Cancer patients commonly exhibit anemia that has a multi-factorial etiology and involves a variety of symptoms, including fatigue, dizziness, dyspnea, headache, and lethargy.[1-5] This anemia can have an adverse impact on these patients, potentially resulting in increased morbidity and decreased quality of life.[2,5] The frequency and severity of anemia are dependent upon many factors, including the type, duration, and extent of the malignancy, as well as the type and intensity of the chemotherapy. Severe anemia or symptomatic mild-to-moderate anemia requires medical management, possibly through the use of red blood cell (RBC) transfusions, which involves potential risks including acute transfusion reactions or transmission of infectious agents.[6,7] Such risks may prove to be unacceptable, as frequent RBC transfusions with allogeneic blood may adversely affect the immune system of these patients, thereby increasing the likelihood of infections, decreasing times to relapse, or shortening survival times. Even mild (10 to 12 g/dL) and moderate (8 to 10 g/dL) anemia may be poorly tolerated by some patients because of the resultant increased fatigue and decreased quality of life; however, RBC transfusions are no longer considered routine medical management in these patients because of the associated risks.[5,8,9]
The availability of recombinant human erythropoietin(Drug information on erythropoietin) (rHuEPO) for the safe and effective treatment of chemotherapy-induced anemia in cancer patients has provided an alternative, or supplement, to blood transfusions in this population. Furthermore, some studies have shown rHuEPO to be associated with improvements in health-related quality of life.[8,9] Many studies have demonstrated generally similar effects of rHuEPO on the reduction of the requirement for RBC transfusions and the ability to increase hemoglobin concentration in patients across a broad range of nonmyeloid malignancies and chemotherapy agents, although a range of response rates has been observed.[8,9,11-15]
As observed by Seidenfeld et al, comparisons between studies are difficult because different studies used varying definitions of response, different analysis populations (eg, intent-to-treat vs efficacy evaluable subsets), and an assortment of treatment period durations. Abels and colleagues reported 48% and 58% response rates (³ 6 hematocrit points) for patients treated with cisplatin(Drug information on cisplatin) and noncisplatin chemotherapy, respectively, during a 12-week treatment period in which rHuEPO dose increases were permitted, while Glaspy et al reported a 53% hemoglobin response rate (³ 2.0-g/dL increase in hemoglobin) after a 16-week treatment period.
Recently, in a report of a meta-analysis of the use of rHuEPO to treat chemotherapy-induced anemia, Seidenfeld et al indicated that evaluation of a treatment effect for rHuEPO was impeded because there were a limited number of studies with large populations, and few studies with consistent designs. However, based on this analysis, Seidenfeld et al concluded that there was no evidence that earlier initiation of rHuEPO therapy spared more patients from transfusions or resulted in greater quality-of-life improvements than waiting for hemoglobin concentrations to decline to nearly 10 g/dL.
Darbepoetin alfa (Aranesp) is a next-generation erythropoietic protein that has been shown to be safe and effective in treating chemotherapy-induced anemia in cancer patients.[17-22] Compared with epoetin alfa, darbepoetin alfa(Drug information on darbepoetin alfa) has an increased sialic acid content, which contributes to its extended serum half-life (approximately threefold longer) and increased biologic activity.[23,24] Darbepoetin alfa and rHuEPO appear to act by similar mechanisms, essentially by binding to the erythropoietin receptor and stimulating erythropoiesis, thus causing RBC precursors to proliferate and enhancing their survival. Darbepoetin alfa, however, exhibits an early and sustained erythropoietic effect, allowing darbepoetin alfa to be administered less frequently than rHuEPO while maintaining efficacy.
At the time of initial licensure of a new agent, many questions regarding its clinical utility are still not yet fully reported in the literature. There exists a need to elaborate the various characteristics of the new agents to permit effective clinical use. These characteristics include the dose response, the impact of important covariates (ie, age or sex) on the treatment effect, the nature of any specific recommendations that may be needed if a differential treatment effect is observed in specific subpopulations, and any specific safety precautions that should be undertaken with regard to high-risk groups, eg, those with cardiovascular comorbidity. Frequently, a single study cannot provide the answers to all these questions, and a comprehensive evaluation of all the experience gained in clinical studies is required to draw meaningful conclusions. While the answers to these questions are unlikely to differ significantly between darbepoetin alfa and rHuEPO due to the identical mechanism of action, comprehensive reviews addressing these important data are limited even for rHuEPO, despite 10 years of clinical use.
