Anemia Drugs May Influence Tumor Growth/May Have Test

[Barb73]

http://health.usnews.com/articles/healt ... -some.html

Excerpt from article:

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Drugs used widely to treat anemia in cancer patients may actually speed progression of the cancer in certain individuals, but researchers report they may found a way to determine who those individuals are.

"We may have a test to predict whether a patient is susceptible to having their tumor progress if treated with erythropoietin and, alternatively, we may be able to predict patients it would be safe to treat with erythropoietin," study author Dr. Tony Blau, of the University of Washington in Seattle, said during a Sunday news conference at the American Society of Clinical Oncology annual meeting in Chicago.

Recent controversy over erythropoiesis-stimulating agents (ESAs) such as Procrit, Epogen and Aranesp has centered around whether the blood-boosting drugs should be withdrawn from the market because of troubling side effects.

In March, a U.S. Food and Drug Administration advisory panel voted to recommend continued use of the drugs for patients on chemotherapy, unless the patient is likely to be cured. They also voted to recommend against the drugs' use in patients with breast or head and neck cancer.

Eight clinical trials now suggest these medications actually speed the growth of tumors and shorten the lives of cancer victims.

The drugs' manufacturers added a "black box" warning to the medications last November.

"There has been lots of controversy over these stimulating agents, and we have an FDA advisory committee to act on this as we speak," said Dr. Julie Gralow, director of breast oncology at the University of Washington and Fred Hutchinson Cancer Center in Seattle and moderator of the Sunday news conference. "The drugs offer benefits in terms of reducing anemia and reducing transfusions, but several large trials in a variety of tumor types suggest that . . . these agents may have some stimulatory effects on tumor cells, faster progression in some cases, and more death in others."

Until recently, Blau added, these drugs represented the biggest U.S. federal expenditures for oncology patients.

The results of the current study were based on analyses of tumor samples from 101 patients diagnosed with head and neck cancer who had participated in a previous phase III trial of erythropoietin.

Scientists measured levels of erythropoietin receptor (EpoR) messenger RNA (mRNA).

High levels of EpoR mRNA in patients who had undergone radiation but not surgery tended to signal a worse prognosis. There was a similar effect with Janus Kinase 2 (Jak2), the main intermediary of EpoR signaling, Blau added.

"These are preliminary findings, but they're very exciting," Gralow said. "If they hold up, they may mean that we may be able to use ESAs in targeted ways."

"These findings must be considered preliminary until confirmed," added Blau. "We believe that the definitive answer to this question lies locked in the filing cabinets of pathologists' offices that contain tumors of patients who participated in already completed phase III studies." That, of course, would be much easier than initiating entirely new studies.

A second study found the multiple drugs elderly cancer patients may already be taking could interact significantly with chemotherapy.

In particular, patients taking drugs that interfered with protein binding such as Norvasc for high blood pressure, Prilosec for heartburn, and the pain reliever Celebrex were more likely to experience hematologic side effects such as low white blood cell counts.

Patients taking drugs that act on a group of enzymes known as cytochrome p450 were more likely to experience effects such as fatigue or diarrhea. Examples of these drugs include the heart medications such as Pacerone and Cordarone.

"We found that all drugs patients are taking besides chemotherapy are likely to affect their tolerance to chemotherapy," said study author Dr. Mihaela Popa, of the H. Lee Moffitt Cancer Center in Tampa, Fla.

More information

The American Cancer Society has more on cancer-related fatigue and anemia.

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(HealthDay News, By Amanda Gardner, HealthDay Reporter, June 1, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

[gpawelski]

Some cautionary information about being "overtreated" with anemia drugs. A study, published in the Canadian Medial Association Journal, suggests patients with anemia due to chronic disease are being dangerously overtreated. Anemia may actually help heal the body rather than harm it, says the new study.

Dr. Ryan Zarychanski, the study's co-author and a scientist at the Ottawa Health Research Institute, feels that doctors have been taught for generations that anemia is bad and they want to help their patients by treating it. However, they failed to consider that anemia may be adaptive and may be exactly the response that the body needs at that time.

