Assessment of Components Contributing to Recommendations
Quality of Life
To enable an adequate critical appraisal of quality of life indices, the description of quality of life instruments used in the studies and the assessments of those measures are detailed in Appendix I of the original guideline document.
The impact of erythropoietic agents on quality of life is difficult to assess. Six of the seven trials included in this review reported improvement in some quality of life parameter. However, these reports did not follow the proposed guidelines for analyzing, interpreting, and reporting quality of life measures. Recommendations for reporting quality of life include reporting raw scores, reporting the proportion of patients who improve, detailing methods of handling missing data, and defining clinically important differences, and significant limitations in these properties were identified in each report. In particular, missing data can have important implications for the validity of an oncology study, as missing values are likely related to the underlying illness (i.e., patients who drop out or miss appointments are likely to be the sicker patients). Given these limitations, we could not reach definitive conclusions regarding the influence of erythropoietic agents on quality of life in patients with hematologic malignancies. American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) reached a similar conclusion in their evidence-based guidelines on the use of erythropoietin in patients with cancer.
Heterogeneity of Response to Erythropoietic Agents
The reviewed studies varied in inclusion criteria, transfusion triggers, dosing regimens, durations of assessment, and the use of co-interventions. Inclusion criteria for hemoglobin requirements ranged from less than 80 g/L to less than 110 g/L. Transfusion thresholds ranged from 70 g/L to 100 g/L. Variation of the transfusion threshold may exaggerate or minimize the effects of either erythropoietin or darbepoetin alpha. The dose of the erythropoietic agent, the increments in the dose during the trial, the chemotherapy regimens, and the timing of the initiation of chemotherapy and the erythropoietic agent also differed among the studies.
The reporting of renal insufficiency was variable. As renal insufficiency would further contribute to anemia and inadequate erythropoietin production, the number of patients included with decreased renal function might affect the results showing the responsiveness of patients to erythropoietic agents. Four studies did not state the creatinine levels of patients entered into their trials. Only one study included patients with a normal range of serum creatinine, and two indicated a creatinine level for inclusion.
The monitoring for iron deficiency and the use of iron supplementation also differed among the studies. Iron indices used to detect iron deficiency are known to inconsistently detect iron deficiency in patients with malignancy. As iron deficiency may occur with erythropoietin or darbepoetin alpha therapy, and may account for a poor response to such therapy, the use or omission of iron supplementation may impact on the degree of the hemoglobin increment. Some authors feel that iron therapy should be initiated for all patients who receive an erythropoietic agent, unless their serum iron or iron saturation is elevated. One study indicated that iron therapy would be initiated when the serum ferritin fell below 100mg/ml. Two studies administered iron to all patients. The remainder of the trials indicated that they would initiate iron depending on the iron indices or did not mention whether iron deficiency would be investigated or left the decision to the discretion of the investigators.
Because of this heterogeneity, and given the conclusions already reached by the Cochrane meta-analysis, we did not perform another meta-analysis.
Predictors of Response
Various parameters have been considered in trying to establish predictors of response to erythropoietin or darbepoetin alpha therapy, including an early change in hemoglobin concentration, an increase in reticulocyte count, the platelet count, the pretreatment endogenous erythropoietin level, and the observed/predicted (O/P) erythropoietin ratio (the O/P ratio is a ratio that was formulated to determine the appropriate erythropoietin response to anemia). The utility of any of the above parameters in the prediction of response to either erythropoietin or darbepoetin alpha has not been established prospectively in trials. Predictors of response to erythropoietic agents for adequate patient selection, therefore, cannot yet be determined.
Adverse Events
Therapy with erythropoietic agents appears to be well tolerated in most patients. Hypertension is a known adverse event associated with erythropoietic agents.
Disease Site Group (DSG) Consensus and Recommendations
The Hematology DSG recognizes that survival, quality of life, and economic benefit are important outcome measures that should influence the decision to adopt new therapies. The importance of transfusion avoidance as an endpoint that should influence practice was debated. The DSG recognized significant limitations to chronic transfusion therapy, notably increasingly limited availability, increasing cost and complexity, and the potential risks of emerging infections. These factors, as well as the recommendations of the Commission of Inquiry on the Blood System in Canada stressing the importance of alternatives to transfusion, influenced the DSG to consider the avoidance of transfusion to be an outcome measure of sufficient importance to guide practice. Although anemia was an outcome measure in many of the identified trials, the members of the Hematology DSG considered it to be an intermediate outcome and only to be of significance if a change in hemoglobin affected survival, transfusion requirements, or quality of life.
With respect to survival, the DSG did not find any evidence to suggest a treatment effect. As indicated above, the DSG also concluded that there is insufficient evidence of erythropoietic agents influencing quality of life to allow for a recommendation that treatment be given to improve this outcome. In contrast, the DSG found the evidence that erythropoietic agents reduce the requirements for transfusion to be sufficiently compelling to recommend therapy for this purpose. The absolute risk reduction in transfusions ranged from 15% to 24%, and the number needed to treat to prevent a transfusion ranged from four to six.
The DSG had difficulty in defining a precise threshold that identifies patients who may be at risk of requiring transfusion. Based on consensus, the threshold hemoglobin value of 100 g/L recommended by American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) and the Cancer Care Ontario (CCO) Systemic Treatment DSG in their guidelines was endorsed as a reasonable value. As there are no clear predictors for a response to erythropoietic agents, the DSG felt that this therapy should be offered to patients who fulfill the above criteria.
The Hematology DSG discussed the relative merits of erythropoietin and darbepoetin alpha. Randomized trials of both agents demonstrated a reduction in red cell transfusion requirement. The DSG considered that, while the magnitude of benefit in transfusion requirement appeared to be comparable with both agents, the evidence in support of erythropoietin was more abundant and mature. For this reason, at this time, the DSG recommends that erythropoietin be considered the preferred agent in patients with hematologic malignancies.
In considering dosing for erythropoietic agents, the Hematology DSG acknowledged that the optimum dose has not yet been determined for either erythropoietin or darbepoetin alpha. However, several trials have used erythropoietin at 150 IU/kg three times per week or 40,000 IU weekly, and those doses were considered reasonable. For darbepoetin alpha, there have only been two reports of its use in patients with hematologic cancers, a dose-finding study, and one report using the 2.25 μg/kg once-weekly dosing regimen. In patients with non-hematologic malignancies, a number of dosing regimens have been reported, 2.25 μg/kg weekly, 200 μg flat-dose every two weeks, and 500 μg flat-dose every three weeks for three doses followed by 300 μg every three weeks.
