Introduction
Patients with cancer experience a multitude of bodily changes and symptoms during cancer survivorship. Fatigue is common during the entire course of cancer treatment and has been reported to persist 10 years after cancer diagnosis in breast and gynecologic cancer patients. For patients and their families, this can be a devastating barrier to participation in all aspects of one’s day-to-day experiences, including at work and home. In addition, usual approaches to treating fatigue with self-regulation, such as getting additional rest, may not be entirely effective in pathological fatigue. For providers, cancer-related fatigue (CRF) can also be frustrating to treat given the overall limited understanding of its pathophysiology, treatment options, and prognosis over time.
The American Society of Clinical Oncology (ASCO) endorses CRF to be very common among those treated for cancer, and the majority will experience some amount of fatigue during their treatment course. Prevalence is reported to range from 25% to 99%. Not surprisingly, fatigue has a negative impact on patients’ mood, sleep, and quality of life. In one telephone interview of cancer patients, fatigue was reported to be worse than pain and disrupted day-to-day activity more than nausea, pain, or depression.
Several studies examining fatigue in the general population have found a higher incidence of fatigue in women, which may be in part due to physiologic changes, including menopausal symptoms associated with lower estrogen levels, loss of bone density, and increased atherogenic risk factors. These physiological changes can lead to fatigue. This has certain implications for the breast and gynecologic patient population, as the majority are women, and many undergo treatments that affect estrogen levels or lead to premature menopause.
Thirty percent of breast cancer survivors are estimated to experience CRF up to 5 years after treatment. Others estimate the number to be as high as 50%. Less is known about the amount of fatigue prior to treatment. Numbers of CRF in gynecologic cancer populations were similar. Thirty percent of patients with invasive epithelial ovarian, peritoneal, or fallopian tube cancer reported fatigue in one study. In another study of cervical cancer survivors, 23% of them reported chronic fatigue 11 years after their initial cancer diagnosis. This was double that of an age-related normative sample, estimated at 11.4%.
Definitions
Historically, there is a lack of consensus about the definition of CRF and the method of measurement in research. This, along with heterogeneity of fatigue assessment tools, variation in treatment types, timing of assessments, and when the study was performed, impacts the differences in prevalence of fatigue cited in the cancer population.
The National Comprehensive Cancer Network (NCCN) defines CRF as “an unusual, persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning.” Other descriptors of fatigue include lack of energy, malaise, exhaustion, impaired concentration, and amotivation. Some also suggest making the distinction between central and peripheral fatigue. Central fatigue is defined as the failure to initiate or sustain tasks and activities requiring motivation. Patients may describe themselves as feeling “foggy,” endorse changes in memory or concentration, or experience symptoms akin to depression. Peripheral fatigue, on the other hand, is independent of the central nervous system and is due to neuromuscular fatigue, for example, from cardiopulmonary deficits.
Mechanisms
Despite the pervasiveness of CRF, the mechanisms behind it are not entirely understood. The development and persistence of CRF are multifactorial and at this time can largely be divided into inflammatory, cellular, hormonal, genetic, and metabolic pathways ( Fig. 4.1 ).
Inflammatory
Cytokines are chemical signaling molecules that play a critical role in inflammatory processes in the body. They can induce behaviors associated with sickness, including fatigue, and changes have been noted in those suffering from chronic fatigue syndrome and depression. Multiple cytokines implicated to play roles in CRF may in part explain the persistence of fatigue in patients even after cancer treatment and in those who are devoid of disease. Breast cancer survivors with ongoing fatigue 3–5 years out from treatment were found to have higher than normal levels of proinflammatory cytokines. Fatigue also correlated with increased proinflammatory markers prior to treatment.