Tired blood (anemia) involves a shortage of healthy red blood cells to carry oxygen to the body tissues. In the past, blood transfusions were the only way to treat anemia, until a drug derived from erythropoietin (EPO), a hormone that stimulates bone-marrow cells to produce red-blood cells.

Dr. Zarychanski pointed to evidence that suggests anemia is an evolutionary response to illness occuring in humans. The body has adapted over thousands of years to be anemic at times of stress because it needs to conserve energy. It needs help to fight infection. And when you're anemic, bacteria doesn't grow so well in the blood (an evolutionary response to infection before antibiotics).

In general, healthy adults have red blood cell levels of 14 grams or more per 100 millilitres of blood, while patients are considered to need treatment if their levels are below 10 grams. Patients with mild to moderate anemia (those with levels between 10 and 14 grams) would be better off not being treated.

What Dr. Zarychanski argues is that we should exercise some caution when thinking the best treatment is to automatically transfuse or give drugs to correct anemia.

Source: Ottawa Health Research Institute

[gpawelski]

Increased death rates among cancer patients taking erythropoiesis-stimulating agents were supported in a large meta-analysis.

Among nearly 14,000 patients in 53 studies, those taking the anemia drugs were 17% (95% CI 6% to 30%) more likely to die during the study, and their overall survival chances were reduced by 6% (95% CI 0% to 12%), reported Julia Bohlius, M.D., M.Sc.P.H., of the University of Bern in Switzerland.

The findings, disclosed at the American Society of Hematology meeting, confirmed results reported earlier in individual studies.

The trials included Epogen, Procrit, NeoRecormon and Aranesp. The analysis was notable for relying on full data on each patient, contributed by the trial sponsors and individual investigators, not on outcome data as published.

And in fact, the on-study mortality results were higher than previously published. On-study mortality was defined as death from any cause occurring from randomization to four weeks after the active study's end. Overall survival was measured from randomization to the end of available follow-up.

When the patient pool was limited to about 10,000 patients treated with chemotherapy, the relationship between erythropoiesis-stimulating agents and mortality fell just short of statistical significance.

On-study mortality in the chemotherapy population was increased by 10% for those taking the anemia drugs (95% CI -2% to 24%), and the overall death rate was increased by 4% (95% CI -3% to 11%), the researchers found.

The results changed little when the researchers controlled for known risk factors.

Age, sex, hemoglobin, hematocrit at baseline, type and stage of tumor, and type of study were among the factors researchers took into account.

Patients getting no cancer treatment showed a 33% increase in on-study mortality if they were receiving erythropoiesis agents (95% CI 7% to 67%).

There were even higher increases in patients receiving other forms of cancer treatment (52% for chemoradiation, 52% for radiation alone, and 53% for "other" non-chemotherapies), but these did not reach statistical significance.

Moreover, a test for interaction among all the non-chemotherapy patient groups yielded a P value of 0.42.

Co-author Andreas Engert, M.D., of the University of Cologne in Germany, said the specific reasons for the increased deaths associated with erythropoiesis agents remained unclear, but on the basis of more recent studies, most of the excess deaths are probably from thromboembolic events.

The American Society of Hematology and the American Society of Clinical Oncology would convene a new guideline panel early in 2009 to consider revisions derived from these findings and other developments since the existing version was published.

Since the current guideline was produced, the FDA had required a boxed warning on epoetin and darbopoetin about increased mortality risks for cancer patients.

Source:

Bohlius J, et al., "Recombinant human erythropoiesis stimulating agents in cancer patients: individual patient data meta-analysis on behalf of the EPO IPD Meta-Analysis Collaborative Group" Blood 2008; abstract LBA-6.

[gpawelski]

A recent review in the Lancet suggests that using erythropoiesis-stimulating agents like Aranesp, Epogen and Procrit may reduce fatigue and combat anemia in cancer patients, while promoting tumor growth, hasten their deaths from cancer and increase their risk of early death from strokes and other cardiovascular events. The study combined data from nearly 14,000 patients in 54 clinical trials.

Although the FDA had slapped a black box warning on the drugs, the study, which was funded by firms that made them, suggested that doctors explain to their patients that treatment of anemia with EPO agents may improve their quality of life by reducing anemia and fatigue, but their survival may be shortened. According to a MedPage Today analysis of the study, the drugs, which stimulate red blood cell production, increased mortality by 17 percent.

