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Introduction

Fatigue, defined as a persistent sense of tiredness which is not relieved by sleep or rest, is an extremely common problem amongst palliative care patients and causes significant distress. A systematic review of symptoms in patients with advanced cancer indicated that more than half of them had experienced fatigue. It is likely that the presence and intensity of these symptoms increases as the patient’s disease progresses. The negative impact on the quality of life of patients and their caregivers is substantial. The prevalence of fatigue is likely to be similar or indeed higher in patients with other progressive chronic diseases, including HIV/AIDS, heart disease, chronic obstructive pulmonary disease, and renal disease. Careful assessment is needed to ensure appropriate differentiation of fatigue and depression^(1,2).

Fatigue is considered one of the most frequent symptoms in palliative care patients, reported in 80% of cancer patients and in up to 99% of patients following radio- or chemotherapy (Lukas Radbruch, et al.).

Causes of fatigue

Cancer-related fatigue is often multifactorial. A thorough assessment will help in identifying the unique physiologic and psychologic factors contributing to patients’ fatigue. 

A possible cause of fatigue is depression. Sometimes depression could be confounding with fatigue. Depression has an overall prevalence of 21%, with depression or adjustment disorder seen in 32% of patients, and any mood disorder in 38% of patients⁽³⁾.

Patient Health Questionnaire (PHQ-2) has a sensitivity of at least 80% and a specificity of 90%. The PHQ-2 asks the questions: “During the last month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the last month, have you often been bothered by having little interest or pleasure in doing things?”. Patients with cancer and depression generally respond to antidepressants⁽⁴⁾.

Demoralization was considered a relatively new clinical entity with which many healthcare providers and patients are not familiar. This entity is part of the depressive syndromes, but has different causes and is included in existential distress⁽⁵⁾. It is recommended to listen to the patients and help them by refocusing on personal coping strategies that have worked in the past⁽⁶⁾. Many other causes of fatigue are mentioned in Table 1.
 

All treatments of cancer may have as side effects the occurrence of fatigue. Any chemotherapy drug may cause fatigue. Patients frequently experience fatigue after several weeks of chemotherapy, but this varies among them. In some patients, fatigue lasts a few days, while in others it persists throughout and after the treatment is complete.

Radiation therapy can cause cumulative fatigue. This can occur regardless of the treatment site. Fatigue usually lasts from three to four weeks after treatment stops, but can continue for up to two to three months.

Other therapies like biological therapy with interferons and interleukins in high amounts can be toxic and lead to persistent fatigue.

Other factors that may contribute to cancer-related fatigue include: tumor-induced hypermetabolic state and decreased nutrition as a side effect of treatments (such as nausea, vomiting, mouth sores, taste changes, heartburn or diarrhea). Anemia, which is frequent in cancer treatments, can be manifested by fatigue.

Other causes of fatigue could be hypothyroidism or hyperthyroidism. Medications used to treat side effects, such as nausea, pain, depression, anxiety and seizures, can cause fatigue. It is also known that chronic, severe pain increases fatigue⁽⁷⁾.

The main effect of fatigue is the modification of the quality of life. For some patients, cancer-related fatigue is not so badly perceived, while others find that it makes life difficult, negatively affecting different aspects of life:

• Mood and emotions.
• Daily activities.
• Job performance.
• Hobbies and other types of recreation.
• Social relationships.
• Ability to cope with treatment.
• Hope for the future.

Diagnosis

The state of fatigue is diagnosed by the application of a questionnaire, FACIT-F being one of the most complex questionnaires. Sometimes, a unique question can lead to establishing the diagnosis.

The etiologic diagnostic of fatigue is made by clinical examination and special laboratory elements, which characterize the many clinical entities that can underpin it.

The FACIT-F questionnaire include: physical well-being, social/family well-being, emotional well-being, functional well-being, additional concerns.