Interleukin-6 (IL-6) is a cytokine heavily implicated in immune function, as it is a crucial component to the development and function of lymphocytes. It can act as an activator or inhibitor of T-cell responses, frequently elevated during infections, autoimmune diseases, and in cancer. IL-6 has interesting significance in the ovarian cancer population, as levels are increased compared to patients with other types of gynecologic cancers and may play a critical role in cellular metastasis. IL-6, in addition to other cytokines, including IL-1 and TNF-alpha, contributes to symptoms of anorexia, nausea and vomiting, weight loss, and changes in energy metabolism in ovarian cancer patients. High levels of IL-6 are also associated with stress and depression, while social support appeared to have a protective effect. In patients with ovarian cancer who were to undergo surgery, there were higher levels of IL-6 in those experiencing fatigue. In a separate study, those with higher levels of IL-6 also had worse physical and functional well-being.
Not surprisingly, proinflammatory markers are also noted to increase during cancer treatment. In radiation treatment for early-stage breast cancer, C-reactive protein and IL-1 receptor antagonist level increases were associated with increased levels of fatigue. Similar findings were seen in levels of IL-6 during chemotherapy in breast and ovarian cancers. In ovarian cancer patients, positive associations between levels of IL-6 and fatigue were found.
Cellular
Cellular changes such as alterations in T-cell populations are correlated with inflammatory processes. Elevated leukocyte numbers have been noted in breast cancer survivors with persistent fatigue, though this has not been consistently seen among studies.
Endocrine
In addition to cytokine and cellular mechanisms, disruption of the hypothalamic–pituitary–adrenal (HPA) axis has also been implicated in CRF. Proinflammatory cytokines are stimulators of the HPA axis. In addition, cancer and its treatments can alter endocrine pathways.
IL-6, as discussed earlier, is secreted when the HPA is activated. HPA activity and glucocorticoid levels are associated with social support, suggesting that IL-6 is mediated through HPA activity. Cortisol plays a critical role in mediating inflammation and energy. Breast cancer survivors suffering from fatigue appear to have a less robust cortisol response to psychological stress. In ovarian cancer patients before treatment, higher levels of nocturnal cortisol and reduced cortisol variability were associated with fatigue, in addition to higher functional impairments and depression.
Additional Factors
Autonomic, genetic, and metabolic changes have also been implicated in fatigue in cancer patients. The sympathetic nervous system has proinflammatory associations, with higher levels of norepinephrine and decreased heart rate variability seen in breast cancer survivors with fatigue. In one study, homozygous alleles of IL-6 were associated with higher evening and morning fatigue symptoms, and homozygous alleles of the TNF-alpha gene were associated with higher morning fatigue. From a metabolic perspective, those with metabolic dysfunction such as diabetes had higher levels of fatigue. Interestingly, diabetes is one of the most common comorbidities in breast cancer.
Risk Factors
Studies have looked at various contributors to CRF. Here, we will divide them into psychosocial and behavioral, medical, and other factors.
Psychosocial and Behavioral
Higher levels of stress and impaired coping are associated with fatigue. In one study that examined diurnal cortisol patterns in ovarian cancer survivors, those with greater lifetime stress exposure and severity were more likely to have circadian rhythm disruption that was associated with fatigue. In contrast, those with high social attachment had characteristic changes in their cortisol rhythms that suggest social support to be a buffer against stress or release of cortisol from the HPA axis. A metaanalysis that examined risk factors for fatigue in breast cancer patients demonstrated that survivors who had a partner had a lower risk of severe fatigue than those without a partner. Other studies have shown that those who expected to experience fatigue or catastrophized, or frequently engaged in negative thoughts about fatigue, had higher levels of fatigue.
The relationship between depression and fatigue is not unidirectional, but it is clear that both depression and fatigue are correlated in cancer populations. These relationships between anxiety, depression, and CRF are seen during active treatment and also after completion of treatment. In Prue’s study that looked at the gynecological population, psychological distress level was the only independent predictor of CRF during treatment. In cervical cancer survivors, those with chronic fatigue have also reported higher levels of anxiety and depression and showed poorer self-reported health and less healthy lifestyle indicators. Psychological distress is also associated with chronic fatigue in breast cancer survivors. Breast cancer patients with a history of mental disorder prior to their cancer diagnosis appear to be at risk for posttreatment fatigue. To that effect, stress reduction via mindfulness has shown improvement in distress and fatigue, and this will be explored in more detail later in this chapter.
