more concerns about drugs stimulating rbc production

[AlaskaAngel]

http://www.reuters.com/article/healt...28933220070223

[AlaskaAngel]

http://www.fda.gov/medWatch/SAFETY/2...05.htm#aranesp

Aranesp (darbepoetin alfa)
Audience: Oncologists, hematologists and other healthcare professionals
FDA and Amgen notified healthcare professionals of revisions to the WARNINGS and PRECAUTIONS sections of the prescribing information for Aranesp, indicated for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. This safety information alerts physicians to the adverse effects observed with other products in this class in association with off-label dosing strategies. Two recent investigational studies with other erythropoietic products permitted or required dosing to achieve hemoglobin levels of greater than 12 grams per deciliter. An increased frequency of adverse patient outcomes, including increased mortality and thrombotic vascular events were reported in these studies. As indicated in the Aranesp prescribing information, the target hemoglobin level should not exceed 12 grams per deciliter in men or women.

[AlaskaAngel]

Not immediately recent, but more detailed info to consider:

http://www.sciencedaily.com/upi/inde...n-analysis.xml

[AlaskaAngel]

After accessing, scroll down for info on anemia drugs:

http://www.accessdata.fda.gov/script...pt.cfm?show=63

[gdpawel]

EPO is a "natural" substance made by the kidney. It stimulates the bone marrow to make red blood cells. Healthy adults are usually at about 15 grams a deciliter. For cancer patients, upping the production of "natural" EPO via our hair follicles could be very beneficial.

Increasing the hemoglobin level above 12 is very risky with "pharmaceutical" EPO. Pharmaceutical EPO makes sludgy blood. When normal people take it, their blood gets too thick and they die of heart attacks and strokes.

The anemia drugs, which boosts patients' counts of hemoglobin (a protein that carries oxygen in the blood), raise the danger of heart attacks, strokes and death at "high" doses. The FDA has said there is "serious" cardiovascular risks for patients who take "higher than recommended" doses of these drugs.

These anemia drugs are approved to treat patients whose weakness and fatigue is caused by chronic kidney disease or by the side effects of cancer chemotherapy. They stimulate production of oxygen-carrying red blood cells, which can boost patients' energy and strength, if red blood cells are brought back to "normal" levels.

The issue is over the drugs' safety on how big a dose to use to boost concentrations of hemoglobin. The FDA-approved level is doses sufficient to increase hemoglobin to a maximum of 12 grams a deciliter.

The adage of some physicians is that if some improvement in hemoglobin was good, higher levels of hemoglobin would even be better. However, clinical trials have shown the drugs can reduce the need for blood transfusions and improve the quality of life "when used within the original dosing range."

New studies have raised questions whether these drugs might be harming patients. Those study results suggest the drugs may make the cancer worse. One such study published in the New England Journal of Medicine found that patients treated aggressively with Procrit had a higher risk of heart problems or death than those treated less aggressively.

And now there is emerging evidence that pharmaceutical EPO can feed the growth of tumors in cancer patients (it IS a "growth factor" afterall).

A “growth factor” is about twenty small proteins that attach to specific receptors on the surface of stem cells in bone marrow and promote differentiation and maturation of these cells into morphotic constituents of blood.

And blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction.

As Dr. Weissmann stated, "the study also is important because it suggests that there is still much to learn about well known processes in the body." The problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for.

Take medical oncologists out of the retail pharmacy business and force them to be cancer "doctors" again!

[gdpawel]

New studies have raised questions whether these drugs might actually be harming them. Those study results suggest the drugs may make the cancer worse.

Dr. Eric Winer, director of the breast oncology center at Dana-Farber Cancer Institute feels that these drugs are presumed to be entirely safe, given for supportive care and to improve quality of life, but not actually used to treat cancer. But the drugs may have been used in ways not approved on the labels.

A study published in the New England Journal of Medicine last November found that patients treated aggressively with Procrit had a higher risk of heart problems or death than those treated less aggressively.

Amgen, the maker of Aranesp, announced late January that in one of its clinical trials, patients were more likely to die than those getting a placebo. The trial was testing the drug in patients whose anemia was caused by the cancer itself, not by chemotherapy. While a Danish study in patients with head and neck cancer had to be stopped early because the cancer seemed to recur more in patients being treated with Aranesp.

In February, the Journal of Clinical Oncology published a paper describing a small Canadian trial in lung cancer patients had also been stopped early because those getting Eprex were dying sooner. While Roche suspended patient enrollment in a lung cancer trial comparing its Cera against Amgen's Aranesp because of greater than expected number of deaths in at least some of the arms of the trial.

It is not known why the drugs may cause these problems. It is known that raising hemoglobin levels too high increases the risk of blood clots. While most of these trials did aim to increase hemoglobin above the levels recommended in the drugs' labels, that was not the case with Amgen's own trial.

There is some evidence that clots were not the problem in the trials, but that Epo may spur tumor growth. Some studies suggest that certain tumor cells, such as those in head and neck cancer, have proteins on their surface that bind to Epo. When that happens, it sets off a cascade of reactions spurring growth.

Studies done by Dr. Jennifer R. Grandis, professor at the University of Pittsburgh, found enough biologic possibility that they can serve as a growth factor for the cancer cell.

Concerns about the safety of the drugs for cancer were first raised in 2003 by two studies that showed patients getting Epo had worse outcomes. Until then, these drugs had shown signs that they could improve the quality of life for cancer patients, even though their safety labeling has already been revised three times since 1997.

Whiz bang therapies often get a pass on toxicities because they are just so darn cool. The problem is that few drugs work the way we think and few physicians/scientists take the time to think through what it is they are using them for.

