Epoetin Alfa and Improved Quality of Life for Anemic Cancer Patients
Epoetin Alfa and Improved Quality of Life for Anemic Cancer Patients
ABSTRACT & COMMENTARY
Synopsis: Previous studies have reported improved quality of life in cancer patients treated with recombinant erythropoietin, presumably on the basis of increased hemoglobin and tissue oxygen delivery. However, these studies had not accounted for the possible role that response to chemotherapy had in achieving the observed increased well being.
Source: Demetri GD, et al. J Clin Oncol 1998;16: 3412-3425.
A large, multicenter, community-based study was undertaken to prospectively assess the effectiveness of erythropoietin (epoetin alfa) as an adjunct to chemotherapy in patients with cancer and anemia based upon changes in quality of life parameters and hemoglobin levels and to correlate these changes with antitumor response. Two thousand three hundred patients with nonmyeloid malignancies who received chemotherapy were enrolled in this study from 621 U.S. community-based practices. Patients received epoetin alfa 10,000 U three times weekly and the dose was increased up to 20,000 U three times weekly depending on the hemoglobin response. Treatment continued for a maximum of 16 weeks in patients who showed evidence of hematological response.
Patients enrolled in the study had a wide range of malignancies and received varying chemotherapy regimens. Lung cancer accounted for 24% of the cases, breast cancer 17%, gynecologic malignancy 13%, and gastrointestinal malignancy 9%; 22% had miscellaneous malignancies. About 44% of patients did not complete the study; reasons for not completing treatment included death (10%), failure to have a rise in hemoglobin of more than 1 g/dL (7%), intercurrent illness (6%), lost to follow-up (6%), or other factors. Only 2% had an adverse response to the epoetin alfa.
Approximately 70% of patients achieved a hematological response (rise in hemoglobin of > 2 g/dL or reaching a level of 12 g/dL), and transfusion requirements were observed to be decreased for the group as a whole, but especially for those that responded.
Quality of life measures correlated significantly with hemoglobin levels and were independent of tumor response. Patients evaluated their symptoms using the linear analog scale assessment, a 10 cm scale. The mean change in energy level from baseline to study end was + 11.5 mm (P < 0.001), activity level was + 11.1 mm (P < 0.001) and overall well being was + 9.8 (P < 0.001). Furthermore, a direct and significant correlation was shown by regression analysis between the increase in overall quality of life and the increase in hemoglobin level from baseline.
Patients who achieved a complete response, partial response, or stable disease (with the various chemotherapy regimens) but had no increase in hemoglobin level did not have a meaningful or significant increase in quality of life as measured by linear analog scale assessments. The linear analog scale assessment correlated well with the more comprehensive quality of life measure, the FACT-An (Functional Assessment of Cancer Therapy-Anemia).3
Thus, epoetin alfa appears to have a benefit on patient reported quality of life for those cancer patients with anemia who are receiving chemotherapy and this seems to be independent of the response of the tumor to cancer chemotherapy.
COMMENTARY
This is the second large clinical trial published within two years on the role of epoetin alfa in cancer patients. The first was enthusiastically anticipated, but it was inconclusive because an important host variable was not reported and could not be retrieved.1 Although hemoglobin increases were noted and transfusion requirements were less, it was not possible to determine whether the observed increased quality of life was the result of effective tumor response to chemotherapy or the increased hemoglobin level. Common sense would suggest that both would be important, but to the extent that it needed to be proven, the study was inadequate. Thus, epoetin alfa was approved by the FDA for improving hemoglobin levels and reducing transfusion requirements in patients receiving cancer chemotherapy, but not for improving quality of life.
Not to be denied, Demetri and associates went back to the drawing board and developed this second study in which tumor responses were carefully monitored and analyzed in the context of quality of life and epoetin response. The numbers of patients were large and the magnitude of the effect is hard to refute, despite the relatively large number of patients who dropped out of the study. The 70% of patients who achieved a hemoglobin response had a self-reported energy level that was greater and their overall quality of life was improved. What’s more, for those who achieved a hemoglobin response, the improvement in quality of life was significant and comparable for those whose tumors responded completely to chemotherapy, those whose tumors responded partially to chemotherapy, or those who had stable disease. Patients with progressive disease despite chemotherapy did not have improved quality of life with epoetin, even if they had a significant hemoglobin response.
Like the management of pain or nausea in cancer patients, oncologists now have an approach to offer patients with the pervasive symptom of fatigue, which so often accompanies chemotherapy. For those with anemia, the response is simple. The data are clear that correction of anemia will improve energy level and sense of well being. The question of how much epoetin and how often it should be administered remains to be clarified. Perhaps once a week dosing will be as effective as three times per week as performed in this trial, but this remains to be demonstrated. The other question that remains is what is the role for epoetin in non-anemic, but fatigued cancer chemotherapy patients. Perhaps another trial is in the offing.
An equally important issue to address is the cost. It would be of interest to compare the use of epoetin with packed red blood cell transfusion to a target hemoglobin level. One wonders whether the cost and toxicities are substantially different. Fatigue in the cancer patient whose hemoglobin level is abnormal but above 8 gm/dL could also benefit from transfusion to a level of 12 gm/dL. However, transfusions are rarely given until the hemoglobin falls below 8 gm/dL. Transfusion has a high response rate. The infectious complications of transfusion are exceedingly rare. It would be of interest to know whether there are economic, toxicity, efficacy-related advantages to epoetin compared to transfusion. The comparison of epoetin to liberalized criteria for transfusion could provide useful information. Epoetin’s superiority over nothing (i.e., no effort to augment hemoglobin level) may exaggerate the magnitude of the effect. Further information is also needed on the 30% of patients who do not respond. From prior work, it seems likely that at least some of the nonresponders have high endogenous levels of erythropoietin. However, others who do not respond may have anemia of chronic disease, a cytokine-mediated defect in iron reutilization. It may be cheaper to choose candidates for epoetin by measuring endogenous erythropoietin serum levels and performing serum iron studies to exclude patients less likely to respond.
Reference
1. Glaspy J, et al. J Clin Oncol 1997;15:1218-1234.
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