Fatigue is common in cancer patients treated with chemotherapy, and it has detrimental effects on their quality of life. Chemotherapy-induced anemia, however, is often under-recognized and under-treated. There is a clear association between hemoglobin (Hgb) levels and fatigue, with fatigue being greater in patients with lower Hgb levels. Managing fatigue requires that its causes be determined and corrected, and it is important that patients report their fatigue. Patients, however, are unlikely to mention such adverse events unless they are asked about them. In addition, busy practitioners generally have very little time to discuss anemia-related fatigue with their patients. Many studies have used the validated quality-of-life instrument Functional Assessment of Cancer Therapy-Fatigue (FACT-F) to assess fatigue and quality of life in patients treated with chemotherapy; these studies have shown a relationship between chemotherapy-induced anemia, fatigue, and quality of life. Studies of erythropoiesis-stimulating proteins to treat chemotherapy-induced anemia have shown increases in patients' hemoglobin levels, improvement in their FACT-F and FACT-General scores, and improvements in their quality of life.
Fatigue is common in patients treated with chemotherapy, and it has substantial adverse physical, psychosocial, and economic consequences. Cancer-related fatigue is generally under-recognized and under-treated. Fatigue occurs on at least a few days of each month in 76% of patients treated with chemotherapy, and has been reported to occur daily in 32% of patients treated in the United States and in 24% of patients treated in Ireland. Physicians in the United States either offered no treatment or prescribed bed rest in 77% of cases, as did physicians in Ireland in 87% of cases.[1,2] Patients and their physicians are now paying closer attention to fatigue and anemia. These and other adverse events are often managed in the context of maintaining the chemotherapy dose and schedule.
Discussions about fatigue and anemia generally lack the interactivity to distinguish the cause of the fatigue from other problems such as sleep disorders, poor nutrition, cancer, and depression. Patients are often reluctant to volunteer information about adverse events and will discuss them only if they are asked specifically about them. The physician or nurse generally initiates these discussions: they are usually short—less than a minute—and often only one question about fatigue is asked. In contrast, the most commonly used fatigue scale in this setting contains 13 items. Physicians do not generally use such instruments for assessing fatigue, or use only parts of them. In addition, 90% of the questions about adverse events are simple yes or no questions that cannot fully capture the patient's feelings and experiences. Furthermore, physicians often speak in words and terms that their patients cannot understand. In this article I discuss the use of erythropoiesis-stimulating proteins (ESPs) in patients with fatigue resulting from chemotherapy-induced anemia, and their effects on patients' quality of life (QOL).
Managing fatigue requires that it be properly assessed and its causes determined and treated. It is not linked solely to anemia or any other disease or cause, and it can also result from depression, pain, sleep disorders, and other conditions.[1,4] The symptoms of fatigue can be treated with pharmacologic and nonpharmacologic interventions, but many of the pharmacologic interventions, such as psychostimulants and low-dose corticosteroids, have not been thoroughly tested in the setting of fatigue. Among the nonpharmacologic interventions for cancer-related fatigue are patient education, exercise, modification of activity and rest patterns, stress management, cognitive therapies, and dietary changes.
The precise relationship between hemoglobin (Hgb) levels and fatigue is not known, but it is clear that there is a link, and fatigue is greater in persons with lower Hgb levels.[5,6] Even small increases in patients' Hgb levels can improve their fatigue and anemia-related symptoms. Instruments that measure QOL such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An, consisting of the FACT-General [FACT-G] plus 13 fatigue items and 7 nonfatigue anemia-related items) can be used to discriminate patients on the basis of Hgb level and fatigue. Gabrilove and colleagues conducted a trial of epoetin alfa (Procrit) given once a week in patients with nonmyeloid malignancies and showed that the scores on the FACT-An were significantly higher in those with an increase in Hgb levels of 2 g/dL or more than in those with smaller increases.
Cella and colleagues administered the FACT-G to patients with cancer and found that the scores on the FACT-G, as well as on the items for fatigue and nonfatigue, physical well-being, and functional well-being, were significantly better in those with Hgb levels of 12 g/dL or higher than in those with lower levels (P ≤ .02) (Table 1). These findings were confirmed in a large community trial in patients with anemia who were treated with chemotherapy and epoetin alfa, in whom the improvements in QOL measures correlated significantly with Hgb levels (r = .235; P < .001), independent of the response to chemotherapy. Cella and colleagues also administered the FACT-Fatigue (FACT-F, consisting of the FACT-G plus 13 fatigue items) (Table 2) to 375 patients with cancer and to a sample of 1,400 persons in the general population, and, as expected, fatigue was more severe and more common in the patients with cancer.
Decreasing Fatigue and Improving Quality of Life
Erythropoiesis-stimulating proteins are indicated for the treatment of chemotherapy-induced anemia, and they have been shown in clinical trials to correct or prevent anemia and to decrease the need for red blood cell transfusions. In an analysis by Cella and colleagues of pooled data from five clinical trials in patients with cancer who were treated with the long-acting ESP darbepoetin alfa (Aranesp), there was a significant correlation between increases in Hgb level and reductions in fatigue. Similarly, multivariate regression analysis of data from a randomized double-blind placebo-controlled study showed significantly greater benefits in QOL in patients treated with epoetin alfa than in those treated with placebo (Table 3).
Dr. Cella serves as a consultant for Amgen and Ortho Biotech.
1. Curt GA, Breitbart W, Cella D, et al: Impact of cancer-related fatigue on the lives of patients: New findings from the Fatigue Coalition. Oncologist 5:353-360, 2000.
2. Curt G, Johnston PG: Cancer fatigue: The way forward. Oncologist 8(suppl 1):27-30, 2003.
3. Hamilton H, Blum D, Cella D, et al: Communication regarding chemotherapy-induced anemia and related fatigue: Recommendations from an observational linguistic study. J Clin Oncol 23(16 suppl):740s, 2005.
4. Portenoy RK, Itri LM: Cancer-related fatigue: Guidelines for evaluation and management. Oncologist 4:1-10, 1999.
5. Stone P, Richards M, A'Hern R, et al: A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer. Ann Oncol 11:561-567, 2000.
6. Cella D, Kallich J, McDermott A, et al: The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: Results from five randomized clinical trials. Ann Oncol 15:979-986, 2004.
7. Cella D: The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34:13-19, 1997.
8. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:2875-2882, 2001.
9. Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 16:3412-3425, 1998.
10. Cella D, Zagari M, Vandoros C, et al: Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 21:366-373, 2003.
11. Fallowfield L, Gagnon D, Zagari M, et al: Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer 87:1341-1353, 2002.
12. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001.
13. Glaspy J, Jadeja JS, Justice G, et al: Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer 87:268-276, 2002.
14. Vansteenkiste J, Pirker R, Massuit B, et al: Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211-1220, 2002.
15. Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 23:2606-2617, 2005.
16. Chang J, Couture F, Young S, et al: Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 23:2597-2605, 2005.
17. Browman GP: Standards of proof, standards of practice, and proof of standards: A tale of two trials. J Clin Oncol 23:2583-2585, 2005.