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. I am reminded it is still a "chemotherapy concession."

Last year, U.S. Oncology, which funds, develops and helps manage 443 cancer centers in 39 states, complained that patients were harmed by new Medicare coverage policy for anemic cancer patients. The Centers for Medicare & Medicaid Services (CMS) decision limited ESA (erythropoiesis-stimulating agents) treatment to a maximum of eight weeks after a chemotherapy session. It also required physicians to wait until hemoglobin levels dropped below 10 g/dl before starting therapy.

Because CMS did not receive any documented cases of negative outcomes from the oncology community, it stuck to its decision. The FDA backed CMS' National Coverage Decision (NCD), which limited use of the drugs because they have been shown to spur tumor growth. The FDA believed the approved labeling and CMS' NCD were generally consistent in their recommendations regarding the use of pharmaceutical EPO in patients with cancer undergoing chemotherapy.

However, major insurance companies had not embraced the CMS protocol. It was a "shot over the bow" by the oncology community of government stepping directly into patients lives and saying that they know what is a better course of treatment than doctors. During the ensuing year, we found out that drugs, given by injection, had been heavily advertised, and there was gathering evidence that they had been overused, in part because oncologists could make money by using more of the drug.

Resulting studies had suggested the drugs may make the cancer worse. Much of that evidence came from studies in which patients were treated more aggressively than the drugs' labels recommended. The FDA found mounting evidence of documented effects on survival, tumor progression and thrombotic events which required reassessment of the net benefit of this class of drugs.

Gee, could it be that increased numbers of red cells deliver more oxygen to the tumor cells and thereby their activity across the board, including with respect to invasion, proliferation and metastasis? 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.

Having said all of this, physicians, scientists and the public occasionally apply their own judgement and determine when the existing evidence is sufficient to support a personal decision to adopt - as opposed to impose upon others - certain drug treatments. No wonder the National Coalition for Cancer Survivorship emphasized the need for drastic changes in how physicians are reimbursed for care. Reward doctors for whole patient care - not just treatments.

http://www.medpagetoday.com/HematologyO ... logy/14007

[RandyW]

Its sad that the drugs that are supposed to help us actually may wind up doing more harm than good!! Deb was getting aranesp almost weekly for a while..........

[gpawelski]

Yeah! I remember Ann getting them too. I'd tell people that they would "shoot her up" for five days, before chemo, and "shoot her down" for five days, after chemo. They were giving her Taxol also without having any idea why they were giving it to her. Taxol has harmed far more than it has helped.

[gpawelski]

A new review of data confirms that erythropoietin - a drug to treat anemia in many cancer patients - might be harmful. The review found that patients with head and neck cancers who received erythropoietin in combination with radiation had poorer outcomes than those who received radiation treatment alone.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Severe anemia in cancer patients can lead to decreased oxygen supply to tumor cells. A lower level of oxygen in tumor cells is associated with more rapid tumor progression and a poorer response to therapy. Many use erythropoietin, or EPO, a hormone that controls red blood cell production, to correct anemia.

"It has therefore been thought logical that using erythropoietin to correct anemia before or during chemotherapy, radiotherapy or both would improve prognosis," the review authors write.

Dr. Philippe Lambin and colleagues at the MAASTRO (Maastricht Radiation Oncology) Clinic in the Netherlands conducted the review.

The investigators analyzed data from five published clinical trials that looked at whether combined radiation and EPO was better than standard radiation therapy alone in the treatment of head and neck cancers. Nearly 1,400 patients were included in the analysis. The researchers compared overall survival, the length of time during and after treatment in which the cancer did not progress, local tumor control and toxicity in the two different treatment groups.

Researchers found that patients who received EPO had significantly worse overall survival compared to patients who did not receive the drug. In addition, patients who took EPO had significantly shorter times before their cancers worsened.

Data included in the review suggest that decreased survival rates in cancer patients who took EPO were not due to some toxic effect of the drug itself, such as an increase in deaths due to blood clots. Instead, researchers have hypothesized that the drug might actually cause some types of tumors to grow.

