Phase III clinical trials with darbepoetin: implications for clinicians

Abstract

Anemia occurring in patients with renal failure on dialysis has been shown to both increase transfusion requirements and decrease functional status and quality of life. As a result, treatment of these patients with an erythropoietic agent such as epoetin alfa or darbepoetin alfa has become established as an essential part of optimal patient care. Anemia resulting from cancer or chemotherapy is a common problem in oncology, and has been shown similarly to increase transfusion risk and decrease patient reported outcomes. For reasons that are not clear, but may include either frequently encountered slow response or nonresponse and higher doses and hence higher costs, treatment of anemia in oncology has not become a standard treatment for all patients. Erythropoietic agents (epoetin alfa and darbepoetin alfa) have been used to improve anemia-related fatigue and quality of life in cancer patients. Epoetin is administered 1 to 3 times per week whereas darbepoetin, with up to a 3-fold greater half-life, is given once every 1 or 2 weeks. Recent data demonstrate that darbepoetin can be administered as infrequently as every 3 weeks with comparable erythropoietic efficacy. Several studies have been carried out to determine the optimum schedule of dosing to obtain maximum patient benefit. Following treatment with darbepoetin, antibodies to darbepoetin were not detected, no unusual adverse event was seen with darbepoetin, and the mean increase in hemoglobin remained unchanged when the dosing interval was increased from 1 to 2 weeks. The safety and efficacy of darbepoetin was also determined in patients with solid tumors receiving chemotherapy; the lowest clinically effective dose was determined to be 3.0 and 5.0 microg/kg every 2 weeks with a 66 and 84% response, respectively. No additional benefit was seen with higher doses. A multicenter study evaluated the safety and efficacy of darbepoetin administered either weekly, every 3 weeks, or every 4 weeks in anemic patients with cancer who were not receiving chemotherapy or radiotherapy. The results indicated that with weekly dosing, 70% of patients showed an increase in hemoglobin. The dose of 4.5 microg/kg/week resulted in 100% hematopoietic response. In a randomized, active control, pilot trial, front-loading darbepoetin followed by lower doses or less frequent doses also appears to be efficacious and may decrease the time to response. At the present time, darbepoetin improves anemia, reduces requirements for transfusion, and improves the quality of life for these patients. To compare efficacy of these erythropoietic agents it is important to analyze the data using intent to treat rather than analysis of patients who complete the study. This way a true evaluation of the change of hemoglobin can be assessed corresponding both to dose and an improvement in the QOL.