Treatment

The recommendations for fatigue management focus on identifying factors that may be contributing to fatigue. Because the only definitive causal mechanism demonstrated by research to date is chemotherapy-induced anemia, most clinical recommendations for managing fatigue with other causes than chemotherapy-induced anemia rely on careful development of clinical hypotheses, as outlined in the National Comprehensive Cancer Network guidelines on fatigue. The only level 1 intervention for CRF at this time is exercise. Much more research is needed to better define fatigue and its trajectory, understand its physiology, and determine the best ways to prevent and treat it⁽⁸⁾.

Pharmacologic interventions

The use of pharmacologic agents for the management of cancer-related fatigue is a dynamic area of practice and study, because for the moment there are not sufficiently effective drugs.

Steroids

Steroids are one of the most common medications used to treat fatigue and a number of other symptoms in patients receiving palliative care. The existing data are derived from studies focused primarily on cancer patients with advanced disease managed in a palliative care setting. A randomized clinical trial from 1985 found a significant improvement in the “activity” in 77% of patients receiving methylprednisolone at a dosage of 32 mg daily compared with 68% of those receiving placebo⁽⁹⁾.

Another study  showed that methylprednisolone had  significant improvement in the quality of life, but authors do not provided the score of the test⁽¹⁰⁾.

Two other studies used 32-mg/day methylprednisolone orally for 7 days, and yielded conflicting results^(11,12).

Another study demonstrated the efficiency of dexamethasone: the administration of dexamethasone at 4 mg twice a day significantly alleviated fatigue for 2 weeks in patients with advanced cancer, without important side effects.

Stimulants

Psychostimulants are one of the most widely studied pharmaceutical classes used for the treatment of cancer-related fatigue. This drug class includes methylphenidate, D-methylphenidate, dextroamphetamine, modafinil and armodafinil. Most randomized controlled trials have been conducted with methylphenidate and modafinil; however, the results have been mixed, with several studies showing no benefit. Secondary analyses have shown that patients with more severe fatigue or more advanced disease may benefit from the use of psychostimulants, whereas those with mild to moderate fatigue do not^(13,14).

Day 1 responses predict longer-duration responses with 85% accuracy, so the drug can be stopped in a few days if it is found to be ineffective⁽¹⁵⁾. In Romania, we have not experience with these drugs.

Other compounds

Selective serotonin reuptake inhibitor paroxetine demonstrated no benefits^(16,17).

American ginseng (Panax quinquefolius) was studied in a dose of 2,000-mg daily; the authors identified a significant improvement in physical fatigue at 8 weeks⁽¹⁸⁾.

The extract from the highly caffeinated guarana (Paullinia cupana) plant, at a dosage of 50 mg orally twice daily, and the extract from bojungikki-tang (a mixture of 10 medicinal plants) at a dosage of 2.5 g thrice daily have been shown to statistically significantly reduce fatigue after 3 weeks and 2 weeks of treatment, respectively^(19,20).

A recent Japanese study of a proprietary amino acid jelly containing coenzyme Q10 and L-carnitine did show an improvement in fatigue in breast cancer patients receiving chemotherapy⁽²¹⁾.

Other strategies to cope with fatigue are lifestyle changes. These include:

Physical activity. Staying or becoming active can help relieve cancer-related fatigue. Ask your doctor which types of physical activity are best for you. And ask about recommended levels of physical activity. These recommendations may change during and after cancer treatment. Some people may benefit from working with a physical therapist, particularly if they have a higher risk of injury. This may be due to cancer, cancer treatment, or other health conditions. Physical therapists help patients increase or maintain physical functions.

Counseling. Talking to a counselor may help reduce fatigue. For example, cognitive behavioral therapy may help you do the following:

• Reframe your thoughts about fatigue
• Improve coping skills
• Overcome sleep problems that contribute to fatigue.

Mind-body strategies. Evidence suggests that these can reduce fatigue in cancer survivors:

• Mindfulness practices
• Yoga
• Acupuncture.

In addition, the following methods may be helpful:

• Touch therapy
• Massage
• Music therapy
• Relaxation
• A form of touch therapy called reiki
• A type of relaxation and meditation called qigong.

However, researchers have not yet thoroughly studied the results of these strategies. 

Cancer.Net Editorial Board, 3/2017, https://www.cancer.net/navigating-cancer-care/side-effects/fatigue