January 03, 2008
New Warnings on EPO Use in Cancer Patients
Remember those Procrit television and magazine ads showing bright-eyed, middle-aged women declaring they were ready for chemotherapy because they'd taken a biotech wonder drug? Last spring, after reviewing the evidence, a member of a Food and Drug Administration advisory committee suggested a better name for the drug might be Miracle-Gro for cancer.
Turns out he wasn't far off the mark. Breast cancer and cervical cancer patients who use erythropoiesis-stimulating agents (called ESAs by the FDA and EPO by most physicians) to keep up their strength while on chemotherapy saw their tumors grow faster and suffered higher death rates compared to patients not given the drug. The data came from two new trials whose results Amgen, which manufactures the drugs, submitted to the FDA in November and December.
Late this afternoon, the agency issued a new warning asking oncologists to rethink using the drug at all. They also asked them to promptly report adverse events. EPO is marketed as Epogen and Aranesp by Amgen and Procrit by Johnson & Johnson.
After last year's advisory committee meeting, the agency slapped black box warnings on the three drugs that cautioned patients and physicians to avoid excessive use. In today's announcement, the FDA said it plans to hold another advisory committee meeting in the next few months. Given the latest data, it's possible that outside advisers may recommend banning use of the drugs in cancer patients entirely.
The breast cancer trial involved 733 German patients receiving chemotherapy who were given Aranesp prior to surgery and compared to a placebo group. The cervical cancer trial, run through the National Cancer Institute's Gynecologic Oncology Group, enrolled just 109 of the planned 460 patients treated with chemotherapy and radiation before the trial was stopped "because of a higher rate of potentially life-threatening blood clots occurring in the patients who received an ESA."
According to the FDA, both studies "showed higher rates of death and or tumor progression in patients who received an ESA compared to patients who did not receive an ESA."
The agency asked oncologists to compare the risks of tumor progression and decreased survival to the risk from blood transfusions before prescribing EPO. "FDA strongly recommends that healthcare professionals discuss the risks of ESA-associated tumor progression and shortened survival with their patients before starting or continuing ESA therapy," the agency press release said.
Posted by gooznews at January 3, 2008 10:11 PMThis issue was already well known in 2004; see my Letter to the Editor (Lancet 363(9413):993-4, 2004)
Sir--Michael Henke and colleagues1 show that administration of erythropoietin corrects anaemia in patients with head and neck cancer treated with radiotherapy, but does not improve cancer control or overall survival.
The rationale for doing such a study includes a general notion that the greater the oxygen-carrying capacity of a patient's blood, as indicated by the haemoglobin concentration, the greater the tumour oxygenation and the better the response to radiotherapy. Erythropoietin can indeed increase the haemoglobin concentration, but there seems to be a price to pay for this benefit. Dale and Alberio have proposed that erythropoietin can increase the aggregability of platelets, and thus enhance thrombogenesis.2 Furthermore, patients with head and neck cancer, as in Henke's study, are often chronically dehydrated because the cancer and the treatment make swallowing very difficult. This hypovolaemic state might further contribute to peripheral thromboembolic events. This cascade could explain Henke's findings of worse overall survival, especially from cardiac events, despite increased haemoglobin concentrations.
But how might erythropoietin result in the observed earlier cancer recurrence? With the above in mind, multiple thromboembolic events might also occur within the tumour bed, creating hypoxia. This state in turn could be a factor in promoting tumour angiogenesis and thus its earlier recurrence.
If this hypothesis proves correct, the next phase of erythropoietin trials could include antioxidant supplementation.3 Additional hydration should also be considered.
Ivo P Janecka
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Health Research International, 3404 Heards Ferrry Drive, Tampa, FL 33618, USA (e-mail:Janecka@post.harvard.edu)
1 Henke M, Laszik R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255-60. [Text]
2 Dale G, Alberio L. Is there a correlation between raised erythropoietin and thrombotic events in sickle-cell anaemia? Lancet 1998; 352: 566-67. [Text]
3 Boaz M, Smetanea S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000; 356: 1213-18. [Text]
Thanks for reminding readers that this issue has been well known for a while. It's a shame that the FDA took so long to issue warnings. It will be interesting to see what happens at the next FDA advisory committee meeting, which may happen as early as March.
Posted by: Merrill at January 5, 2008 02:05 PMWhat do we do about the anemia drug controversy?
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!