Standards of Proof, Standards of Practice, and Proof of Standards: A Tale of Two Trials

Abstract

In this issue of the Journal of Clinical Oncology, Chang et al and Witzig et al report two randomized controlled trials evaluating the role of recombinant human erythropoietin (epoetin alfa) for the management of anemia in cancer patients receiving chemotherapy. Previous rigorous trials and systematic reviews of randomized trials have demonstrated the efficacy of this agent in maintaining hemoglobin levels and reducing transfusion requirements in cancer patients receiving chemotherapy. Recommendations from high-quality, evidence-based clinical practice guidelines confirm the role for epoetin alfa in anemia management in this clinical setting. The drug is already commonly used in practice. Furthermore, the public and patients welcome the availability of a therapeutic option that can reduce exposure to what they perceive as the risks of blood transfusion. Both trials reported in this issue confirm, yet again, that epoetin alfa works in achieving the objectives of maintaining hemoglobin levels and reducing transfusion requirements in cancer patients receiving myelosuppressive therapy. So, what do these trials add to our current knowledge, and how should they affect routine practice? Both trials indirectly address the issue of drug scheduling. Whereas virtually all previous randomized trials tested epoetin alfa using an inconvenient three-times-per-week schedule, clinicians had already migrated towards the more convenient weekly schedule, and the wording of recommendations from clinical practice guidelines reflected this situation. Now, as a result of these trials, we can confirm both the efficacy of weekly dosing in maintaining hemoglobin levels and the reduction of transfusion requirements across a spectrum of cancer patient populations undergoing chemotherapy. Considering the current clinical context of the usage of routine epoetin alfa and the total body of available evidence, it would seem appropriate for updates of current guidelines and for future guidelines to endorse the weekly schedule for hemoglobin maintenance without demanding the higher standard of proof, which would involve a direct comparison to three-times-per-week treatment. The trial by Witzig et al also addressed the clinical utility of a tool for better selection of patients who might benefit from epoetin alfa treatment. This is important because one of the practical difficulties of using epoetin alfa is that, once it is started, the clinical effect takes several weeks to be observed. This means that timing the initiation of therapy must be done carefully and proper selection of those patients who can truly benefit from treatment should be performed because not all patients will develop a degree of anemia requiring intervention. The secondary question posed by this trial is specifically targeted to a corrective intervention strategy for anemia. The trial by Chang et al addressed a clinical question with more far-reaching implications, involving an expanded indication for epoetin alfa as a preventative, as opposed to corrective, intervention to manage anemia. Waiting for significant decreases in hemoglobin after initiation of myelosuppressive therapy to determine a patient’s eligibility for treatment with epoetin alfa may unnecessarily expose patients to an increased amount of time with symptoms of anemia. The preventative approach can be expected to minimize the burden of anemia symptoms by reducing the time spent in a symptomatic state. The Chang et al study included a relatively homogeneous population of breast cancer patients (79% receiving adjuvant chemotherapy) who were randomly assigned to receive the experimental therapy (epoetin alfa once weekly) or best supportive care when the hemoglobin decreased to or just below 12 g/dL. This threshold for initiation of treatment is higher than that used in previous trials (and in the study by Witzig et al). Given this potential expansion of clinical indications for this relatively costly drug, it seems appropriate that the standard of proof for clinical benefit for any trial ought to meet two more stringent criteria. First, the trial should JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 12 APRIL 2