Source: TherapeuticsDaily

[AlaskaAngel]

Erythropoietin Stimulating Agents: Where Are We Now?

http://www.oncolink.upenn.edu/resour...&ss=222&id=937

-Abramson Cancer Center, U of Penn

[gdpawel]

The U.S. Food and Drug Administration approved revised boxed warnings and other safety-related product labeling changes for erythropoiesis-stimulating agents (ESAs), which treat certain types of anemia.

For patients with cancer, the new boxed warnings emphasize that ESAs caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer when they received a dose that attempted to achieve a hemoglobin level of 12 grams per deciliter (g/dL) or greater.

The boxed warnings also emphasize that no clinical data are available to determine whether there is a similar risk of shortened survival or increased tumor growth for patients with cancer who receive an ESA dose that attempts to achieve a hemoglobin level of less than 12 g/dL. This is the hemoglobin level commonly achieved in clinical practice.

Health care providers determine whether a patient is anemic and decide on ESA dosing by measuring how much of the protein known as hemoglobin is present in a patient's red blood cells.

An earlier boxed warning, approved in March, described the results of six studies demonstrating that survival was shorter and tumors progressed faster when ESAs were used to achieve hemoglobin levels of 12 g/dL or greater in cancer patients.

Today's new boxed warning also clarifies that ESAs should only be used in patients with cancer when treating anemia specifically caused by chemotherapy and not for other causes of anemia. Moreover, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed.

Health care professionals need to consider the risks of increased tumor progression and decreased survival in patients with cancer when prescribing ESAs. ESAs should be used in patients with cancer only when their anemia is due to chemotherapy and only at the lowest dose necessary to avoid the need for blood transfusions.

http://www.fda.gov/cder/drug/infopage/RHE/default.htm

[gdpawel]

The FDA received new data on risks of anemia drugs, which is consistent with previous data on tumor growth and death. Two more studies provide further evidence of the risks of anemia drugs. The studies show that patients with breast or advanced cervical cancers who received EPO drugs to treat anemia caused by chemotherapy died sooner or had more rapid tumor growth than similar patients who didn't receive the anemia drug. The two studies were not among the six studies that were described in revised labeling approved by the FDA November 8, 2007.

http://www.fda.gov:80/bbs/topics/NEW.../NEW01769.html

Gee, could it be that increased numbers of red cells deliver more oxygen to the tumor cells and thereby increase their activity across the board, including with respect to invasion, proliferation, and metatstasis? On one hand we're developing drugs to halt and reverse angiogenesis while on the other hand we're helping the tumor to obtain more oxygen with existing vasculature. And nobody in charge foresaw that? Amazing how they can apply differing standards for proof or benefit when profit is involved.

Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. But companies can rebate part of the price that doctors pay for drugs, like the anemia medicines, which they dispense in their offices as part of treatment. The anemia drugs are injected or given intravenously in physicians’ offices. Doctors receive the rebates after they buy the drugs from the companies. But they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors’ purchase price.

[michka]

This is frightening. I received EPO. It should be known now by all the oncs.
Michka

[gdpawel]

Most doctors and patients would agree the drugs are very helpful for patients when used to correct "severe" anemia, which can be debilitating and even life-threatening. The drugs reduce the need for somewhat risky blood transfusions and can give patients more energy and improve their quality of life.

''These are drugs that were presumed to be entirely safe, given for supportive care and to improve quality of life,'' not to actually treat cancer, said Dr. Eric Winer, director of breast oncology center at the Dana-Farber Cancer Institute in Boston. ''So any concern that they could shorten someone's life are taken quite seriously.''

There is little evidence that the drugs make much difference for patients with "moderate" anemia. Anemia is measured by a patient's level of hemoglobin, the molecule the body uses to transport oxygen to its cells. Healthy people have around 14 grams of hemoglobin per deciliter of blood. Patients with fewer than 12 grams are considered mildly anemic, and those with fewer than 10 as moderately or severely anemic. The labels on the drugs approved by the FDA encourage doctors to aim for a hemoglobin level of 10 to 12.

Critics of the drugs say their increased use has been driven by profit. According to Dr. John Glaspy, director of UCLA's Outpatient Oncology Clinic, one complicating factor is that oncologists make significant revenue buying cancer drugs from manufacturers and charging patients a higher price for receiving the drugs in their offices. That profit motive could influence some doctors' decisions.

Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, told UPI last year that "probably more than a billion dollars is spent on erythropoietin each year, which makes it one of the most expensive cancer drugs." A six-month course of treatment can cost more than $10,000 per patient.

After this issue had started to be reported, U.S. Oncology took an 8-10 million dollar hit in its first-quarter SEC report last year, including reduced pre-tax income due to lower use of anemia drugs. They also were handicapped by CMS stopping the Medicare Demonstration Project which paid chemotherapy providers $130 per report, per infusional-chemotherapy recipient, on a patient's level of nausea, vomiting, pain and fatigue, something that Congress found out that they were supplying free of charge anyway.

A continuance of the Medicare Demonstration Project would have exacerbated existing economic and clinical problems instead of resolving them by increasing the temptations for physicians to overuse injectable drugs and promise to aggravate the economic problems Congress attempted to fix with the new Medicare law.

A New York Times article reported last year that Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. However, companies can rebate part of the price that doctors pay for drugs, like the anemia medicines, which they dispense in their offices as part of treatment. Doctors receive the rebates after they buy the drugs from the companies, but they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors' purchase price.

Although the new Medicare bill tried to curtail this kind of drug concession, private insurers still go along with it. What needs to be done is to remove the profit incentive from the choice of drug treatments. Let's take physicians out of the retail pharmacy business and force them be doctors again!