Barbara Burtness, M.D., chief of the Head and Neck Medical Oncology division at the Fox Chase Cancer Center in Philadelphia, commented on the use of erythropoietin in head and neck cancer.

"The primary use of erythropoietin in cancer patients is to raise hemoglobin when patients become anemic, either because of the cancer or because of a side effect of the cancer treatments," she said. "It's been a part of practice for a long time."

Burtness said that there has been a specific reason for studying EPO in head and neck cancers. "When radiation treatments are given for bulky cancers in the head and neck area, it's thought that cancer cells that don't have a high oxygen content are less susceptible to being killed by radiation. The hypothesis has been that if you could correct a patient's anemia, there would be more red blood cells traveling to the area of cancer. This would lead to correction of the low oxygen content in the tumors - and the patient would be more likely to respond to the radiation treatment," she said.

"But what we've been hearing for some time is that erythropoietin is actually making cancer outcomes worse," she said.

She said the United States has tightened guidelines EPO use in response to data from recent studies. "Giving erythropoietin can have a negative impact on survival. We certainly are not using it here [at Fox Chase Cancer Center]. Among our patients who've received radiation elsewhere, its use does not appear to be common."

Manufacturers promoted EPO to improve anemia, and to help anemic patients to feel better overall. However, the U.S. Food and Drug Administration has issued several public health advisories underscoring the possible risks of using EPO in cancer, including faster tumor growth and early death. The FDA warnings also say that EPO does not improve symptoms associated with anemia, such as fatigue. Nor does EPO improve a patient's quality of life or sense of well-being, the advisories say.

The authors of the review conclude that patients with head and neck cancer should not receive EPO as an addition to radiation therapy.

Source: Health Behavior News Service and GoozNews on Health

Drug therapy for the management of cancer related fatigue

http://www.cfah.org/hbns/archives/viewS ... gDocID=527

[gpawelski]

Nearly two years after a Food and Drug Administration advisory committee called for restrictions on the use of red blood cell-stimulating drugs in cancer patients (erythropoiesis-stimulating agents or ESAs), the agency unveiled a stringent risk management plan that should further lower use of the drugs, which are already in freefall in cancer patients. The plan, which affects Amgen's Aranesp and Epogen and Johnson & Johnson's Procrit (manufactured by Amgen and identical to Epogen), requires the companies:

Register oncologists who prescribe the drugs;

Educate them about their risks, which include tumor progression and earlier death; and

Fully inform patients about the risks with an updated medication information guide, both at the time they are initially treated and every time treatment is given; and

Obtain signatures from patients that they've been apprised of the risks.

The updated medication guide will contain information for chronic and end-stage renal disease patients, who also get ESAs for anemia. But renal physicians will not be facing the same registration and education requirements.

The company was given a year to come into full compliance. Officials at a press briefing yesterday were uncertain what would happen to oncologists or the companies if they prescribe or use the drugs without giving the proper warnings.

The program is called, appropriately enough, APPRISE. And while it's tough, it's not unprecedented. The FDA adopted a similar registration program for some opioids.

When pressed by a reporter on why it took so long to come up with the program, Richard Pazdur, head of the oncology office at the Center for Drug Evaluation and Research at FDA, said "this took many many months of discussion. It's a delicate balance. We don't want to interfere in a draconian fashion with the practice of medicine."

Pazdur distinguished between patients undergoing therapy where there is a chance of cure, and those receiving palliative care for incurable cancers. In the latter case, patients may opt for the greater energy that comes from alleviating cancer- and chemo-related anemia, even if it results in a shorter end game.

"The risks-benefit balance is a delicate one," Pazdur said. The goal of the program wasn't to restrict use of the drugs, but "to help patients make the best choice given their individual situation."

The failure to simultaneously force the companies to reeducate the renal physician community was disappointing. There's mounting evidence that high doses of ESAs in renal disease patients is associated with increased risk of heart attacks, strokes and earlier mortality. Many of these patients are poor and unaware of the quality of care they receive at dialysis centers. They, just as much as cancer patients, need to be informed about the risks posed by overuse of ESAs.

Source: Gooznews on Health