ANOTHER FAILURE OF ESAs

November 10, 2009 — A large study of cancer patients receiving chemotherapy in the community has found that the use of erythropoiesis-stimulating agents (ESAs) is associated with an increase in the risk for venous thromboembolism (VT), which confirms previous reports, but also found — surprisingly — that there was no decrease in the use of blood transfusions, which is the raison d'être for the use of these drugs.

The study was published online November 10 in the Journal of the National Cancer Institute.

In this study, there was no increase in mortality associated with the use of these agents. However, an increased risk for death has been seen in other studies and in meta-analyses, and is listed in a black box warning on the product labeling of these drugs. The black box also warns of an increase in the risk for VT.

Lead author Dawn Hershman, MD, from Columbia University Medical Center in New York City, told Medscape Oncology that in recent years the use of ESAs in cancer patients "has fallen out of favor, and there are now very clear guidelines that help regulate their use."

"I would not say that there is no benefit from ESAs," she explained. "There may be a substantial benefit for some patients," she continued, adding that "we need to better figure out who benefits the most and how we decide what a reasonable benefit is."

"The most important thing is to discontinue their use if they are not having the desired effect," Dr. Hershman explained.

ESAs are particularly interesting from a public policy perspective because they are expensive, the authors note. Total sales of ESAs in the United States increased from $4.6 billion in 2002 to $10 billion in 2006, accounting for a greater Medicare Part B expenditure than any other drug, they report. "We speculate that this use was fuelled by aggressive marketing to patients and physicians that focused on a promise of increased energy during chemotherapy treatment," they add.

"Further efforts at monitoring use and long-term toxicity of expensive oncology drugs should be put into place to ensure that for any drug the benefits outweigh the risks in community practice," the authors conclude.

No Decrease in Blood Transfusions

ESAs were approved by the US Food and Drug Administration (FDA) — erythropoietin in 1991 and darbepoietin in 2002 — for use in cancer patients being treated with chemotherapy to reduce their need for blood transfusions, the researchers explain. The approval was based on clinical trials that showed a 50% decrease in blood transfusions, decreased fatigue, and an increase in patients' ability to participate in daily activities.

The current study set out to evaluate the use of ESAs in elderly cancer patients receiving chemotherapy who were being treated in community practices in the 10 years since the drugs were first approved.

The researchers used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database, and found 56,210 cancer patients treated with chemotherapy from 1991 to 2002.

Overall, just over a quarter (27%) of these patients were treated with an ESA. However, the proportion of patients who received these drugs rose rapidly after they were approved, increasing from 4.8% of patients in 1991 to nearly half of all patients (45.9%) in 2002 (P < .001), the authors note.

"Given the rapid rise in the use of ESAs since their approval by the FDA, we were surprised to find that the rates of red blood cell transfusion did not decrease substantially during this time," the researchers note. The rate of blood transfusions per year from 1991 to 2002 remained constant at 22%.

Asked about the stark difference between this finding and that from the clinical trials that resulted in approval — in which the need for blood transfusions was halved — Dr. Hershman noted that there were several differences between the 2 study populations. The patients taking part in clinical trials were monitored more closely and might have had a higher rate of blood transfusions in the placebo group, she explained. In addition, the clinical trials were based on short-term outcomes — the initial approval was based on 2 trials that evaluated patients for 12 weeks, the authors point out.

Those initial short-term trials of ESAs in cancer patients also showed no hint of an increase in the risk for VT, the authors note. In fact, there were fewer events in the patients taking ESAs than in the placebo group.

Significant Increase in VT Risk

In this study of long-term use in the community, the risk for VT was nearly doubled in patients treated with ESAs. This complication developed in 14.3% of patients taking ESAs (1,796 of 12,522 patients) and in 9.8% of patients not taking ESAs (3,400 of 34,820 patients). The hazard ratio was 1.93 (95% confidence interval, 1.79 - 2.07).

This nearly 2-fold increase in the risk for VT is "significant," Dr. Hershman said. It was observed after controlling for all factors that could have confounded the finding, she added.

The authors note that the increase in the risk for VT confirms the finding from a recent meta-analysis (JAMA. 2008;299:914-912), but in this case is "slightly higher." However, there were several differences between the 2 patients cohorts, they note: those in the meta-analysis were taking part in clinical trials and were followed prospectively, but for a shorter period of time. This study was retrospective, but patients had a longer follow-up. In addition, all the patients in the current study were older than 65 years, which might also have contributed to the risk, the authors write.

The authors point out that, although the association between ESAs and an increased risk for VT is "biologically plausible" and has been established in short-term randomized trials, it remains unclear from observational studies whether it is the reason for administering the ESA that places the patients at higher risk or whether it is the agent itself that increases the risk. "This problem of confounding by indication is particularly true for patients with more claims for ESAs, who may be sicker as a result of the underlying cancer," they add.

Another point that the authors make is that the claims data used in their study showed an association between ESAs and an increased risk for VT "as early as 4 years after FDA approval," (that is, in 1995). But a warning about this risk and others, including decreased survival, was added in a black box to the product labeling only in 2007.

"Thus, the use of claims data for monitoring outcomes appears to be warranted as a potential way for detecting long-term toxicities," they say.

About the finding that there was no affect on mortality in this study, Dr. Hershman pointed out that all of these cancer patients were receiving chemotherapy, and meta-analyses that have been limited to this group of patients have also not shown any impact on mortality. "The studies on mortality have only found an increase when ESAs were given to patients not on chemotherapy," she noted.

Funding came from the US National Cancer Institute and the American Cancer Society. The researchers have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online November 10, 2009.