ESAs Increase Mortality in Cancer Patients, Meta-Analysis Confirms CME/CE

News Author: Zosia Chustecka
CME Author: Charles Vega, MD, FAAFP

CME/CE Released: 05/04/2009; Valid for credit through 05/04/2010

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May 4, 2009 — The huge meta-analysis of individual patient data that confirmed an increased mortality in cancer patients treated with erythropoiesis-stimulating agents (ESAs) has been published in the May 2 issue of theLancet.

The researchers analyzed individual data for 13,933 cancer patients participating in 53 trials, and found that ESAs increased the relative risk for mortality by 17%. When they considered only cancer patients who were undergoing chemotherapy (10,441 patients in 38 trials), they found that ESAs increased the relative risk by 10%.

These results were first presented at the 2008 annual meeting of the American Society of Hematology (ASCO), and were reported by Medscape Oncology at the time.

"The increase in mortality is very worrisome," J. Evan Sadler, MD, PhD, from Washington University in St. Louis, Missouri, commented at the time, noting that these products should be used with "appropriate caution."

These new data will reignite concerns over the use of ESAs in cancer patients, Dr. Sadler said. But another expert, Samuel Silver, MD, PhD, FACP, from the University of Michigan in Ann Arbor, suggested that there was "no new cause for concern."

The safety of these drugs in cancer patients has already been extensively discussed by regulatory authorities in both the United States and Europe, and both have restricted their use in this patient population. In the United States, these products also carry a black-box warning stating that they can increase the risk for death in cancer patients. The restrictions are already in line with these new data, Dr. Silver said, adding that he does not anticipate any further regulatory moves in the near future.

New Data Back Regulatory Moves

Lead author of the meta-analysis, Julia Bohlius, MD, from the Institute of Social and Preventive Medicine at the University of Bern in Switzerland, said that the US Food and Drug Administration was right in restricting the use of these products in cancer patients, and that her team's results — which were not available at the time the regulatory moves were made — "back this decision." The individual patient data meta-analysis provides a clearer picture of the risk for mortality with these agents, showing a larger treatment effect and greater statistical significance than had been reported previously in literature-based meta-analyses, she said. In addition, the team was able, for the first time, to separate on-study mortality from overall survival. "I am more convinced now that the adverse effect is real," she said.

"The increased risk of death associated with treatment with these drugs should be balanced against their benefits," Dr. Bohlius and colleagues conclude in their paper.

On the benefits of ESAs, which are used to treat anemia in cancer patients, Dr. Bohlius told Medscape Oncologythat she is convinced by the evidence from the literature that these products reduce the need for blood transfusions. However, she is less convinced by the evidence that they improve quality of life and reduce fatigue, because some studies are positive and others are less so, and there might be a publication bias here.

"In clinical practice, the increased risk of death and thromboembolic events should be balanced against the benefits of treatment with ESAs, taking into account each patient's clinical circumstances and preferences," the researchers write.

No Way of Identifying Patients

From a physician's point of view, one of the most perplexing issues with the use of these agents is that there is no way of identifying which cancer patients are most likely to benefit — only about 50% to 60% respond to treatment with ESAs with an increase in red blood cell count, Dr. Bohlius noted.

There is also no way to identify those in whom the risk for death is increased with the use of ESAs, she added. None of the factors that the team analyzed were predictive — not hemoglobin levels at baseline, target hemoglobin levels, or the planned doses of ESA. "But there may be something else, something that wasn't measured, or something that we don't know about yet," she added.

"The patients who respond to ESA treatment are the ones who show better survival," she said, but this might not be related to the treatment. It might be that these are the "healthier" cancer patients; the ones with the most severe anemia are likely the ones who have the most aggressive cancers and are the ones who are the most likely to die.

When asked about the mechanism by which ESAs raise the risk for mortality, senior author Andreas Engert, MD, from the Cochrane Haematological Malignancies Group at the University of Cologne in Germany, said he felt the most likely explanation was an increase in thromboembolic events.

