Is anemia of cancer different from chemotherapy-induced anemia?

Anemia has myriad causes. In patients with cancer, the chief culprits are direct myelotoxicity from antineoplastic drugs and cytokine-mediated inhibition of erythropoiesis. A host of other malign influences may also be at work, including bleeding, renal injury, nutrient deficiency, and so on. A single patient may suffer from several causes of anemia simultaneously, and it is not always easy to distinguish these. However, it is important to try: although the physiological consequences of a low hemoglobin level are similar regardless of its origin, treatment differs considerably. In this issue of the Journal of Clinical Oncology, Smith et al report results from the Amgen 20010103 clinical trial (Amgen 103). These results suggest that whether or not an anemic patient is receiving myelosuppressive chemotherapy is a clinically relevant distinction, with therapeutic implications. Data from this trial were first presented by John Glaspy in April 2007 at the clinical plenary session of the annual meeting of the American Association for Cancer Research, an event that garnered considerable media attention. The Amgen 103 investigators randomly assigned 989 patients with cancer and hemoglobin 11 g/dL to receive either the erythropoiesis-stimulating agent (ESA) darbepoetin alfa or a placebo. Although 70% of enrolled patients had undergone prior chemotherapy, which finished a median of 9 months before trial participation, patients were not permitted to receive cytotoxic chemotherapy or myelosuppressive radiotherapy during the 16 weeks of study intervention. However, patients were allowed to receive nonmyelosuppressive radiotherapy or hormonal therapy, and many did. The results of the Amgen 103 trial are negative in two senses. Neither the primary end point—reduction in RBC transfusion needs with darbepoetin—nor a secondary quality of life end point was met. More disturbingly, patients who received darbepoetin did not live as long as those who received placebo (37 weeks v 47 weeks median survival; P .022). The trial’s sobering findings are included in the new ESA prescribing information approved by the United States Food and Drug Administration (FDA) in November 2007, and the study results have influenced the ongoing debate in the United States about Medicare beneficiaries’ access to ESAs. Several of the Amgen 103 study findings are difficult to interpret. Enrolled patients were diverse, with more than 15 different primary tumor sites and all stages of disease; anemia and ESA treatment may have distinct consequences in different cancer settings. Furthermore, survival was not the study’s primary end point, so the two study arms were not balanced for known prognostic markers. A retrospective analysis demonstrated that if the groups had been better balanced, the observed survival difference would no longer have been significant— similar to what happened with the Breast Cancer Erythropoietin Survival Trial (BEST) and ENHANCE studies, which also pointed to potential harm from off-label use of ESAs. In another echo of BEST, the Amgen 103 investigators were unable to adjudicate long-term causes of death in trial participants, so we don’t know what proportion of the patients died from progressive cancer, thromboembolism, or something else. The transfusion end point is also murky. The Amgen 103 study was multinational, and 75% of patients enrolled in Europe, including areas of Eastern Europe where blood bank shortages occur. Of the 75 study patients who did not undergo transfusion when their hemoglobin level decreased to less than 8 g/dL, 95% were from Eastern Europe. The trial’s primary end point of transfusion reduction with darbepoetin could have been met if these patients had undergone transfusion according to protocol guidelines. In retrospect, it was probably not a good idea to conduct a study with a transfusion primary end point at sites where access to blood is not assured. United States–based drug companies often pursue clinical trials overseas when they want to accrue patients rapidly, especially when the study question would be difficult to answer in North America because of entrenched clinical practice patterns. In the case of the Amgen 103 study, the study sponsor may have had little choice, because placebo-controlled studies of ESAs are notoriously difficult to conduct to in the United States. There are many reasons for this, but a major factor is the widespread use of drug purchasing contracts that limit physicians’ choice of ESA products in exchange for discounted pricing—an important but controversial revenue source for many oncology practices. If the results of the Amgen 103 study had appeared several years ago in the golden age of ESAs, they might have been chalked up to limitations of study design and execution. The possibility could still have been left open that in anemic cancer patients who aren’t getting chemotherapy, ESAs might modestly reduce transfusion needs and have no impact on survival. Instead, these results arrive at a tumultuous time, when ESAs and their manufacturer, Amgen, are subject to intense scrutiny, after the fallout from a February 2007 expose in The Cancer Letter about poorer survival in head and neck cancer patients treated with darbepoetin in the Danish Head and Neck Cancer study 10 trial. Now, ESA safety is on every oncologist’s mind, and the Amgen 103 study results only heighten those concerns. We need to take these results seriously, and unless new data emerge, I believe we can’t afford to risk testing ESAs in this population again. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 7 MARCH 1 2008