Increased mortality risk cannot be excluded

A large meta-analysis of individual patient data from clinical trials of ESAs in cancer patients found that ESAs increased on-study mortality by 17% and overall survival by 6% in patients randomized to receive ESAs, compared with controls. When patients who were on chemotherapy were analyzed separately, the increased risk in on-study mortality and overall survival with ESAs was less pronounced, but cannot be excluded, said Dr. Bohlius from the University of Bern, Switzerland.

“The increased risk of death must be balanced against the benefit of ESAs for each patient on an individual basis,” Dr. Bohlius stated during her presentation at ASH 2008.

Dr. Bohlius emphasized that this meta-analysis, unlike previous reviews of ESA studies, collected data on individual patients from investigators involved in the different studies and from makers of ESAs. The manufacturers of ESAs had no involvement in the study design, analysis, interpretation of data, and writing of the report. “The study was funded by industry-independent sources, including the German Ministry of Education and Research and Onco-Suisse,” Dr. Bohlius stated.

The detailed analysis was based on individual patient data from 13,933 cancer patients enrolled in 53 different trials. Overall survival and on-study survival were significantly lower in all cancer patients who received ESAs. However, among 10,441 patients enrolled in chemotherapy trials, no significant difference in overall survival or on-study mortality was found for those who received ESAs, compared with those who did not.

Dr. Bohlius and Dr. Engert said they failed to find significant differences for ESAs related to the type of treatment patients received: chemotherapy, radiotherapy, chemoradiotherapy, or no treatment. No evidence was found for an interaction between ESAs and specific tumor types. Among 20 different factors analyzed, no strong evidence emerged for any of them as a risk factor. Dr. Bohlius said there was a suggestion that a history of thromboembolic disease, baseline hematocrit, and planned frequency of ESA administration may have modified the effect of ESAs, but the study did not prove this.

Dr. Engert said that the European agencies are even more restrictive with regard to ESAs than the FDA. “The wording of the (EU) regulations is difficult for physicians and patients. If a patient sees that the drugs are only for patients who are ‘not curable,’ he may think he is dying. The wording of the regulations is very likely subject to another revision, and we will probably follow the FDA wording,” Dr. Engert said.