One of the most important advances in the area of quality of life for

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1 Cancer-Related Fatigue: New Directions for Research Supplement to Cancer 1719 Anemia and Fatigue in Cancer Patients John Glaspy, M.D. Division of Hematology-Oncology, University of California Los Angeles School of Medicine, Los Angeles, California. Presented at Cancer-Related Fatigue: New Directions for Research, held at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, February 19 20, Address for reprints: John Glaspy, M.D., Division of Hematology-Oncology, University of California Los Angeles School of Medicine, 200 UCLA Medical Plaza, Suite , Los Angeles, CA Received December 20, 2000; accepted March 15, One of the most important advances in the area of quality of life for cancer patients has been the relatively recent observation that fatigue is among the most frequent and severe symptoms limiting function and diminishing overall well-being. 1 The fatigue experienced by cancer patients is multifactorial; depending upon the individual patient, factors may include poorly controlled pain, sleep disturbances, malnutrition, adverse effects of chemotherapy or biologic treatments, and depression. Moreover, cancer, like other chronic inflammatory processes, is often associated with alterations in the production of endogenous cytokines, such as tumor necrosis factoralpha (TNF- ) and interleukin-1-beta (IL-1- ) and these alterations can cause profound fatigue. This endogenous cytokine syndrome may be a more pervasive driver of fatigue and inhibitor of function and quality of life for cancer patients, particularly those with liver metastases, B-cell neoplasms, lung cancer, and renal cell cancer. It is also involved in the pathogenesis of cancer cachexia and the anemia of chronic disease (ACD) observed in these patients. Cancer patients are frequently anemic. Occasionally, this anemia is due to bleeding, hemolysis, or nutritional deficiencies, and therefore amenable to straightforward evaluation and treatment of the underlying cause. More often, the anemia is due to the cancer itself (as with ACD) or the myelosuppressive effects of cancer treatment. ACD in cases of cancer is associated with a blunting of the endogenous erythropoietin (EPO) response to anemia, resulting in a relative EPO deficiency state. In addition, patients with ACD frequently evidence blunting of the hematopoietic response to EPO, resulting in a relative EPO resistance that may be due to an inability to mobilize iron from the reticuloendothelial system and/or due to the direct suppressive effects of inflammatory cytokines on hematopoietic cells. It has long been accepted that patients with severe anemia (hemoglobin concentration 8 g/dl) will experience symptoms including lethargy, decreased exercise tolerance, shortness of breath, and palpitations. In addition, it has been recognized that these patients are at risk for serious medical sequelae of decreased oxygen delivery to the tissues, especially when there are comorbidities and rapid development of anemia. For this reason, cancer patients with severe anemia have traditionally been treated to maintain a minimum hemoglobin level of 8 9 g/dl. Until recently, mild and moderate degrees of anemia (hemoglobin concentration of 9 12 g/dl) were assumed to have relatively little impact on patients well-being and were managed with observation. Historically, this approach to mild and moderate anemia was also consistent with an understandable inclination on the part of clinicians to avoid red cell transfusions, with their attendant risks, in the absence of a compelling medical indication American Cancer Society

2 1720 CANCER Supplement September 15, 2001 / Volume 92 / Number 6 FIGURE 1. Quality-of-life linear-analog scale assessment. (Reprinted with permission from Glaspy J, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1220.) Recombinant Human Erythropoietin The cloning and introduction into clinical trials of recombinant human erythropoietin (epoietin alfa) improved our understanding of the pathophysiology and impact of cancer-associated ACD. Anemic patients with cancer and patients with cancer undergoing chemotherapy responded to therapy with epoetin alfa, although the doses required were somewhat higher than for patients with renal failure, demonstrating the relative EPO resistance of ACD. Consistent with the standards of practice regarding the management of anemia in cancer patients at the time, the clinical endpoint sought during the initial clinical development of epoetin alfa was a decrease in red cell transfusion requirements. Epoietin alfa therapy was associated with a statistically significant decrease in transfusions for anemic cancer patients undergoing myelosuppresive chemotherapy. For a time, the focus of epoetin alfa therapy was solely upon the treatment and prevention of severe anemia, and the sole perceived benefit was a reduction in red cell transfusion needs. Following the introduction of epoietin alfa into the clinical practice of oncology, it became clear that this therapy was safe and frequently resulted in a normalization or near-normalization of hemoglobin levels. Thus, it represented a safe, effective treatment for mild and moderate anemia in the cancer setting. The question of whether there is any benefit to patients in increasing hemoglobin levels substantially above 8 9 g/dl was addressed initially in communitybased, uncontrolled studies and later in a randomized, controlled clinical trial. The results of these studies transformed our understanding of the impact of mild and moderate anemias on the fatigue level and overall quality of life of cancer patients; they also changed the goals of epoietin alfa therapy in this setting. These data, especially when buttressed with data from other settings, demonstrate that cancer patients are significantly impacted by levels of anemia previously believed to be relatively asymptomatic, and hence trivial. One piece of the cancer/fatigue puzzle was falling into place. The Symptomatic Impact of Anemia on Patients without Cancer The first clinical trials of epoietin alfa began in 1985 and involved patients with chronic renal failure undergoing dialysis; the primary efficacy endpoint was a

