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Should IV iron be given to every patient with chemotherapy-induced anemia assigned ESA therapy?
ESA plus IV iron better than ESA alone
We learned from the nephrologists that even in what we consider iron-replete patients who are receiving ESAs, there seems to be an improvement in response to ESAs with IV iron. What we think is happening is that you have iron stored, but it is not readily mobilized to developing young red cells. The addition of a different source seems to help supply those young red cells and allow for more efficient use of ESAs. In patients receiving dialysis, the data show that even in patients who are not iron deficient, there has been an improvement in ESA efficiency by giving IV iron.
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Now to oncology. There are now five studies showing that this benefit extends to patients with chemotherapy-induced anemia. These are patients with chemotherapy-induced anemia who received ESAs with or without IV iron. Their iron tanks are, arguably, full, yet, they had a significant improvement in ESA response with the addition of IV iron. One of the studies even showed a decrease in transfusion requirement. The others all showed a significant improvement in hemoglobin response rate.
These data have not had a high uptake in oncology, however. Why is that? There is a general fear among oncologists that IV iron is not safe. That was true long ago when Imferon, which had about a 50% adverse reaction rate, was on the market. Now we have three very safe iron preparations on the market: low-molecular weight iron dextran, iron sucrose, and ferric gluconate. These have a very low adverse reaction rate — less than 1%. The high-molecular weight iron dextran is associated with much higher adverse reaction rate — around 25%. The iron sucrose and ferric gluconate do not even need premedication.
Part of the problem is how to know that iron stores are fine, short of a bone marrow biopsy. Ferritin levels can be hard to interpret in patients with cancer. Several studies show that if the ferritin level is greater than 100 ng/mL then the patient is more than likely not iron-deficient. What most of us look for now is a ferritin higher than 100 ng/mL and a transferrin saturation less than 15% to 10%. In the five IV iron studies in oncology, those patients seem to benefit most from IV iron.
The moral of the story is that there is increasing literature available in well-done peer-reviewed studies that have all shown that ESAs plus IV iron is better than ESA alone in terms of response and ESA efficiency. You have to factor in the current ESA controversy. People are now saying ESAs are unsafe, but this is an opportunity for iron to enhance response rates. The FDA says to use the lowest possible dose of ESA. What better way to do that than to give IV iron?
David Henry, MD, is a Clinical Professor of Medicine at Pennsylvania Hospital, and Vice-chair of the Department of Medicine.
IV iron may not be necessary
IV iron use probably should be more common than it is in patients with cancer. There are five randomized trials comparing IV iron with oral iron or placebo. The trials differed somewhat in the types of patients they included, the type of iron used and the iron status of the patients. Basically, they all showed something similar: if you use IV iron, the response to ESAs improves. In some, the response occurred more quickly.
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Despite the trials, why don’t I start IV iron immediately in all patients commencing on treatment with ESAs? There are many patients who respond well to ESAs without any supplementary iron. The randomized trials suggest that 50% to 70% of patients will respond to ESAs alone or with the addition of oral iron. Giving all patients IV iron would seem to be unnecessary and expensive. It also adds the potential for more adverse effects, although IV iron is safe.
However, my practice has been influenced by the IV iron studies so that I would now use IV rather than oral iron who do not respond to ESAs alone. There are patients who respond to oral iron. One of the problems with oral iron is that it does cause adverse effects, primarily stomach upsets, and therefore compliance is an issue. With IV iron, you can give a larger dose within a quick infusion, and very few adverse effects. In past years, years ago, IV iron was considered a dangerous drug because there were risks of severe anaphylactic reactions, but the newer preparations are much safer, with very few adverse effects.
The trials available now are convincing, but they are still limited by a relatively small patient numbers. Some of the patients were iron replete, some were iron deficient and others had functional iron deficiency. There needs to be larger trials with more patients who have a clear iron status at enrollment.
Tim Littlewood, MD, FRCP, is a Clinical Hematologist at Oxford Radcliffe Hospitals NHS Trust in Oxford, England.