Fatigue is one of the most common symptoms in cancer. This article aims at listing the most important causes that can lead to fatigue in advanced cancer patients. These are the causes of malignancy, the causes of various oncological treatments or the causes of comorbidities. The diagnosis of fatigue is first established through specific questionnaires or even 1-3 targeted questions. The etiological diagnosis is determined by specific laboratory examinations. The psychological consultation is essential. I described the main therapeutic methods represented by non-pharmacological treatments and pharmacological treatments, among which we mention corticosteroids therapy, CNS stimulants, and some natural preparations such as American ginseng.
Oboseala este unul din simptomele cele mai frecvente în cancer. Scopul acestui articol este de a enumera cele mai importante cauze care pot duce la oboseală la pacienții cu cancer avansat. Astfel, sunt citate cauzele legate de existența tumorii maligne, cauzele reprezentate de diversele tratamente oncologice şi cauzele reprezentate de comorbidități. Diagnosticul stării de oboseală este stabilit întâi prin chestionare specifice sau chiar prin 1-3 întrebări țintite, diagnosticul etiologic stabilindu-se prin examene de laborator specifice. Consultul psihologic este esențial. Am descris principalele mijloace terapeutice, reprezentate de tratamente nefarmacologice și tratamente farmacologice, dintre care cităm corticoterapia, stimulentele sistemului nervos central şi unele preparate naturale, cum este ginsengul american.
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.
Hobbies and other types of recreation.
Ability to cope with treatment.
Hope for the future.
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 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).
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 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.
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.
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:
In addition, the following methods may be helpful:
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.
1. Velthuis MJ, Agasi-Idenburg SC, Aufdemkampe G, Wittink HM. The effect of physical exercise on cancer-related fatigue during cancer treatment: a meta-analysis of randomised controlled trials. Clin Oncol (R Coll Radiol). 2010; 22:208-21.
2. Shelton ML, Lee JQ, Morris GS, et al. A randomized controlled trial of a supervised versus a self-directed exercise program for allogeneic stem cell transplant patients. Psychooncology. 2009; 18:353-9.
3. Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol. 2011; 12:160-74.
4. Laoutidis ZG, Mathiak K. Antidepressants in the treatment of depression/depressive symptoms in cancer patients: a systematic review and meta-analysis. BMC Psychiatry. 2013; 13:140.
5. Grassi L, Nanni MG. Demoralization syndrome: new insights in psychosocial cancer care. Cancer. 2016; 122:2130-3.
6. Clarke DM, Kissane DW. Demoralization: its phenomenology and importance. Aust N Z J Psychiatry. 2002; 36:733-42.
7. Laura J. Martin, MD on January 22, 2017, https://www.webmd.com/cancer/fatigue-cancer-related#5
8. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 2.2017. Fort Washington, Pa: National Comprehensive Cancer Network, 2017. Available online with free registration Exit Disclaimer. Last accessed June 29, 2017.
9. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep. 1985; 69:751-4.
10. Della Cuna GR, Pellegrini A, Piazzi M. Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: a placebo-controlled, multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol. 1989; 25:1817-21.
11. Eguchi K, Honda M, Kataoka T, et al. Efficacy of corticosteroids for cancer-related fatigue: a pilot randomized placebo-controlled trial of advanced cancer patients. Palliat Support Care. 2015; 13:1301-8.
12. Paulsen Ø, Klepstad P, Rosland JH, et al. Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial. J Clin Oncol. 2014; 32:3221-8.
13. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy. Cancer. 2010; 116:3513-20.
14. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010; 28:3673-9
15. Yennurajalingam S, Palmer JL, Chacko R, Bruera E. Factors associated with response to methylphenidate in advanced cancer patients. Oncologist. 2011; 16:246-53.
16. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003; 21:4635-41.
17. Roscoe JA, Morrow GR, Hickok JT, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005; 89:243-9.
18. Barton DL, Liu H, Dakhil SR, et al. Wisconsin ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013; 105:1230-8.
19. de Oliveira Campos MP, Riechelmann R, Martins LC, et al. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J Altern Complement Med. 2011; 17:505-12.
20. Jong Soo Jeong JS, Bong Ha Ryu BH, Jin Sung Kim JS, et al. Bojungikki-tang for cancer-related fatigue: a pilot randomized clinical trial. Integr Cancer Ther. 2010; 9:331-8.
21. Iwase S, Kawaguchi T, Yotsumoto D, et al. Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: a multi-institutional, randomized, exploratory trial (JORTC-CAM01). Support Care Cancer. 2016; 24:637-46ç