3 Anemia and Fatigue in Cancer Patients/Glaspy 1721 decrease in red cell transfusion requirements. Despite a decrease in transfusion requirements, epoietin alfa therapy was also associated with increased mean hemoglobin levels in treated patients. The question emerged regarding the symptomatic benefit of this decrease in the incidence and severity of mild and moderate anemias. For hemodialysis patients, epoetin alfa therapy was associated with improvements in functional ability, health status, socialization, appetite, affect, sexual function, life satisfaction, and happiness Importantly, these questionnaire-based observations were consistent with objective physiology-based studies that demonstrated improvements in peak oxygen consumption and ventilatory anaerobic processes associated with epoietin alfa therapy. 14 The quality-of-life impact of improvements in degrees of anemia not severe enough to warrant transfusions was also observed in predialysis patients, patients undergoing peritoneal dialysis, 19 pediatric 20 and elderly 21 renal failure patients, and patients with AIDS. 22,23 By 1994, it was becoming clear that there might be important quality-of-life benefits associated with increasing hemoglobin levels above traditional transfusion targets. Stated another way, there was evidence in several clinical settings, including relatively pure EPO deficiency states and conditions associated with ACD, that mild and moderate degrees of anemia were not asymptomatic, but rather associated with significant diminution in function and well-being. Given this, the findings of subsequent quality-of-life studies involving patients with cancer-related fatigue might have been predictable. FIGURE 2. Changes in mean linear analog scale score for patients at the beginning and termination of recombinant human erythropoietin therapy. The results for different hemoglobin (Hb) response cohorts are shown. The p values shown for each cohort were by paired tests. The mean energy level scores (A), mean activity level scores (B), and mean overall quality of life scores (C) are shown. (Reprinted with permission from Glaspy J. Erythropoietin therapy for the cancer patient. In Rosenberg SA (ed): Principles and practice of biologic therapy of cancer. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000: 168; adapted from Glaspy J, et al. Impact of therapy with the epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15: ) The Effects of Anemia on Fatigue in the Cancer Patient In randomized, placebo-controlled clinical trials involving patients with cancer who were undergoing myelosuppressive chemotherapy, therapy with epoeitin alfa was associated with a decrease in red cell transfusion requirements and a higher mean hemoglobin level In some of the initial clinical trials of epoietin alfa therapy for cancer patients, improvements in functional status, energy level, and/or overall quality of life were observed in patients whose anemia improved These studies were neither designed nor statistically powered to characterize fully the quality-of-life benefits of increasing hemoglobin levels above those usually achieved through red cell transfusions. However, these data suggested that mild and moderate anemia may be a frequent contributor to fatigue in cancer patients, and that the problem was amenable to treatment. After epoietin alfa was introduced into the clinical practice of oncology, three large, open-label, community-based studies were carried out in the United States. In the first study, more than 2,000 patients were treated. 32 Patients completed a simple, threequestion linear analog scale instrument before and at the completion of up to 4 months of treatment; this questionnaire is reproduced in Figure 1. There was a statistically significant increase in the mean energy, activity, and overall quality of life observed in association with an increase in mean hemoglobin level from approximately 9 to 11 g/dl. Moreover, the magnitude

