Πέμπτη 28 Οκτωβρίου 2010

USE ERYTHROPOIETIN ONLY FOR HEMOGLOBIN BELOW 10 AND ONLY FOR PATIENTS RECEIVING PALLIATIVE CHEMOTHERAPY

October 26 2010 — The use of erythropoiesis-stimulating agents (ESAs) in cancer patients became controversial when clinical trial data showed shortened survival in some patients. Since then, these agents have been restricted by a flurry of labeling changes by the US Food and Drug Administration (FDA), as well as by an FDA-mandated Risk Evaluation and Mitigation Strategy program introduced earlier this year.

Clinicians left reeling by the many changes now have a blueprint to follow in their daily practice — an updated guideline has been issued jointly by the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO), and was published online October 25 in both Blood and the Clinical Journal of Oncology.

"These guidelines touch on almost all aspects of the use of ESAs in patients with cancer and myelodysplastic syndromes," said Samuel Silver, MD, professor of internal medicine at the University of Michigan in Ann Arbor. He was not on the guideline panel, but is a member of the ASH Committee on Practice.
These are issues that confront practicing hematologists and oncologists on a daily basis. We hope that these evidence-based recommendations will influence practice standards and result in better care for patients," Dr. Silver said in a statement.

This updated guideline offers clinicians the latest synthesis of the medical evidence surrounding the use of ESAs in patients with cancer," said J. Douglass Rizzo MD, MS, cochair of the panel that produced the guidelines. Plus, it contains "appropriate cautions where evidence is lacking or where risk may outweigh benefits," he added. Dr. Rizzo is professor of medicine at the Medical College of Wisconsin in Milwaukee.

Risks that have been recently recognized for these agents include an increased risk for thromboembolism and tumor progression, as well as shorter survival. In updating the guideline, the panel focused on recent data showing risk; it did not revisit the data supporting the benefit of ESAs in increasing hemoglobin levels and reducing the need for red blood cell transfusions, "because the evidence on these outcomes is robust."

"We need to understand better the mechanism by which these drugs can be harmful," Dr. Rizzo said in an interview. The new evidence of risk has led to restrictions on their use, and this in turn has led to in a decline in the use of these drugs in cancer patients, as reported previously by Medscape Medical News. Dr. Rizzo said he can believe that because "the more barriers that must be crossed to prescribe, the more use declines." He also suspects that some of the use of these agents in the past was discretionary, perhaps driven more by "belief" than by evidence.

Other experts criticized the overenthusiastic use of ESAs in cancer patients when they were first launched, noting that the demand for these products was driven by direct-to-consumer advertising.

Fine-Tuning the Recommendations

The guideline was last issued in 2007, and many of the recommendations have been updated or fine-tuned since then.

For instance, initiation of ESA therapy is now recommended when hemoglobin drops below 10 g/dL. The 2007 guideline suggested ESAs could be considered when the hemoglobin level was 10 to 12 g/dL, on the basis that it might improve quality of life in patients with cancer. But experts have disagreed on whether the magnitude of the improvement in quality of life that has been reported is "clinically meaningful," the panel points out. Furthermore, any benefits to quality of life must now be considered in the context of increasing evidence of risk, it notes. Hence, the updated guideline recommends that the goal of ESAs should be to avoid transfusions, "without specific consideration of improvement in quality of life as a target outcome."

The updated guideline confirms the effectiveness of ESAs in reducing the need for blood red cell transfusions, which is a "major benefit" of these agents, because transfusions can potentially cause serious infections and adverse reactions in the immune system. They are also inconvenient for the patients, Dr. Rizzo noted.

"There are plenty of data to show that you can spare blood transfusions with the use of ESAs; of course, these are the data that led to these drugs being approved in the first place," Dr. Rizzo said. The initial studies were designed with this as the outcome of record, he explained, so they were powered to detect that. But small studies designed to detect transfusion avoidance were not powered, and not designed, to detect later outcomes, such as survival. These data on risk came later, when larger, longer studies were conducted and combined in meta-analyses.

The main difference between 2007 and 2010 is that there are now more data, Dr. Rizzo said, and this new evidence confirms that there is a risk for thromboembolism and a risk for shortened survival in certain cancer patients.

Chemo With Curative Intent

The updated guideline highlights the need for clinical judgement in following the new labeling that restricts the use of ESAs to cancer patients who are receiving chemotherapy for palliative intent. Because of the data on shortened survival, the FDA decreed that these agents should not be used in patients who are receiving chemotherapy with a curative intent.

However, this distinction is not always clear-cut in clinical practice. "Determining the goal of treatment requires clinical judgement," the panel points out.

For instance, patients with multiple myeloma and chronic lymphocytic leukemia often respond to first- or subsequent-line therapy, but these malignancies recur in most patients; hence, "determining the treatment intent requires clinical judgement of an individual patient's circumstances."

The treatment goal would generally be considered curative in, among other instances, testicular cancer, first-line therapy of Hodgkin's disease, and early-stage solid tumors (e.g., breast, colon, and lung) being treated with adjuvant chemotherapy, the panel notes.

Dr. Rizzo explained that this distinction between chemotherapy for curative and palliative intent is not based on "formal criteria" defined in the evidence — there were no clinical trials in which subgroups of patients in these categories were compared with one another.

The underlying message is that these drugs can be potentially lethal and should not be given to patients expected to be cured, he explained.

"In general, physicians know when they are treating with a curative intent and when it is palliative," he said, adding that "this in not always easily described to the patient." In addition, there are always surprises — occasionally patients who were not expected to be cured respond extremely well to a therapy — and there is often no way of knowing which patients may do so beforehand. ESAs are not recommended for use in cancer patients who are not receiving chemotherapy, but there is an exception here — they can be used in patients with lower-risk myelosuppressive disorders to avoid transfusions, the panel notes. ESAs are also not recommended for use in cancer patients who are receiving radiation therapy.

Adding Iron Not Standard of Care

Several of the recommendations remain unchanged from the 2007 guideline, despite new data having been considered.

For instance, new data have suggested that adding iron is beneficial. Three clinical trials have shown that iron given orally or intravenously in addition to darbepoetin in cancer patients with chemotherapy-induced anemia improved the hematopoietic response and resulted in fewer transfusions. However, the panel explains that "study limitations" led them to conclude that the currently available clinical evidence is insufficient to support adjuvant intravenous iron as a standard of care.

Need for More Research

"There is clear evidence regarding the ability of ESAs to increase hemoglobin and avoid transfusions," the panel concludes, but "there is also evidence of harm associated with their use."

"Perhaps the most pressing need for additional research is studies that further clarify the mechanism of harm and, particularly, the groups of patients or circumstances of clinical use that are least associated with these risks. This understanding is paramount to the ability of clinicians to extend the benefit of these drugs while reducing the risks," the panel writes.

Coauthor Jerry L. Spivak, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, reports having served in a consultant or advisory role for Johnson & Johnson. Dr. Rizzo and the rest of the panel members have disclosed no relevant financial relationships.

Blood. Published online October 25, 2010.
J Clin Oncol. Published online October 25, 2010.

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