Erythropoietic Agents: Recent Clinical Data
Walter Sall, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 14, 2003
Over the last several decades anemia management has evolved. Use of transfusion is now limited to symptomatic severe anemia. The use of stem cell growth factors to prevent the occurrence of anemia has become the norm. Epoetin alpha (Procrit) and darbepoetin alpha (Aranesp) are the two FDA approved stem cell growth factors approved for the correction of cancer induced anemia. Validated quality of life (QOL) assessments have shown a conclusive link between hemoglobin level and QOL. Cognitive function, fatigue and dyspnea are independently related to hemoglobin level. Efficacy of epoetin and darbopoetin have been validated in multiple clinical trials involving thousands of patients.
Epoetin's efficacy has been demonstrated in randomized and non-randomized studies of over 8,000 solid tumor patients. Response rates (defined as increase in hemoglobin of at least 2g/dL or increase of hgb to at least 12g/dL) have been shown to be at least 53-71%. Statistically significant decreases in transfusion requirements have been shown in these patients, the vast majority of whom continued to receive cytotoxic chemotherapy during their epoetin therapy. The dosing in these trials has varied: generally either the accepted standard of 10,000u SC 3x weekly or 40,000u SC once weekly. Though randomized trials involving a non-epoetin receiving control arm have not been designed to demonstrate survival benefit, several trials have revealed a trend towards a survival benefit with epoetin. Further trials investigating this question are ongoing. Several recent trials, primary of head and neck patients undergoing radical chemoradiation, have shown significant Hgb increases with epoetin and a trend towards improved disease control. It has been hypothesized that these potential improvements in tumor control may be due to decreased tumor hypoxia and maintenance of chemo and radiosensitivity. However, it must be noted there was a recent trial of Epoetin in head and neck cancer patients receiving chemotherpy and radiation therapy that showed a worse outcome with using this growth factor.
Epoetin and darbopoetin are structurally similar. However, differences in their carbohydrate and sialic acid side chains lead to several pharmacokinetic and pharmacodynamically significant differences. Epoetin binds with higher affinity to the erythropoietin receptor. However, darbopoetin has a longer half life and takes longer to reach peak concentration. The clinical ramifications of these differences have yet to be elucidated. A head-to-head phase III trial comparing darbopoetin and epoetin is currently underway. The primary endpoint is the fraction of patients sustaining a 1g/dL increase in Hgb after 4 weeks. Preliminary data from 40 patients show a mean Hgb increase at 4 weeks of 0.71g/dL for epoetin and 0.44g/dL for darbopoetin.
Darbopoetin has also been shown to result in significant Hgb increases and decreased transfusion need in cancer patients. The usual dosing schedule is 2.25mcg/kg weekly. Various variations in the dosing regimen are underway to see if the time to response can be reduced. One such strategy involves front-loading the dosing schedule, i.e. giving a higher dose for the first four injections (4.5mcg/kg/week) followed by reduced weekly dose (1.5mg/kg/week).
The use of growth factor support will likely increase with the rapid acceptance of dose dense treatment regimens for breast cancer. Previous trials of epoetin in breast cancer have shown improved quality of life and decreased acute cognitive dysfunction during chemotherapy.
In summary, erythrocyte growth factor support continues to be an important component of cancer chemo- and radiotherapy. Significant increases in Hgb, correlating with better cognitive function, QOL and possibly disease response have been linked to epoetin and darbopoetin therapy in multiple randomized trials. These agents also allow the avoidance of potentially hazardous blood transfusions. Continued studies are underway to determine the ideal schedule of drug delivery and the possible superiority of epoetin vs. darbopoetin or vice versa.