We pooled data from four completed, similarly designed studies of darbepoetin alfa[17-19] to perform an integrated analysis of the relationship of darbepoetin alfa dose to a number of efficacy variables. Additionally, results are presented that evaluate the treatment effect of darbepoetin alfa among a number of subgroups based on important patient characteristics, including age, sex, baseline hemoglobin, tumor type, and chemotherapy type.
The main differences between the eligibility criteria in the four studies included in this analysis were tumor type (lung cancer vs solid tumors vs lymphoproliferative malignancies) and chemotherapy restriction (platinum-containing only vs no restrictions). Common eligibility criteria included the following: Eligible patients had to be of legal age with a diagnosis of cancer (solid tumors or lymphoproliferative malignancies) and anemia (hemoglobin concentration £ 11.0 g/dL) primarily due to cytotoxic chemotherapy or cancer, and had to be receiving concomitant chemotherapy for the duration of the study treatment period (12 weeks). Patients also were required to have adequate renal function (serum creatinine level of ≤ 2.0 mg/dL) and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2 (three studies) or 0 to 3 (one study).
Patients who were anemic for reasons other than cancer or its treatment and patients who had received RBC transfusions immediately before study entry (two RBC transfusions within 4 weeks or any RBC transfusions within 2 weeks) were excluded. To ensure that patients were not anemic due to nutrition or iron deficiency, patients were required to have a vitamin B12 level of ³ 200 pg/mL, a folate level of ³ 2.0 ng/mL, and ferritin and transferrin saturation levels of at least 10 mg/dL and 15%, respectively. Patients with primary or metastatic cancer involving the central nervous system, and patients with seizures, unstable angina, or uncontrolled hypertension, were also excluded from all studies.
The institutional review boards or ethics committees of the participating centers approved the protocol. Informed consent was obtained from all patients before any study-related procedure was performed.
Study Design and Conduct
Four multicenter, randomized studies were conducted in the United States, Europe, Australia, and Canada. One study was open-label in design and used rHuEPO as an active control. The remaining three studies were double-blind and placebo-controlled.
The studies included doses of darbepoetin alfa from 0.5 to 8.0 µg/kg once weekly and 3.0 to 9.0 µg/kg every 2 weeks. In addition to similar eligibility criteria, all of the studies had identical, planned treatment lengths (12 weeks), identical dose adjustment rules upon reaching predefined hemoglobin thresholds, and identical recommendations regarding transfusions. Two studies allowed dose increases of darbepoetin alfa if the patient’s hemoglobin had not increased by at least 1 g/dL after approximately 1 month of therapy (week 5 or 6).
Rationale for Pooling Data
The information from each of the selected studies was integrated to obtain a larger patient sample in which to evaluate the dose-response relationship for a nonmyeloid malignancy population as a whole, as well as to evaluate the impact of important covariates such as age, sex, baseline hemoglobin, chemotherapy type, and tumor type on the treatment effect of darbepoetin alfa. As the individual studies included in this analysis involved specific tumor types, pooling of the data from these studies resulted in a patient population with a broader spectrum of tumor types and chemotherapy regimens consistent with the previously published data on rHuEPO.
The criteria for pooling were mainly clinicalthe studies had been designed with common characteristics in terms of treatment length, intervention strategies, and assessments, as well as patient eligibility criteria. Importantly, both the hemoglobin- and transfusion-based results from the four studies were similar where common average weekly doses existed for such a comparison. For example, in the average weekly dose range 1.5 to 2.25 µg/kg, the difference between darbepoetin alfa and placebo with respect to change in hemoglobin over a 12-week treatment phase was between 1.3 and 1.6 g/dL for the three placebo-controlled studies. In the active controlled study, similar changes from baseline were observed.