Medical and Treatment-Related Characteristics
There is conflicting data on whether sociodemographic variables, age at diagnosis, and treatment-related factors are associated with CRF. For example, mixed findings exist on whether age, marital status, disease stage, and treatment characteristics are associated with fatigue in breast cancer patients; most of these studies included small numbers of patients. In a metaanalysis of over 12,000 breast cancer survivors, those with more advanced disease had increased risk of posttreatment fatigue. Risk was also higher in those treated with chemotherapy than those without. Isolated radiotherapy, hormone therapy, and targeted therapy were not significant risk factors. Those treated with combination surgery, chemotherapy, and radiotherapy were at higher risk than other treatment combinations; additional hormone therapy increased the risk. In studies of women with gynecologic cancers, single chemotherapy and combination chemotherapies have been associated with higher levels of fatigue.
It is important to remember that even in survivorship, patients can experience effects from original treatment, such as peripheral neuropathy, lymphedema, sexual dysfunction, GI distress, and urinary problems. All of these conditions have been shown to have an association with chronic fatigue. In a case–control study, epithelial ovarian cancer survivors, neurotoxicity, depression, and sleep disturbance were significant predictors of severe, long-term fatigue. This emphasizes the importance of performing a thorough review of systems throughout the care continuum, including in survivorship, and to treat symptoms that may contribute to CRF.
Other Risk Factors
Variations in genes associated with inflammatory markers have been suggested to play a role in the development of CRF. There are inconsistent findings of polymorphisms in TNF-alpha, IL-6, and IL-1B associated with higher levels of fatigue in breast cancer patients. Physical activity levels have also been implicated to affect CRF, with inactivity, impaired cardiopulmonary status, and high BMI correlating with the presence of CRF in breast cancer patients.
Screening
In an effort to identify patients who have CRF, those who are at risk and provide efficient treatment, screening of most patients who have a diagnosis of cancer or have completed cancer treatment should be performed. There is a lack of consensus on a primary fatigue screening tool. The NCCN recommends that once fatigue is identified, then determine the degree of fatigue on a numeric scale (0–10) or by discerning among mild (1–3), moderate (4–6), or severe fatigue (7–10). Those with no fatigue or mild fatigue can be provided with education and basic management tips with ongoing evaluation at routine clinic visits; patients with “red flags” such as new or worsening fatigue should be encouraged to reach out to their healthcare provider. Those who rate higher levels of fatigue or with moderate–severe fatigue should trigger a more extensive and thorough workup of fatigue in addition to being provided with basic educational and management information. A multitude of fatigue screening tools have been identified; some common fatigue scales used in breast and gynecologic CRF screening are included in Table 4.1 .
| Instrument | Type of Instrument | Comments |
|---|---|---|
| FSI | 11-Point Likert | Studied in breast and mixed cancers that included ovarian and endometrial cancers |
| BFI | 11-Point Likert | Studied in mixed cancers that included breast and gynecologic |
| EORTC-QLQ-C30 | 4-Point Likert | Studied in mixed cancers, including breast and gynecologic |
| MFSI-SF | 5-Point Likert | Studied in breast and mixed cancers, including ovarian, endometrial, and cervical cancers |
| PROMIS Cancer Fatigue | 1 (never) to 5 (always) | Studied in mixed cancers, including breast and gynecologic |
Approach to Patient With Cancer-Related Fatigue
Assessment
Patients with moderate-to-severe fatigue determined by the aforementioned systematic screening approaches require a comprehensive clinical assessment, including a focused physical examination, select laboratory studies, and pertinent imaging to best direct treatment. When gathering the history, clinicians should focus on onset, duration, temporal pattern throughout the day, alleviating/aggravating factors, and trajectory (i.e., whether the fatigue is getting worse or better over time). Particular attention should be devoted to ruling out medical- and substance-related causes of fatigue. A thorough review of current medications, including supplements, substance use, sleep pattern, and nutrition, is warranted. Table 4.2 outlines medical and substance use causes of fatigue.
