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Old 02-06-2007, 04:00 PM
Dross Dross is offline
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Default Increase in Breast Cancer treatment related MDS when GCSF given with Chemo

Women with breast cancer who receive compounds that stimulate white blood cell production to help their bodies better tolerate chemotherapy are at an increased risk of developing a type of leukemia or a condition called myelodysplastic syndrome, according to a new study in the February 7, 2007 Journal of the National Cancer Institute.

The authors note that the absolute risk of the conditions is very small, but that risk should still be taken into consideration when making treatment decisions. The growth factors granulocyte or granulocyte-macrophage colony-stimulating factor (G-CSF or GM-CSF) have been used to reduce the risk of infections from neutropenia, an abnormally low count of a certain type of white blood cell that helps control infections. Chemotherapy destroys these cells, and it is difficult for the body to quickly replace them. However, there is some concern that these growth factors may keep cells alive that have been mutated by chemotherapy.

Ordinarily, certain cell processes would recognize such damage and instruct the cell to die, but growth factors may save the mutant cell, allowing it to develop into a cancer called acute myelocytic leukemia (AML). There's also concern about the risk of a disease called myelodysplastic syndrome (MDS), in which the bone marrow, which produces blood cells, does not function normally. Indeed, some studies have hinted that cancer patients who receive growth factors with chemotherapy may have an increased risk of these two diseases.

Dawn Hershman, M.D., of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and New York Presbyterian Hospital, and colleagues set out to determine the association between G-CSF or GM-CSF use and the risk of AML or MDS among women treated with chemotherapy for early-stage breast cancer. Using a database that links cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) program with data from Medicare, the researchers identified 5,510 women age 65 and older who were diagnosed with breast cancer and treated with chemotherapy between 1991 and 1999. A total of 906 (16%) were treated with at least one course of G-CSF (832), GM-CSF (29), or both (49). Among these 906 patients, 16 (1.77%) developed AML or MDS; among the 4,604 women who didn't get growth factor treatment, 48 (1.04%) developed one of the diseases. The authors calculated that women who received GM-CSF or G-CSF had twice the risk of developing AML or MDS as women not treated with the growth factors.

"Our study demonstrates that the elevated risk of AML or MDS associated with adjuvant chemotherapy may be further increased by the concurrent use of growth factors," the authors write. "It is unclear if the growth factors cause an increased risk or if the requirements for their use cause an increased risk; however, the absolute overall risk appeared to be small, even among the elderly patients we studied. Nevertheless, if further research confirms this finding, this risk should be factored into clinical decisions with regard to the use of growth factors." In an editorial, Ivo P. Touw, Ph.D., and Marijke Bontenbal, of the Erasmus University Medical Center Rotterdam in the Netherlands, review the possible biologic mechanisms for the increased risk, and point out that growth factor use has increased in recent years. They also note that the benefits of adjuvant chemotherapy for breast cancer may far outweigh any risk of a second cancer. "In clinical practice, the benefits of adjuvant chemotherapy are of a different order of magnitude than the risk of secondary MDS or AML," they write. "Furthermore, given all the unknown factors, associations could be found that have no causal relationship. The evidence for a potential role of G-CSF in the onset of AML/MDS, derived from only a few retrospective studies, thus has to be qualified as hypothesis generating rather than conclusive."

Last edited by gdpawel : 08-23-2012 at 04:27 PM. Reason: post full article
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Old 07-17-2012, 11:33 AM
gdpawel gdpawel is offline
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Default Growth Factor of Anemia Drugs

EPO is a natural substance made by the kidney. It stimulates the bone marrow to make red blood cells (it is literally a "growth factor"). Healthy adults are usually at about 15 grams a deciliter. When normal people take it, their blood gets too "thick" and they die of heart attacks and strokes.

But it now looks as if increasing the hemoglobin level above 12 is very risky with pharmaceutical EPO. Pharmaceutical EPO makes sludgy blood.

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 took "higher than recommended" doses of these drugs. Also, patients who don't respond well to initial anemia therapy (hyporesponders) are exposed to the highest heart risks.

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. 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.

Blood transfusions are generally needed when patients slip to less than 8 grams. The adage of some physicians was 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.

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.

[url]http://cancerfocus.org/forum/showthread.php?t=294
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Old 07-17-2012, 12:43 PM
gdpawel gdpawel is offline
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Default Cytokine treatment during chemotherapy (Adjuvant Chemotherapy) linked with Leukemia

Breast cancer patients given colony stimulating factors to overcome chemotherapy-driven neutropenia have an increased risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), according to researchers.

When a patient undergoes chemotherapy, all dividing cell types are affected. Cancers are rapidly dividing cells and this is the property that chemotherapy looks to exploit. Unfortunately, since this is a non-targeted approach, several other dividing cells types in the body are also affected. White blood cells are one such affected group of cells along with Red blood cells and platelets (which are all derived from the Bone Marrow, which is a rapidly dividing cell type). This depression of WBC numbers is known as the Myelosuppressive effect. This usually ends up being the limiting factor on how much dosage a patient can withstand. If too many WBCs are destroyed, then it will lead to a weakened immune system and that will lead to secondary infections and sepsis. So to counter this, patients undergoing chemotherapy to treat breast cancer are given a supplement of a certain kind of growth factors called Cytokines that stimulate the growth of subtypes of white blood cells.

