Date: June 7, 2006
by Chaya Venkat
Erythropoietin drugs are familiar to most CLL patients who have had to to struggle with anemia. You may be more familiar with their brand names: epoetin drugs “Epogen” by Amgen and “Procrit” by Ortho Biotech or the darbepoetin drug “Aranesp” from Amgen.
Low red blood cells and low hemoglobin levels can lead to chronic fatigue and play havoc with a patient's quality of life. The anemia can be due to late stage disease where the bone marrow is not producing enough of the oxygen-carrying red blood cells with healthy levels of hemoglobin, or it could be due to toxicity of the chemotherapy used to control the CLL in the first place. Autoimmune disease where perfectly healthy red blood cells are destroyed (AIHA, autoimmune hemolytic anemia) is another potential cause of anemia. Erythropoietin drugs work wonders in some of these patients, improving red blood cell counts and quality of life almost miraculously.
More than two years ago we published an article titled The Dark Side of Epoetin, in which we discussed the potential serious risks of overindulging in epo drugs. Too much of a good thing can be bad for you! The reason for re-visiting the subject now is that the latest information published in the May 17, 2006 issue of the Journal of the National Cancer Institute suggests the risks are even greater than we thought they were. The earlier information discussed an important clinical trial for head and neck cancer. Patients were randomized to receive epoetin beta or placebo, given along with radiation therapy for the cancer. The primary endpoint of the study was progression-free survival. The researchers targeted for a very healthy hemoglobin level of 14 g/dl or more in women and 15 g/dl or more in men, and patients received a relatively high dose of epoetin beta to get these levels of hemoglobin. Quite unexpectedly, the rate of tumor progression was higher in the patients getting the epo drug. Patients were better off if they did not get the epo. Bummer!! Please read our earlier article to get more of the details.
Based on the warnings such as the head and neck cancer study, the FDA issued a major advisory in May 2004 regarding the safety concerns associated with Procrit and Aranesp. You can read all 66 pages of the FDA document by clicking on the link below. (We were a tad quicker than the FDA in sounding the warning on our website, with the Dark Side of Epo published in November 2003.)
At about the same time the American Society of Oncology / Hematology came up with guidelines on how to use these epo drugs. Use them we must, but it is now becoming clear they are a double edged sword and need to be handled with care. Below are the guidelines put forward by this professional society. These are important guidelines and therefore I have not modified the wording. But I did highlight the stuff that I thought was interesting from our perspective.
I am beginning to wonder if these guidelines for use of epo drugs are too liberal, in light of the latest information presented in the May 17 issue of the Journal of the National Cancer Institute.
The abstract of this important article is given below, along with my summary of the highlights.
J Natl Cancer Inst. 2006 May 17;98(10):708-14.
Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients.
Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A.
Department of Internal Medicine I, University of Cologne, Germany.
This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.
Analyzing ten years worth of data, Dr. Bohlius and her team looked at randomized controlled trials that compared epo drugs + transfusion versus transfusion alone for preventing or treatment of anemia in cancer patients, some of them undergoing chemotherapy. They looked at 57 trials and more than 9350 cancer patients. They found that those treated with Epogen, Procrit or Aranesp had a lower risk of needing transfusions, much as you would expect. But these patients getting the epo drugs were also at an increased risk (relative risk, 1.67) of heart attacks and stroke. The authors comment: "survival was not improved by treatment and raises the possibility that survival may be decreased among patients treated with epoetin or darbepoetin."
I can hear some of you thinking: “Doc, are you saying what I think you are saying, I can shoot myself in the foot (or higher up) by paying good money to get these epo shots, trying to get my hemoglobin levels up to the point where I can play golf like I used to?” For those of you who like to get a little adrenalin flowing with a nice conspiracy theory, here is a strange “coincidence”. Individual members of the research team reported that they received funding from Amgen and Ortho Biotech, the two drug manufacturers that have the lion's share of the epo market. These latest findings conflict with the authors' earlier meta-analysis, which had suggested that use of epo drugs increase survival.
"The difference in survival between the study cohorts published before and after 2001 is striking," says Dr. Bohlius. "However, this change in direction from beneficial to detrimental might be caused by bias, confounding, or chance or may truly reflect the changes in the design of the trials." Holy cow! Bias may have skewed the results of important meta-analysis in prior studies! What is the world coming to, if drug company funding may be remotely responsible for biasing the results in favor of the drugs they sell!
Here is the moral of the story, ladies and gentlemen. Targeting Beyond the Clinical Definition of Anemia (hemoglobin level of 10g/dL) May be Hazardous to Your Health. Don’t be shy about using epo drugs if they are indicated for your particular variety of anemia, and hopefully the drug chosen will help bring your hemoglobin levels up to the 10 g/dL level. But do resist the temptation to bully your oncologist to prescribe more shots of epo, to get your hemoglobin levels even higher. This is not like getting an extra little bit of Viagra, because you want to feel frisky like you used to feel as a healthy twenty-something. There is a dark side to epo drugs, and you should be aware of the risks you are taking in overusing these potent drugs.
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