| Sleep disturbance |
| Hypothyroidism |
| Depression |
| Anxiety |
| Pain |
| Dyspnea |
| Dehydration |
| Infection |
| Anemia |
| Electrolyte abnormality (hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia) |
| Progression of disease |
| Malnutrition |
| Medications |
| Alcohol |
| Marijuana medicinal or recreational |
Finally, one of the most important aspects of the patient assessment is to determine how fatigue is affecting a patient’s quality of life and function, including mobility, ability to perform activities of daily living, social, leisure, and vocational pursuits.
Physical Exam
After obtaining a detailed history a focused physical exam should be completed. For general appearance, clinicians should note any apparent distress, frailty, or cachexia. A focused exam should include evaluation for dry mucous membranes (dehydration), conjunctival pallor (anemia), and angular cheilosis (vitamin deficiencies). Cardiopulmonary exam should note any arrhythmias, cyanosis, tachypnea, or accessory muscle use. A musculoskeletal exam should note any atrophy and include evaluation of overall strength with manual muscle testing. Neurological exam can assess for polyneuropathy that may be contributing to fatigue. A flat or withdrawn affect noted on psychiatric exam may indicate underlying depression.
Laboratory Studies
Initial diagnostic workup should include specific laboratory studies to help determine underlying contributors to fatigue. A complete metabolic panel can show disturbances in sodium, calcium, potassium, magnesium, and glucose that can all worsen energy levels. Blood urea nitrogen and creatinine are important to rule out dehydration and renal insufficiency. Underlying hepatic dysfunction as noted by transaminitis and hyperbilirubinemia can also contribute to a patient’s presentation. Albumin and total protein are markers of nutritional status. Studies such as HgbA1C and thyroid-stimulating hormone can rule out endocrine dysfunction. Complete blood count with differential can assess for factors related to fatigue such as underlying infection or anemia.
Other Diagnostic Testing
Imaging can be important to look for progression of disease, overall disease burden, and infection that all could be contributing to fatigue. Conversely, stable imaging may lead to looking for alternative causes of worsened fatigue. Electromyography and nerve conduction studies can assess for underlying neuromuscular disorders that can possibly contribute to fatigue. Finally, an echocardiogram and electrocardiogram can determine if poor cardiopulmonary reserve or arrhythmias are involved.
Ultimately, a comprehensive history, physical examination, and diagnostic workup are crucial to determining appropriate patient-centered treatment plans ( Fig. 4.2 ).
Treatment
For cancer patients with moderate-to-severe fatigue, the first-line approach to treatment is to address any reversible contributing factors. It is important to stop or at least reduce sedating medications. Common culprits in the cancer population include opioids and benzodiazepines. Untreated or undertreated depression, anxiety, and pain can worsen fatigue and thus addressing these contributing factors both nonpharmacologically and pharmacologically is necessary. After careful review of laboratory studies, providers can correct endocrine and fluid/electrolyte abnormalities with medication, supplements, and appropriate specialist consultation. In those patients who have anemia, erythropoietin-stimulating agents may provide some improvement to fatigue although come with risk of adverse events. A nutritionist may need to be seen for any dietary deficiencies. Finally, if poor sleep is an issue, strategies to improve sleep hygiene and potentially pharmacologic treatment may be warranted.
If fatigue remains moderate-to-severe despite adequately treating all contributing factors, nonpharmacologic and pharmacologic management may be indicated. Before reviewing the evidence for a variety of CRF treatment interventions, it is important to note that most robust evidence for the treatment of CRF comes from studies with mixed cancer diagnoses with an ample amount of studies dedicated specifically to breast cancer patients and far less dedicated to the gynecological cancer population. For example, for those studies that evaluated exercise as a treatment modality, there were only two smaller studies done specifically in the ovarian cancer population, and there was sparse data that examines cervical and uterine cancers specifically. Of the many mixed cancer population studies, breast cancer patients tend to make up a high proportion of participants. It is unclear, however, whether results from a mixed cancer population study can be generalized to the specific patient populations of breast and gynecologic malignancies. For the purpose of this chapter, the authors will focus on evidence from the breast and mixed cancer population given the limited amount of studies on the gynecologic cancer population.
