NO EFFECT OF IV IRON ADDED TO ESAs

January 17, 2011— A new study — the largest to date — has found no additional effect from adding intravenous (IV) iron to an erythropoiesis-stimulating agent (ESA) in cancer patients with chemotherapy-associated anemia.

The study, by David Steensma, MD, and colleagues at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, appears in the January 1 issue of the Journal of Clinical Oncology.

The negative result is in sharp contrast to a number of positive studies that have shown benefit from adding IV iron in this setting, as previously reported by Medscape Medical News.

"It is unclear why these results are discordant with the findings of other trials (all smaller than this study)," Dr. Steensma and colleagues write.

Currently, the use of IV iron in cancer patients receiving ESA is "uncommon," they note. In the United States, this is partly due to Medicare rules that do not allow the coadministration of an ESA and IV iron on the same day.

"The results of this study do not support change in the status quo," the researchers conclude.

Positive studies showing a benefit from adding IV iron to ESA in cancer patients receiving chemotherapy were mentioned in the recently updated guidelines issued jointly by the American Society of Clinical Oncology and the American Society of Hematology. However, after reviewing 3 of these positive studies, the expert panel said that "study limitations" led them to conclude that the currently available clinical evidence is insufficient to support adjuvant IV iron as a standard of care.

These guidelines "should be respected, but I disagree with them, based on the preponderance of published data," said Michael Auerbach, MD, clinical professor of medicine, Georgetown University School of Medicine, Washington, DC. He also noted that guidelines from the National Comprehensive Cancer Network recommend IV iron when iron is indicated in chemotherapy-induced anemia.

Dr. Auerbach was the first to report a benefit from adding IV iron, in 2004; since then there have been 8 studies showing a benefit from adding IV iron to ESAs, he told Medscape Medical News. There were 2 meta-analyses of these data presented at the 2010 American Society of Hematology annual meeting, he noted, and both concluded that IV iron added to ESAs for chemotherapy-induced anemia was associated with improved response rates, decreased ESA exposure to target hemoglobin levels, and decreased transfusions without an increase in adverse effects.

"I routinely use IV iron with ESAs in cancer," Dr. Auerbach said.

He had several suggestions as to why the latest study was negative, and highlighted the fact that the researchers used a smaller dose of iron than has previously been used.

Negative Results

The study conducted by Dr. Steensma and colleagues involved 502 patients with hemoglobin levels below 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies.

All patients received the ESA darbepoetin alfa once every 3 weeks, and were then randomly assigned to receive either IV iron (ferric gluconate 187.5 mg) every 3 weeks, or oral iron (ferrous sulfate 325 mg daily) or an oral placebo daily, for a period of 16 weeks.

The results show no differences between the groups in the erythropoietic response rate (i.e., the proportion of patients achieving hemoglobin levels 12 g/dL or above or an increase of 2 g/dL from baseline), in the proportion of patients requiring red cell transfusions, in changes in quality-of-life measurements, or in the dose or darbepoetin administered.

At the same time, there were more adverse events in the IV iron group, with 54% of patients reporting grade 3 or higher adverse events, compared with 44% of those who received oral iron and 46% receiving oral placebo (P = .16).

The researchers suggest that part of the reason for this increased proportion of adverse events with the IV iron might have resulted from the use of premedications (such as diphenhydramine) in those patients, which was left to the local investigator's discretion. However, the fact that grade 3 and greater adverse events were also common in the placebo group suggests that many of the reported adverse events might actually have been attributable to other agents (e.g., concomitant cytotoxic chemotherapy) or to underlying disease rather than study drugs, they note.

Dr. Auerbach questioned the high rate of reported adverse events, and said he wondered what the "real adverse event rate was."

"We just don't see anything that resembles that rate in practice," he said. "I've given thousands of doses of IV iron, and adverse events are extremely uncommon."

Dr. Auerbach suggested that the dose of IV iron administered in this trial was too low. Dr. Steensma and colleagues administered 187.5 mg every 3 weeks (a total mean dose of iron actually delivered of around 650 mg), whereas a previous study with positive results administered 200 mg every 3 weeks (a total mean dose of iron of around 1050 mg), he said.

This suggestion is supported by the observation that in the Steensma study, the transferrin saturation increases were higher in patients treated with oral iron than in those treated with IV iron, when typically the reverse has been seen, Dr. Auerbach explained.

Another possibility is that the negative study enrolled patients with higher transferrin saturations than have been seen in previous trials, which could have skewed the response rate to some degree, Dr. Auerbach reported.

Differences From Other Studies

Dr. Steensma told Medscape Medical News that he agrees with some of the explanations of why their study was negative.

The total iron dose was "a little bit lower," Dr. Steensma agreed, although he also said that there was not a large difference in the dose that had been administered. Also, the iron parameters of the patients in this trial might have been different from those in other studies, although he pointed out that the patients enrolled in this trial reflect a typical chemotherapy-associated anemia population, because the North Central Cancer Treatment Group is made up of a broad group of community-based practices. He added that the ferric gluconate used in this trial is less "potent" than other preparations (some of the European trials used iron sucrose).

"I don't put too much stock in transferrin saturations in this population and, in contrast to transferrin saturation, the serum ferritins (reflecting total body storage iron) went up a lot more in the IV iron group than in the other groups in this study, so clearly the patients were getting the iron into their systems," he added.

"I see the negative result as something interesting and provocative, rather than disappointing," Dr. Steensma said. "Clearly, we don't have the whole 'parenteral iron in cancer anemia' story worked out yet, and we have much yet to learn and reason to continue studying the issues."

His team is currently analyzing hepcidin data from the study cohort, "which look interesting." This analysis is being carried out in collaboration with scientists at Amgen (the manufacturer of darbepoetin), which helped fund the study.

Dr. Steensma has disclosed no relevant financial relationships. One of his coauthors, Charles Loprinzi, MD, reports receiving research funding from Amgen. Dr. Auerbach has disclosed no relevant financial relationships, and notes that he does not accept honoraria or consulting fees for anything to do with IV iron.

J Clin Oncol. 2011;29:97-105. Abstract