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Meta-analysis shows ESAs increased on-study mortality in patients with cancer

Issue: December 25, 2008

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50th ASH Annual Meeting

According to a meta-analysis, erythropoiesis-stimulating agents increased on-study mortality and worsened overall survival when used for treatment of anemia in patients with cancer.

The meta-analysis included 13,933 patients with cancer enrolled in 53 randomized, controlled clinical trials. The trials compared epoetin alfa, epoetin beta and darbepoetin alfa plus red blood cell transfusions vs. red blood cell transfusions alone for the prevention or treatment of anemia, either while or after patients received cancer treatment. In 38 of the trials (n=10,441), chemotherapy was the therapy used.

The primary endpoints of the meta-analysis were on-study mortality and overall survival in patients with cancer receiving chemotherapy, including all studies where more than 70% of patients enrolled received chemotherapy, and all patients with cancer regardless of the type of anticancer therapy. On-study mortality was defined as death from any cause, occurring between the date of randomization and 28 days after the end of the study treatment phase.

Overall survival was defined as death from any cause between the date of randomization and the longest amount of follow up available.

In all patients with cancer, ESA use increased on-study mortality by 17% (HR 1.17, 95% CI, 1.06-1.30) and worsened overall survival by 6% (HR 1.06, 95% CI, 1.00-1.12). For patients undergoing chemotherapy, the increase in on-study mortality was 10% (HR 1.10, 95% CI, 0.98-1.24) and in overall survival was 4% (HR 1.04, 95% CI, 0.97-1.11).

"The increased risk of death must be balanced against the benefits of ESAs, taking into account each patient's clinical circumstances and preferences," said Julia Bohlius, MD, MScPH, from the University of Bern, Switzerland, during a press conference. "Possible next steps are to further evaluate the impact of post-baseline hemoglobin levels on mortality [and] to better understand the impact of ESAs on thromboembolic and tumor progression. ... To get a better picture of the benefits of ESAs, therefore, we want to do the same analysis for the impact of ESAs on quality of life and transfusion needs." – by Evan Young

This was an important and highly anticipated meta-analysis that looked patient- level data from close to 14,000 patients enrolled on randomized studies in cancer patients receiving ESAs or transfusion. Previous meta-analyses have been at the level of the clinical trial. What these previous meta-analyses have suggested is that ESAs cause increased mortality in cancer patients who are not being treated with chemotherapy. One meta-analysis suggests that ESAs also increase mortality in the anemia associated with chemotherapy. This paper goes down to patient-level data, and we have been waiting for this information for the last six months, with the hope that it would clearly help us understand the risks of ESAs in these populations. What the study shows is that when you look at all cancer patients, irrespective of the therapy they received, there was a statistically significant increase in on-study mortality in those patients receiving ESAs compared to those patients in the transfusion-only arm. When they specifically looked at the population treated with chemotherapy, there was a suggestion of increased mortality, but it was not statistically significant. These data remain consistent with the current ASH/ASCO guidelines that state that patients who are not on chemotherapy not receive ESAs. What probably will happen is a reconvening of ASH/ASCO guideline committee to look at the data from this study, to examine data submitted over last year to the FDA ODAC committee and to look at the FDA's actions with their change of labeling and black box warnings. We await the reconvening of this guideline committee.

– Samuel Silver, MD

HemOnc Today Editorial Board member

For more information:

• Bohlius. #LBA-6. Presented at: 50th Annual Meeting of the American Society of Hematology; December 5-9, 2008; San Francisco.