G-CSF (Granulocyte - Colony Stimulating Factor) and GM-CSF (Granulocyte Macrophage CSF) are commonly used to boost the numbers of Neutrophils and Macrophages. This approach is called Adjuvant Chemotherapy. Boosting the immune system this way provides the advantage that a higher chemotherapeutic dosage can be tolerated by the patient leading to higher chances of cancer remission. However, the long term effects of such treatments had not been studied until now. In a recent issue of the Journal of the National Cancer Institute, Dr. Dawn Hershman and colleagues report that there is an increased risk for certain types of white blood cell related cancers in patients that have undergone adjuvant chemotherapy. They found that "The hazard rate ratio for AML or MDS among those treated with G-CSF or GM-CSF compared with those who were not was 2.14 (95% confidence interval [CI] = 1.12 to 4.08)". What this means is that adjuvant chemotherapy roughly doubles the chance of developing AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic Syndrome). The authors point out that the benefits of adjuvant chemotherapy massively outweigh the risks. The absolute risk of developing secondary cancer in patients that undergo regular chemotherapy is very low to start with (about 1%) and doubling a low risk still remains a low risk (2%).

References:

1. Hershman D, Neugut AI, Jacobson JS, Wang J, Tsai W-Y, McBride R, et al. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 2007;99:196205.

2. I. P. Touw and M. Bontenbal Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy? J Natl Cancer Inst, February 7, 2007; 99(3): 183 - 186.

[url]http://www.medpagetoday.com/HematologyOncology/BreastCancer/5007
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Old 08-27-2012, 12:27 PM
gdpawel gdpawel is offline
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Default White Blood Cell Boosters vs Red Blood Cell Boosters

Granulocyte colony-stimulating factor is one of the about 15 proteins known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth.

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.

Colony-stimulating factor = A substance that stimulates the production of blood cells. Colony-stimulating factors include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and promegapoietin.

Examples:

White Blood count boosters = Neupogen (Filgrastim ), Neulasta (Pegfilgrastim), Leukine (Sargramostim)

Red Blood cell boosters: Procrit, Epogen (epoetin alpha, Erythropoietin), Aranesp (Darbepoetin)

The agents include epoetin alfa (Epogen, Procrit), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp). Neulasta has to do with wbc (white blood cells) and procrit has to do with rbc (red blood cells).

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.

The big difference is that white blood cells help fight infection, red blood cells transport oxygen throughout the body.

Erythropoiesis is basically a process where hemoglobin is synthesized, and eventually passes into the bloodstream.

Erythroprotein (EPO) is a natural substance made by the kidney.

Pharma EPO is a hormone that stimulates bone-marrow cells to produce red-blood cells.

Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels. Pharma EPO is helping them along (growth factor).

Drugs that would stimulate white blood cells would not involve erythropoiesis (above). They would be involved with leukopoiesis, the process of making leukocytes, stimulated by various colony-stimulating factors (CSFs), and hormones produced by mature white blood cells.

Growth factors cause endothelial cell (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide "structural support" for the new blood vessels.

It is recommended to cut down on the use of granulocyte CSF (G-CSF) products for the primary prevention of the chemo-induced adverse effect of febrile neutropenia. ACSO guidelines state that G-CSFs are recommended in patients who have a "high risk" (more than 20%) of developing febrile neutropenia as a complication of chemotherapy (J Clin Oncol. April 3, 2012).

In practice, there is a clear overuse of these agents. Use is inconsistent, the products are used both appropriately and inappropriately. These products are costly and should be used only in patients who are at high risk of developing febrile neutropenia, as specified in the guidelines.

[url]http://jco.ascopubs.org/content/early/2012/04/03/JCO.2012.42.8375.full.pdf+html?cmpid=jco_pap_3Apri %20l2012
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Old 08-27-2012, 08:45 PM
gdpawel gdpawel is offline
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Default Use of CSFs during adjuvant breast cancer chemotherapy critical to discuss

Cary A. Presant, M.D., FACP
Hematologist and Medical Oncologist
Wilshire Oncology Medical Group

The use of CSFs during adjuvant breast cancer therapy is relatively common. The reason for this is not only the use of dose-dense chemotherapy during adjuvant treatments, but also the use of combinations with moderate-to-high risk of neutropenia and neutropenic sepsis.

A recent article discussing this gives us some observations to think about. D. Hershman, et. al. (J. Clin Oncol 2012; 30:806-812) looked at the year-by-year increase in use of colony-stimulating factors during adjuvant treatment of breast cancer. The authors then identified the economic impact of this use. They analyzed patients from the SEER database who were over 65 years of age with stages I to III breast cancer. In this cohort of over 10,000 patients, 48.9% received a CSF. The frequency of use was consistently similar between 1998 and 2002, and then increased from 37% to 75% between 2002 and 2005. The use of CSFs was associated with age and chemotherapy type.

The authors concluded that the rapid increase in use of CSFs occurred over a short period of time which they attributed to the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. They estimated that considerable savings could be realized if physicians could avoid dose-dense chemotherapy and utilize CSFs more judiciously.

After reading this, I was struck by the contrast between the recommendations of geriatric oncologists and the tone of the article by Hershman. We all recognize that the risk of febrile neutropenia is higher in elderly patients. Recommendations for routine prophylactic use of CSFs in elderly patients have become more widely adopted in the years studied by the authors.

Therefore, it is possible that the increased use of CSFs was simply a result of more wide-spread adoption of the geriatric oncology guideline to protect individuals over the age of 65 from the adverse and potentially fatal effects of febrile neutropenia by prophylactic use of a CSF. Indeed, in my practice, most of the use of CSFs is not due to dose-dense therapy, but rather in patients over 65, is due to following the guideline of protecting older patients from potentially fatal febrile episodes Such episodes of neutropenic fever are highly costly as well (due to hospitalization, antibiotics and testing), a fact not considered by Hershman and co-authors.

Contrary to the suggestions in this article and the accompanying editorial, the cautious use of CSFs in patients with comorbid conditions and especially in patients over the age of 65, seems to be not only important but critical to discuss with patients and referring physicians. While we all want to save healthcare costs, frugality must not increase fatality.
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