Background: Anemia is common in cancer patients both as a consequence of cancer treatments such as chemotherapy and as a result of the underlying disease. Up to 34% of patients with lung cancer may present with hemoglobin (Hb) levels less than or equal to 12.5 g/dL.

Objective: To determine whether epoetin alfa therapy improved the quality of life of anemic patients with unresectable locally advanced non-small cell lung cancer (NSCLC) who were not candidates for high dose thoracic radiation and were not treated with chemotherapy during or within two months prior to entering the trial.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial with a twelve-week treatment period. Patients were randomly assigned to receive either 12 weekly subcutaneous injections of 40,000 U of rHuEPO or 1.0 ml of an identical-appearing placebo with dose escalation to 60,000 U (active arm) or 1.5 ml (placebo arm) if Hb increased less than 1.0 g/dL from baseline at the 4 week assessment. Random assignment was stratified by center, entry Hb level (less than 10.0 g/dL vs. 10.0-12.0 g/dL), and concurrent or planned palliative radiotherapy (no/yes). Dose/injection volume decreased by 25% if the hemoglobin increased by 2.0 g/dL over 4 weeks. Treatment was withheld with an Hb of 14.0 g/dL or above and restarted at 75% of the initial dose/volume when the Hb was below 12.0 g/dL. Iron was supplemented at the discretion of the attending physician.

Because of low accrual, the eligibility criteria were modified during the study to allow inclusion of subjects receiving palliative chemotherapy with the exception of platinum-based regimens. Seventy patients were randomized (33 receiving epoetin alfa and 37 receiving placebo). The primary outcome of change in quality of life (QOL) on the Functional Assessment of Cancer Therapy-Anemia (FACT-An) score was evaluated as change from baseline to the 12 week assessment. Secondary outcomes included change in Hb and need for blood transfusions. QOL data were collected through 16 weeks with Hb assessed at 26 weeks and only overall survival was followed after 26 weeks.

Results: The Steering Committee suspended the trial following a review by the study's independent Data Safety and Monitoring Committee (DSMC) requested by Ortho Biotech. The request for the review was prompted by concern about higher than expected rates of thrombotic events found in other studies. The DSMC review of the first 66 patients found low rates of thrombotic events with no difference between study arms, but revealed differences in median time to death (63 days in the epoetin alfa arm and 129 days in the placebo arm; HR 1.84, 95% CI 1.01 to 3.35, p = .04).

Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN. (2007). J Clin Oncol 25(9): 1027-32.

NAAC Expert Commentary:
This study was designed to examine the effects of epoetin alfa on QOL in a previously unstudied population: anemic patients with advanced NSCLC who had disease-related rather than chemotherapy-related anemia. Additional contextual differences from the majority of previously reported epoetin alfa trials were the use of a Hb level of 12 g/dL for defining anemia and the continuation of treatment to a Hb level of 14.0 g/dL. As noted by the authors, the data presented raise a number of questions ranging from whether or not erythropoietic stimulating agents interact with unknown biologic factors to influence the rate of disease progression in subsets of people with cancer to the possibility that there were factors associated with prognosis that were not adequately controlled, or that the variables used to represent prognostic factors lacked the sensitivity required to detect real differences between the groups.

The authors present a thoughtful discussion of several strengths and weaknesses of the trial and emphasize the need to include survival outcomes in current and future trials of erythropoietic agents. Given the lack of data on possible biologic explanations for discrepant findings in some studies, it is important to begin including measures of variables that assess potential mechanisms of thrombosis and disease progression to examine these hypotheses in clinical populations.

Last Updated: June 1, 2007