"Increasing evidence suggests that ESAs might cause thromboembolic and cardiovascular events, independent of hemoglobin concentrations," the researchers write in the article. In their analysis, patients with previous thromboembolic events seemed to be protected, and they speculate that this might be because they had received prophylactic anticoagulation treatment.

There are several other hypotheses explaining how ESAs increase the risk for mortality in cancer patients. One focuses on erythropoietin receptors on tumors, hypothesizing that ESAs act on these receptors and stimulate tumor growth, as previously reported by Medscape Oncology. Some studies have shown such receptors, whereas others have not, Dr. Bohlius said.

Further study is needed to elucidate how ESAs exert this adverse effect, and to find some clinical or molecular factor that identifies patients who are most likely to be harmed and those who are most likely to benefit from these agents, she said.

Dr. Bohlius reported receiving honoraria and travel grants from Amgen, and some of her coauthors declare relationships with pharmaceutical companies, as detailed in the article.

Lancet. 2009;373:1532-1542.

Clinical Context

Many patients with cancer go on to have anemia, which can be the result of effects of the cancer itself or cancer treatment. Bohlius and colleagues performed a meta-analysis of ESAs to find the balance between potential harms and benefits of these medications in cancer patients. Their results, which were published in the May 17, 2006, issue of the Journal of the National Cancer Institute, found that ESAs did improve hemoglobin concentrations and reduced the need for transfusion. However, these medications were also associated with a 67% increase in the risk for thromboembolism. Finally, the risk for mortality was slightly higher in patients receiving ESAs, although this result failed to reach statistical significance.

The current meta-analysis uses individual cancer patient data to examine the issue of ESAs and mortality more closely.

Study Highlights

Researchers examined studies published between 1985 and 2008, which compared epoetin or darbepoetin vs control treatment in patients with cancer. Trials involving patients with myelodysplastic syndromes and acute leukemia were excluded.
The primary outcome was mortality, both during the active trial period and after (overall survival duration).
Researchers attempted to account for individual patient differences that could affect the primary outcome, including age, sex, the type of tumor and its treatment, hemoglobin concentrations, a history of thromboembolism, and the dose of ESAs.
53 studies involving a total of 13,933 patients were included in the meta-analysis. Nearly two thirds of the meta-analysis cohort consisted of women, and the mean age of the patients was 60 years.
72% of the trials focused on patients receiving chemotherapy, and another 9% of research included patients receiving radiochemotherapy.
Mortality was a primary endpoint in only 9% of included research, and it was a secondary endpoint in 28% of the studies. In the other research, mortality was included as a safety outcome.
The duration of treatment with ESAs ranged between 8 and 52 weeks. There was evidence that these medications were not used in compliance with current indications for cancer patients.
The median follow-up period for mortality during the active study period was nearly 4 months. The median follow-up duration for overall survival was 6.2 months.
1530 patients died during the active study period, and 4993 patients died overall. The hazard ratio for mortality associated with the use of ESAs vs control treatment during active treatment was 1.17, and the hazard ratio for overall survival was 1.06. Both of these results were statistically significant.
There was limited heterogeneity between trials in the primary outcome.
Among the subgroup of patients treated with chemotherapy, ESAs were associated with a nonsignificant trend toward a higher risk for mortality during the active study period and for overall survival duration as well.
The particular cancer treatment that patients received did not significantly alter the study's main finding.
Higher-quality trials tended to find a greater risk for mortality associated with ESAs vs lower-quality trials.
Patients with a low baseline hematocrit level of less than 23.5% experienced a higher risk for mortality associated with the use of ESAs, as did patients who did not have a history of thromboembolism. This latter phenomenon may have been the result of wider use of antithrombotic therapy in patients with previous thromboembolic events.

Clinical Implications

In a previous meta-analysis, ESAs were demonstrated to improve hemoglobin concentrations and reduce the need for blood transfusions in patients with cancer. However, they were also associated with a higher risk for thromboembolism. ESAs did not have a significant effect on the risk for mortality in this study.
The current meta-analysis suggests that the use of ESAs may increase the risk for mortality in patients with cancer.

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