to a year posttreatment, which seems to correspond well with the onset and duration of fatigue [4]. In fact, a study comparing the levels of a number of markers in patients’ serum found that the pro-inflammatory cytokine IL-6 was the single best indicator differentiating healthy controls, patients with locoregional breast cancer, and those with metastatic breast cancer [14]. This is of particular interest due to the observation that elevation in the blood levels of pro-inflammatory cytokines, secreted proteins which influence the behavior of other cells, are known to generate fatigue-like symptoms in both humans and animal models [15], potentially through alterations in neuronal dopamine synthesis, release, and reuptake [16].

In early-stage cancer the tumor itself appears to be the source of inflammatory cytokines [17, 18], while after treatment cytokines are generated in the course of the response to treatment-induced tissue damage [19]. Clinical observation of patients with untreated breast cancer, acute myeloid leukemia (AML), and myelodysplastic syndrome reveals that inflammatory markers such as C-reactive protein (CRP) and a number of interleukins are present pretreatment [20–22].

It is well known that many cancer patients who undergo radiation or chemotherapy exhibit a marked increase in their fatigue [12] and a sharp increase in circulating levels of inflammatory markers [23, 24]. The levels of these markers of inflammation appear to correlate with severity of CRF from patient to patient [25]. In a within-subject study of early-stage breast cancer and prostate cancer patients before, during, and after radiation therapy, elevations in the levels of inflammatory markers CRP and IL-1RA correlated with increases in fatigue; however, elevations in IL-6 and IL-1β did not [26], indicating that there may be no single pathway by which inflammation contributes to fatigue.

Studies in animal models have been somewhat informative in unraveling the effects of inflammation and appear to confirm a role for inflammatory cytokines in CRF. Growth of ovarian tumors in mice causes increases in the levels of a number of inflammatory markers, including IL-6 and TNF-α, both locally and in systemic circulation and that these animals, while still physically capable of movement, display a reduction in spontaneous locomotion [27]. Total body irradiation of mice, the best model of radiation therapy, causes an increase in several inflammatory markers, including plasma IL-6, that lasts up to 24 h after treatment [28]. Increase in those markers correlates with a reduction in locomotion, the most common metric of animal fatigue, that persists up to 2 weeks after treatment mirroring the human tissue recovery response to irradiation [28, 29].

Overall, while the correlation between CRF and inflammation in patients remains strong, whether inflammation causes that fatigue remains unclear, and in fact one study of newly diagnosed breast cancer patients found no correlation between levels of CRP and fatigue severity [30]. This confusion exists in no small part due to uncertainty of the neurological mechanism by which inflammation causes fatigue. Further work, both at the clinical and preclinical level, is needed to uncover the mechanisms by which cancer and its treatments influence inflammation both locally and systemically, determine how inflammation affects CRF, and identify biomarkers for diagnosis and targets for intervention that may reduce fatigue.

A number of pharmacologic agents including psychostimulants, corticosteroids, supplements, and antidepressants have been tested in the treatment of CRF with mixed results.

Although there is significant interest in the utilization of herbal and dietary supplements in treating fatigue, few controlled studies have been conducted in cancer patients.

Antidepressants as treatment for CRF are being studied in animal models, but limited data are available in human trials. One placebo-controlled RCT of paroxetine 20 mg daily in patients with mixed solid tumors showed no difference in CRF between the placebo and paroxetine groups [54].

Lack of quality sleep can impact one’s level of fatigue. Cancer treatment and CRF both correlate strongly with a range of sleep disorders often brought on by a disruption in circadian rhythms. Commonly reported issues are insomnia, hypersomnia, and disrupted sleep patterns [55]. Sleep disorders including insomnia are more common in cancer patients compared to the general public [56]. This may be due to the psychological, behavioral, and physical effects of a cancer diagnosis and treatment. The American Association of Sleep Medicine recommends cognitive behavioral therapy for insomnia (CBT-I). CBT-I is defined as “a non-pharmacological treatment that incorporates cognitive and behavior-change techniques and targets dysfunctional attitudes, beliefs, and habits involving sleep” [56].

Results of a systematic review of CBT-I in cancer patients suggest that CBT-I is associated with statistically and clinically significant improvements in subjective sleep outcomes and may improve mood, fatigue, and overall QOL in patient with cancer [56].

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, and loss of adipose tissue and skeletal muscle and is associated with impaired function, quality of life, and fatigue [57]. Interventions under study in cancer cachexia include anabolic steroids, appetite stimulants, ghrelin analogs, and anti-myostatin agents, to name a few. Anabolic steroids are being studied in cancer cachexia but end points are muscle mass and strength and weight and have not included fatigue measures. Novel agents inhibiting myostatin which is a normal negative regulator of muscle growth have shown the ability to increase muscle volume [58]; however correlation between change in the volume of muscle mass and level of fatigue is yet unknown.

Physical activity is reduced in many cancer patients at some time throughout their disease experience. There are few studies that discern the potential contribution of muscle disuse and muscle wasting to CRF. Research is needed to better define skeletal muscle changes that may contribute to CRF and the utility of exercise and other muscle-building strategies in treating fatigue associated with muscle disuse and wasting [59].

Current recommendations include that all patients at the time of diagnosis of cancer undergo an evaluation of the level of fatigue and continue regular assessments throughout treatment and recovery [1, 60]. A variety of validated assessment tools are available to health-care providers to assess for the presence and severity of fatigue, from a simple 1–10 rating scale which is the gold standard to more complex multidimensional scales commonly used in research (Table 10.1). Patients who report moderate or severe fatigue (e.g., ≥4 on a 1–10 scale) should be further assessed and examined for any underlying conditions and treated appropriately.

Evaluating a cancer patient with existing fatigue requires a careful history and physical examination looking for symptoms and signs that suggest contributing factors to the fatigue (Table 10.2). Patients are most worried about the status of their cancer and fear that recurrence or progression of disease is causative. Concurrent medications, especially narcotics, can contribute to sedation and fatigue. In some cases, adding a nonnarcotic such as an NSAID, if not contraindicated to the patient’s analgesic regimen, can decrease the need to escalate the dose of narcotic. A review of the patient’s alcohol and illicit drug use along with any social or financial stresses and symptoms of depression can open a discussion of available resources of support in the community. Sleep quality and disruption should be assessed. Patients who are dehydrated note significant fatigue and can benefit promptly with IV hydration. Attention to the patient’s endocrine function can reveal an undiagnosed hypothyroidism or a low testosterone level. Of note, men who are chronically ill or on chronic narcotics commonly have low testosterone levels that can easily be supplemented. Hemoglobin and hematocrit levels should be assessed and anemia treated according to the ASCO/ASH guidelines [61]. Identifying and treating other organ system dysfunctions, such as CHF from prior anthracycline use, can make a significant impact in the patient’s level of fatigue. A thorough assessment and identification of contributing factors of fatigue in each patient will lead to potential individualized management strategies (Table 10.3).