Volume 357:1262-1263 September 20, 2007 Number 12
Erythropoietins in Oncology
To the Editor: Khuri (June 14 issue)1 highlights safety concerns regarding the use of
erythropoiesis-stimulating agents (ESAs) in patients with cancer. The studies that have given rise to these concerns used significantly higher hemoglobin targets than those used in the community or recommended in widely used guidelines,2,3 and thus do not reflect the current standard of care. The only study that did not use an excessively high hemoglobin target has not been published and cannot be accurately reviewed.
In these studies, treatment with ESAs was initiated in patients with hemoglobin levels as high as 14.5 g per deciliter. Many of these patients never would have received ESAs in the community, where the use of ESAs is generally initiated at hemoglobin levels below 10 to 11 g per deciliter.
Treatment with ESAs has been of enormous benefit to patients with cancer who have anemia, improving their quality of life and decreasing the need for blood transfusions.4,5,6 The safety and efficacy of ESAs, when used in accordance with current guidelines, are well established.
Revising the appropriate standard of care for ESA use in patients with cancer requires evidence of either an inferior outcome with the current standard or a superior outcome with a different approach. Studies that use excessively high hemoglobin targets simply indicate that ESAs should not be used excessively; they do not indicate that the current standard of care is harmful.
Stephen C. Lattanzi, M.D.
Connecticut Oncology Association
Waterford, CT 06385
Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med 2007;356:2445-2448. [Free Full Text]
The NCCN Clinical Practice Guidelines in Oncology (version 3.2007). National Comprehensive Cancer Network, 2007. (Accessed August 29, 2007, at http://www.nccn.org/professionals/physician_gls/default.asp.)
Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer. Alexandria, VA: American Society of Clinical Oncology, 2007. (Accessed August 29, 2007, at http://www.asco.org.)
Cella D, Kallich J, McDermott A, Xu X. The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials. Ann Oncol 2004;15:979-986. [Free Full Text]
Glaspy JA, Jadeja JS, Justice G, Fleishman A, Rossi G, Colowick AB. A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease. Cancer 2003;97:1312-1320. [CrossRef][ISI][Medline]
Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94:1211-1220. [Free Full Text]
The author replies: Achieving the right balance in the use of ESAs in oncology requires a review of the relevant clinical data made available by the Oncology Drug Advisory Committee of the Food and Drug Administration (FDA).1 ESAs were initially approved for chemotherapy-related anemia (not anemia of cancer) on the basis of data from six randomized, placebo-controlled, double-blind clinical trials involving 131 patients with cancer and anemia who were receiving concurrent chemotherapy with or without epoetin alfa (Procrit).2 Despite the expanded indications for both erythropoietin and darbepoetin, no improvements in quality of life were shown.
Misinterpretation of these data has led to the current state of affairs: according to Amgen Pharmaceuticals, 12 to 16% of ESA use in patients with cancer is initiated at hemoglobin levels above 12 g per deciliter.3 As I mentioned in my Perspective article, randomized trials seeking to elevate hemoglobin levels to normal levels showed incontrovertible evidence of harm, including accelerated cancer progression and increased thrombovascular events. This evidence prompted the FDA's black-box warning prohibiting the initiation of ESA use at hemoglobin levels above 10 g per deciliter.1 Given these and additional data suggesting that anemia associated with chronic disease is a compensatory physiologic response to the chronic condition, these warnings are justifiable.4 Although ESAs are effective in reducing transfusion requirements and mitigating severe anemia in patients with cancer who are undergoing chemotherapy, attempts to expand the indications for their use in oncology have been unsuccessful. Ignoring available data on ESAs is unlikely to benefit patients with cancer.
Fadlo R. Khuri, M.D.
Emory Winship Cancer Institute
Atlanta, GA 30322
FDA Oncologic Drugs Advisory Committee briefing information. Rockville, MD: Food and Drug Administration, 2007. (Accessed August 29, 2007, at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-00-index.htm.)
STN BL 103234.1015; FDA's Summary for Basis of Approval.
Background information for Oncologic Drugs Advisory Committee. Thousand Oaks, CA: Amgen, 2007. (Accessed August 29, 2007, at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-01-01-Amgen.pdf.)
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-1023. [Free Full Text]
I am so happy that you brought this up. Too many people believe that Procrit, EPO, Aranesp are very safe drugs and they seem to want to use them indiscriminately. My hematologist has told me that the use of Aranesp in chemo patients as well as HCV patients needs to be monitored very closely and levels should never get above 12.0 by using these drugs.
I have to say that I kept my hgb between 12 and 13, roughly 12.5 for four years prior to having HCV using epogen. And it didn't take much either. Normocytic and macrocytic hemolytic anemias, I'm finding, are VERY different. Boy howdy are they ever different. Geez. The treatment of the type of hemolytic anemia, or even the type of normocytic anemia caused by bone marrow suppression due to chemo agents is much more difficult and intractable than that of anemia caused by chronic disease.