Nonpharmacologic
Education and Counseling
One of the first steps to treating CRF is through educational interventions. Several patient-friendly resources for CRF can be found on the websites of the NCCN, National Cancer Institute, American Cancer Society, and the ASCO’s patient information website Cancer.Net . The NCCN Clinical Practice Guidelines in Oncology for cancer-related fatigue recommends education and counseling as the key management strategy. Patients should be taught how to recognize CRF, including its natural history and temporal relation to specific cancer treatments. In addition, education on how best to manage the condition through energy conservation techniques, optimal sleep hygiene, diet, exercise, and mindfulness should be provided. Patients should be instructed to monitor their fatigue levels throughout the day with the use of a fatigue diary. Energy conservation techniques such as task delegation, adequate pacing of activities and avoiding multitasking are another key component of a fatigue education session. In a systematic review of 14 randomized controlled trials with 2213 participants who had mixed cancer diagnoses, educational interventions had a moderate effect in reduction of CRF distress and a small effect on reduction of fatigue intensity and fatigue’s interference with daily life. Finally, there is substantial high-quality evidence to support cognitive behavioral therapy as an effective treatment tool for CRF.
Exercise
Many randomized controlled trials and metaanalyses have demonstrated the effectiveness of exercise in the treatment of CRF among various cancer types. The breast cancer population in particular has some of the most robust research in support of exercise as an effective treatment strategy for CRF. In a systematic review of nine high-quality studies ( n =1156), supervised resistance and aerobic exercise was found to be more effective than conventional care for treatment of CRF in breast cancer survivors. This review not only showed efficacy but also safety of exercise, even at high volumes for this patient population. Exercise as a treatment for CRF in the breast cancer population is not just beneficial to survivors but also those undergoing chemotherapy.
While there is some evidence that aerobic versus resistive exercise programs show similar benefit in their effect on CRF and that supervised exercise programs may have additional benefit when compared to unsupervised programs, determination of specific exercise prescription and intensity has yet to be determined for our patients with breast and gynecologic malignancies.
While it is widely accepted that exercise is an effective treatment for CRF, it is important to note that this modality may be contraindicated in certain patients. Precautions should be taken for patients with extensive lytic bone metastases, severe thrombocytopenia, active infections, and other safety concerns.
Nutrition
As CRF has been linked to chronic inflammation, there is some evidence to suggest that a diet high in antioxidant nutrients may provide benefit for breast cancer patents. Increased intake of omega-3 fatty acid–rich foods, known for their antioxidant effects, has been correlated with decreased physical aspects of fatigue among breast cancer survivors. In their pilot randomized clinical trial, Zick et al. utilized a fatigue reduction diet that consisted of fruit, vegetables, whole grains, and foods with high omega-3 fatty acid content. Over the course of 3 months, breast cancer survivors who followed the fatigue reduction diet demonstrated significantly less fatigue than the control group.
Carnitine deficiency is also thought to play a role in the development of CRF and while a few nonrandomized and open-label studies showed improvement in fatigue with carnitine supplementation, a metaanalysis failed to show a significant reduction in CRF. Ginseng, ginger, guarana extract, and probiotics have similarly been studied in CRF treatment with promising results.
