It is increasingly recognized that fatigue in cancer patientsprimarily caused by anemia resulting from chemotherapy or other aspects of the disease processis associated with debilitating effects on quality of life and functioning.[1,2] Surveys performed by the multidisciplinary Fatigue Coalition indicated that fatigue was the primary complaint in one-quarter of patients after chemotherapy (ahead of nausea at 13%), and that 61% of cancer patients felt their lives were affected more by fatigue than by pain associated with their disease. Cancer-related anemia has traditionally been treated with red blood cell transfusions; however, concerns over the safety of the blood supply and potential adverse effects of transfusions in cancer patients have led to the development of erythropoietic agents as a safer alternative for increasing hemoglobin levels in these patients.
Improved understanding of the deleterious effects of anemia and the availability of recombinant human erythropoietin(Drug information on erythropoietin) (rHuEPO) have led to a great deal of active investigation of the benefits of erythropoietic therapy in patients with chemotherapy-induced anemia. Most recently, with the development of darbepoetin alfa(Drug information on darbepoetin alfa) (Aranesp) and research into once-weekly therapy for rHuEPO (rHuEPO is licensed for this indication at a dose of 150 U/kg three times weekly), considerable efforts have been focused on reducing the need for frequent injections. For patients with cancer (and their caregivers), each injection can be a reminder of their disease; for those for whom self-injection is not an option, each clinic visit is an interruption of normal life and may create significant logistic challenges relating to transportation, child care, or work. For clinic staff, administrative work and time are increased. A recent study of patients with chronic renal insufficiency reported that, on average, these patients spent 90 minutes traveling to/from the clinic and waiting to be seen, and 49% relied on someone else for transportation. It is likely that these findings would also be true for cancer patients. Thus, reducing the dosing frequency of erythropoietic agents given to patients with chemotherapy-induced anemia would be beneficial.
Weekly administration was shown to be effective in patients with chemotherapy-induced anemia in a large, open-label, uncontrolled study using a single subcutaneous injection of 40,000 U of rHuEPO (this dose could be increased to 60,000 U if a 1.0-g/dL hemoglobin increase had not been observed after 4 weeks). With this regimen, 68% of patients achieved a hematopoietic response (a hemoglobin concentration ³ 12.0 g/dL and/or an increase of ³ 2.0 g/dL without preceding transfusions) by the end of the 16-week treatment period, which is comparable to the response observed with three-times-weekly dosing.[5,6] However, this dose represents an increase of approximately 33% over the more routinely studied dose and schedule of 150 U/kg three times weekly[7-9] or the dosing regimen of 10,000 U of rHuEPO three times weekly, which has also been reported. Based on these results, weekly dosing is now accepted in clinical practice in the United States, although not in other regions.
Darbepoetin alfa, a unique recombinant protein produced by modifying the gene for erythropoietin, is a more potent erythropoietic agent. Darbepoetin alfa stimulates erythropoiesis through the same mechanism as endogenous erythropoietin and rHuEPO. However, darbepoetin alfa was engineered to have additional carbohydrate side chains (five total N-linked glycosylation side chains with up to 22 sialic acid residues) compared with rHuEPO (three total N-linked glycosylation side chains with up to 14 sialic acid residues). Sialic acid content is directly correlated with in vivo activity, possibly due to the degree of clearance by the asialoglycoprotein receptor in the liver; the increased sialic acid content of darbepoetin alfa reduces its clearance and results in an extended serum residence time.
Darbepoetin alfa was initially approved for use in patients with renal failure. Pharmacokinetic studies in this indication showed that darbepoetin alfa had an approximately threefold longer terminal half-life than rHuEPO (25.3 vs 8.5 hours). An extensive clinical development program has evaluated the pharmacokinetics, efficacy, and safety of various dose and schedule combinations of darbepoetin alfa during cancer chemotherapy. Phase I and II studies explored dosing intervals ranging from weekly to every-4-week administration.[14-21] These included an every-2-week dosing schedule, which appeared to be effective in alleviating anemia in patients with solid tumors receiving chemotherapy.[14,19]
Comparisons between rHuEPO studies (or between rHuEPO studies and darbepoetin alfa studies) may be confounded due to differences in factors such as study design, populations, treatment duration, analytical methodologies, response definitions, or the use of analysis sets other than the intent-to-treat set. To obtain a more precise estimate of the effect of darbepoetin alfa administered at 3.0 µg/kg every 2 weeks, and to evaluate the relative effect of this dose and schedule compared with rHuEPO, data from three clinical studies of similar design have been pooled.[14-17,19,20] Unlike comparisons with historical literature, this approach eliminates differences in analytical methodologies, treatment duration, and other potentially confounding factors. This report describes the results of this combined analysis.
The population evaluated and the design of each of the three studies included in these analyses were similar. All study centers were in the United States. Eligible patients were men or women ³ 18 years of age who were receiving multicycle chemotherapy and had anemia (hemoglobin concentration £ 11.0 g/dL). Patients were required to have adequate renal and hepatic function and could not be iron deficient (defined as both transferrin saturation < 15% and ferritin < 10 ng/mL). Patients with known cardiac disease or hematologic disorders that could cause anemia were not eligible. Each center’s independent ethics committee or central ethics committee approved the protocol, and patients provided written informed consent before any study-specific procedures were done.
The principal difference between the eligibilty criteria in the three studies was tumor type (solid tumors were specified in two studies and nonmyeloid malignancies in the third). However, as most patients in both groups had solid tumors, and no difference has been noted between the effect of erythropoietic agents on patients with hematologic malignancies and those with solid tumors,[5,6] this is not thought to have an impact on the validity of the conclusions from this pooled analysis.
All three studies were multicenter and open-label in design. The dose of rHuEPO could be increased in both studies contributing rHuEPO data (at week 8 or week 6), and the dose of darbepoetin alfa could be increased in one of the two studies contributing darbepoetin alfa data (at week 7). The requirement for withholding drug due to reaching specified maximum hemoglobin concentrations (14 g/dL for women, 15 g/dL for men) was the same in all studies. Red blood cell transfusions were recommended if hemoglobin decreased to £ 8.0 g/dL or patients had symptoms