You've probably seen the new gov't warnings about Procrit: http://tinyurl.com/yuf434
That said, the problem with HCV treatment as I see it here, is not that docs prescribe it too much, but that they don't prescribe it often enough. As far as sfx, has anyone read the Peg or Riba insert. Now there is some scary reading :)
Actually, I hadn't seen that one yet since it just came out on the 8th, however, my G.P. who had been the one mainly overseeing my use of epogen under the overall supervision of a hematologist at UAB (though I've now changed to a hema I think is spectacular in Huntsville since beginning my HCV treatment) has always been very cautious. He always made me keep my hgb around 12, never at more than 13. He was always concerned about the possibility of thrombosis. He's my doc that does the housecalls. It was difficult, in fact, to get him to let me start epogen, and until I started having permanent changes on my EKG a few years ago he wouldn't go for it. But EPO has been a miracle drug for me in terms of fatigue. There is a huge difference at being able to live your life at an hgb of 12 instead of an hgb of 8.5 or 9.
When it comes to the differenent types of amenia i am a bit of a dill,.seein as there are around 200 different causes of anemia. But had to ask isnt hemolytic anemia a type of normocytic anemia.
Do you know which chronic illnesses can cause normocytic anemia.
Well yes. It is, BUT. It can also play a part in macrocytic anemia, particularly in liver disease, and also particularly in the hemolysis experienced by those on ribavirin and procrit and increased and accelerated blood cell production occurs.
Normocytic anemia is the broad category of anemias related to poor blood cell production much of the time, but also to hemolytic and other anemias as well. You can have normocytic anemias for many different reasons. If your renal system is damaged and you fail to make erythropoeitin appropriately, you have issues of blood cell production, If your bone marrow is shut down, or just doesn't work properly, it can be termed as anemia of chronic disease. Some people on interferon have this side effect. Other normocytic anemias include iron deficiency anemia, anemia associated with endocrine disorders which cause difficulty in blood cell production like hypothyroidism and/or hyperthyroidism. Issues with the adrenals can cause anemia of chronic disease. Immune system disorders can cause anemia of chronic disease. Red blood cell disorders can cause anemia of chronic disease. G6PD deficiency, red blood cell enzyme deficiencies, the list, as you know, goes on and on. Sometimes they just never can find out what the problem is and they just treat the symptoms.
One very interesting thing I learned when looking into macrocytic anemias may be helpful here. Macrocytic anemia is quite common in those with liver damage and/or jaundice and/or cirrhosis. AND one of the hallmarks of this problem is a sore tongue and mouth. One of the easiest ways to treat this problem is simply using B-12 shots to keep one's B-12 levels up (its said to be important to check folate levels too). Keeping B-12 up is so helpful energy wise anyway, its nice to know it can have additional benefits for us heppers.
Microcytic anemias usually are thought to be due to disease states or toxins affecting the body,
In general though, anemias are broken down like this:
Macrocytic anemias - Look for liver damage or for possible folate or B-12 deficiency
Normocytic anemias - Look for either a bone marrow issue or for any number of chronic disease states which can include, at the most simple, iron deficiency.
Hemolytic anemias - Look for disease states causing hemolysis, or toxins or other hemolytic agents such as medications that may be causing red blood cell destruction.
Checking reticulicyte (sp?) counts and MCV (mean cell volume) usually provides clues as to the type of anemia as it denotes whether the rbc's are smaller or larger in terms of filling up cell volume and lets you know if the bone marrow is producing in terms of making reticulicytes.
I get the impression you have spent a bit of time reseaching anemia - lol.
Funny how having something makes you study the hell out of it ay.
I also find it a little starnge how having HepC ends up leading you down so many different paths that normally I would have little interest in.
As if I dont have enough to do already - lol
for me, my hgb was so low for so many years that it caused very serious quality of life issues due to fatigue so I did a lot of research trying to find answers. After they put me on epogen though, it all became pretty academic to me and I didn't really care very much what the answer was because it didn't take very much epogen at all to keep my blood count up (until that nasty ribavirin came along that is) lol
Yep Riba hates your red blood cells. You should watch it though. The benifits of Riba to you are not as great as when HepC turns Chronic.
Hopefully I dodged that chronic bullet by starting tx in the acute phase of hepc and going UND quickly. We'll see how it pans out.
Just make sure you have some blood left when you finish
Just make sure you have some blood left when you finish
Actually, I pull another draw tomorrow. I'm pulling cbc's twice a week now and the hematologist is getting a copy of them faxed to his office.
I have learnt something outa this thread so thanks.
As for getting blood draws twice a week i would run out of veins. Takes longer than that for the bruising to disappear with me. Cause that depends on who actulaly sticks the needle in, some definately do a better job than others.