4 1722 CANCER Supplement September 15, 2001 / Volume 92 / Number 6 FIGURE 3. The relationship of changes in mean linear analog scale score during recombinant human erythropoietin therapy to the increase in hemoglobin level for patients with cancer undergoing chemotherapy. Patients were segregated into three chemotherapy response groups, based on the physician s assessment of their tumor response. The correlation between increase in hemoglobin and the increase in score was assessed using a simple linear regression model and the corresponding p values shown. The results for questions regarding energy level (A), ability to carry out daily activities (B), and overall quality of life (C) are shown. (Reprinted with permission from Glaspy J. Erythropoietin therapy for the cancer patient. In Rosenberg SA (ed): Principles and practice of biologic therapy of cancer. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000: 169; adapted from Glaspy J. The impact of epoetin alfa on quality of life during cancer chemotherapy. A fresh look at an old problem. Semin Hematol 1998;34:20 6.) of the increase in each individual s score correlated with the magnitude of the increase in hemoglobin (Figure 2), and there was no increase in the mean score for patients who did not experience an increase in hemoglobin. The magnitude of the effects of the mean increased scores was consistent with their being clinically significant, on par with those observed in cancer pain control. In a subset of patients for whom chemotherapy tumor response data were available, the association of increase in mean energy and quality-of-life scores with hemoglobin response category remained significant (Figure 3). 33 Two similar community-based studies have subsequently been carried out. 34 These studies confirmed the association between increases in hemoglobin levels and increases in energy, activity, and overall quality of life. In both studies, an increase in the mean hemoglobin level from approximately 9 to 11 g/dl was associated with significant increases in mean scores for each domain. Data regarding the tumor response to chemotherapy were collected prospectively; the association of hemoglobin increase with increased quality of life was independent of tumor response. 34 In addition to the linear analog scale, quality of life was also assessed using the longer Functional Assessment of Cancer Treatment (FACT) questionnaire and the Fatigue subscale for this instrument. Some of these data, reproduced in Figure 4, and support the conclusions that increases in hemoglobin level are associated with an improvement in quality of life and that this effect is driven by an improvement in fatigue. The impact of epoetin alfa treatment on quality of life in patients with cancer undergoing chemotherapy has now been confirmed in a randomized, placebo-controlled clinical trial. The data from the three community-based studies have been pooled and subjected to a marginal utility analysis. 35 The result of this analysis suggests a larger gain in measures of quality of life due to an increase in hemoglobin levels when the starting point was greater than or equal to 10 or 11 g/dl than when the starting point was between 8 and 10 g/dl. This result suggests that the levels of anemia that were previously assumed to be asymptomatic may actually be the most symptomatically important, and that the opportunity presented by the treatment of mild and moderate anemia to impact meaningfully upon cancer-related fatigue is substantial. Over the last 3 years, there has been very a rapid transformation of our understanding of anemia s role

5 Anemia and Fatigue in Cancer Patients/Glaspy 1723 FIGURE 4. Quality-of-life (FACT-An Anemia subscale) analyzed by tumor response and hemoglobin level changes from baseline to final assessment. *Significantly different from baseline (P.05). Significantly different from baseline (P.01). Significantly different from adjacent group (P.05). Significantly different from adjacent group (P.01) (Reprinted with permission from Demetri GD, et al. Quality-oflife benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study. J Clin Oncol 1998;16:3418.) in the pathogenesis of fatigue in cancer patients. The available data support a recommendation that anemic (hemoglobin level 11 g/dl) patients with cancer who are receiving cancer chemotherapy and complaining of fatigue should receive treatment for the anemia. If successful treatment of the anemia is associated with a decrease in fatigue, attention should be given to preventing a recurrence of the anemia. It is likely that these observations are relevant to, and will soon be made in reference to, patients with cancer who are not receiving chemotherapy and all patients with ACD associated with fatigue. REFERENCES 1. Vogelzang NJ, Breitbart W, Cella D, Curt GA, Groopman JE, Horning SJ, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997; 34(3 Suppl 2): Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase III multicenter clinical trial. Ann Intern Med 1989;111: Wolcott DL, Marsh JT, La Rue A, Carr C, Nissenson AR. Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients. Am J Kidney Dis 1989;14: Delano BG. Improvements in quality of life following treatment with r-huepo in anemic hemodialysis patients. Am J Kidney Dis 1989;14(2 Suppl 1): Barany P, Pettersson E, Bergstrom J. Erythropoietin treatment improves quality of life in hemodialysis patients. Scand J Urol Nephrol Suppl 1990;131: Evans RW. Recombinant human erythropoietin and the quality of life of end-stage renal disease patients: a comparative analysis. Am J Kidney Dis 1991;18(4 Suppl 1): Laupacis A, Wong C, Churchill D. The use of generic and specific quality-of-life measures in hemodialysis patients treated with erythropoietin. The Canadian Erythropoietin Study Group. Control Clin Trials 1991;12(4 Suppl):168S 179S. 8. Deniston OL, Luscombe FA, Buesching DP, Richner RE, Spinowitz BS. Effect of long-term epoetin beta therapy on the quality of life of hemodialysis patients. Asaio Trans 1990; 36:M Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 1990;300: Levin NW, Lazarus JM, Nissenson AR. National Cooperative rhu Erythropoietin Study in patients with chronic renal failure: an interim report. The National Cooperative rhu Erythropoietin Study Group. Am J Kidney Dis 1993;22(2 Suppl 1): Barany P, Pettersson E, Konarski-Svensson JK. Long-term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin. Nephrol Dial Transplant 1993;8: Hosokawa S, Yoshida O. Effect of erythropoietin (rhuepo) on trace elements and quality of life (Qol) in chronic hemodialysis patients. Int J Clin Pharmacol Ther 1994;32: Beusterien KM, Nissenson AR, Port FK, Kelly M, Steinwald B, Ware JE Jr. The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients. J Am Soc Nephrol 1996;7:

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