Complementary and Alternative Medicine
Of the variety of complementary and alternative medicine (CAM) approaches to CRF, acupuncture is perhaps the most studied and has some robust evidence for efficacy, particularly among the breast cancer population. In their metaanalysis, Zhang et al. found that in the 10 randomized controlled trials that met inclusion criteria, there was a marked effect on CRF in patients with mixed cancer diagnoses who were and were not receiving concurrent chemotherapy or radiation. Furthermore, they found that acupuncture could reduce CRF when compared to sham procedure or usual care. This effect was seen with a variety of treatment timing and durations, from 20- to 30-minute sessions multiple times per week for as short as 2 weeks to once weekly sessions for 6 weeks. Effect size was particularly high among breast cancer patients. An earlier metaanalysis also showed favorable results in support of acupuncture in terms of reduction in CRF from baseline to follow-up; however, the majority of pooled comparisons did not show statistically significant differences. Results from yet another metaanalysis of seven RCTs were inconclusive with authors citing low quality and quantity of trials. While there may be mixed results for acupuncture, there appears to be a clear understanding that this modality, when performed by experienced practitioners, is safe and well tolerated. The overall safety of this therapy, along with the most recent metaanalysis’ positive findings, makes acupuncture a promising treatment approach for CRF.
A modality of traditional acupuncture, infrared laser moxibustion, is another exciting potential treatment for CRF. A randomized, double-blind, placebo-controlled trial showed improved Brief Fatigue Inventory scores following 4 weeks of 10.6 μm of infrared laser moxibustion on the ST36 (bilateral), CV4, and CV6 acupoints compared to control group who received sham procedure to the same acupoints. While this study’s patient population consisted of mixed cancer types, breast (25.6%) and ovarian/endometrial/cervical (10.3%) cancer accounted for over a third of the diagnoses. A randomized controlled trial looking specifically at moxibustion’s effects on CRF in breast cancer survivors is ongoing.
Yoga, another popular CAM modality, may provide some benefit to those with CRF especially in the short-term period among breast cancer survivors. There was moderate-to-large effect of yoga on CRF among posttreatment breast cancer patients in a metaanalysis of 17 qualified studies with positive results also noted among intratreatment patients though, with only small effect size. In their review of 11 studies, including a total of 883 patients with breast cancer that compared yoga versus no therapy, Cramer et al. demonstrated moderate-quality evidence showing that yoga reduced fatigue in the short term (6–12 weeks), but only low-quality evidence of longer lasting effects (30–40 weeks). When compared with more traditional forms of exercise, yoga had only very low-quality evidence to suggest similar efficacy. Yoga, thus, appears beneficial, at least in the short term, in reduction of CRF but should not necessarily replace a more traditional exercise program.
Mindfulness-based approaches may be an effective tool to reduce fatigue in cancer patients. In a systematic review of 245 studies, relaxation exercise or meditation was the highest ranked intervention when compared to CBT, aerobic exercise, resistance exercise, and yoga among patients concurrently receiving cancer treatment. In the breast cancer population specifically, a review of 14 studies revealed statistically significant reduction in fatigue following a mindfulness-based stress reduction intervention.
Pharmacologic
Exercise and psychological interventions for the treatment of CRF have been found to be significantly better than pharmacologic options overall. Some clinical guidelines even recommend strongly against the use of pharmacologic agents. While nonpharmacologic approaches may be first-line, pharmacologic interventions may have a role in specific patient groups such as those at the end of life.
Methylphenidate, the central nervous system stimulant used for attention-deficit/hyperactivity disorder, has the most evidence for reducing CRF. However, risks of anorexia and sleep disturbance, issues of great concern in a cancer patient population, may not outweigh the potential benefits. In those patients with advanced disease and limited life expectancy, those risks may not be as important to achieve a good quality of life and thus methylphenidate and other stimulants may be indicated.
Modafinil, another central nervous system stimulant used in the treatment of fatigue related to narcolepsy and shift work sleep disorder, has had mixed results in its treatment of CRF. While at least one randomized, placebo-controlled, double-blind clinical trial of 631 patients with mixed cancer types on active chemotherapy showed a significant interaction between treatment condition and baseline fatigue in a subgroup of those with severe fatigue levels, those with mild-to-moderate fatigue had no significant effect. Modafinil is thus likely best utilized for patients with severe fatigue currently undergoing active treatment.
Glucocorticoids such as dexamethasone are not currently recommended by the ASCO but are commonly prescribed by hospice providers for patients with advanced cancer and at least one double-blind, randomized, placebo-controlled trial showed greater efficacy than placebo ( Table 4.3 ).
