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Common chemotherapy drug triggers fatal allergic reactions
By Dross at 2009-06-10 03:21
Common chemotherapy drug triggers fatal allergic reactions

Patients with curable early stage breast cancer died from chemotherapyterm solvent

CHICAGO -- A chemotherapy drug that is supposed to help save cancer patients' lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA's Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent - a derivative of castor oil -- that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern's Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

"The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them," Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

"The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment," said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication," Bennett said. "Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor."

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

"The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent," said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.



9 comments | 7327 reads

by gdpawel on Wed, 2009-06-10 11:27
In the last decade, the incidence of central nervous system (CNS) metastasis has increased. The very first reference I found of this was a NCI observational study in 1995 that reported experience in their clinic where recurrent systemic disease occurred in all patients for which they received dose-intense Paclitaxel (Taxol) therapy. Brain metastasis was the only site of disease recurrence. The cerebellum was involved in two out of three patients, presenting with headache, dizziness, unsteady gait, nausea and vomiting (all the things that happened to my wife in 1998, after her adjunct Taxol treatment in 1997).

This is what led me to research this further and found out about the rarity of ovarian cancer cells metastasizing to the brain. Ovarian cancer uncommonly involves the nervous system. Brain metastasis was a "rare" complication of ovarian cancer with only 67 well-documented cases in medical literature, until 1994. A multi-institutional study of 4027 ovarian cancer patients over 30 years identified only 32 cases while an autopsy study of ovarian cancer reported an incidence of 0.9%. Even more "rare" is the occurrance of Carcinomatous Meningitis. Until 1994, there have been only 14 cases reported. This presentation is similar to metastases from other solid tumors (breast, lung). (1)

In 2002, I came across a study by Christos Kosmas, M.D., consultant medical oncologist, Department of Medicine and Medical Oncology Unit at Helena-Venizelou Hospital, Athens, Greece entitled, "Carcinomatous Meningitis: Taxane-Induced," which found what is called "dissemination after taxane-based (Taxol) chemotherapy." The study conclusions stated that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectively to non-taxane-treated patients. (2)

A commentary by Dr. Lawrence N. Shulman, Vice Chair for Clinical Services and Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, in the September, 2002 issue of The American Journal of Oncology Review, describes the complete lack of progress in the chemotherapeutic treatment of metastatic breast cancer since 1970. Dr. Shulman noted that a retrospective comparision of a well-characterized "standard-dose" database with a less well-characterized "high-dose" database suggested that there was increased early mortality for "high-dose" therapy. (3)

An editorial by Drs. V. Valero and G.N. Hortobagyi in the March 15, 2003 issue of the Journal of Clinical Oncology, reviewed all of the large, prospective, randomized trials published comparing taxane-based chemotherapy regimens. They conclude that none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at two years or less, or precisely the same results which were being obtained over thirty years ago. (4)

In 2004, as reported at the 27th Annual San Antonio Breast Cancer Symposium, using a technique that quantifies circulating tumor cells, German investigators from Friedrich-Schiller University in Jena, have shown that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding could help explain the fact that complete pathologic responses do not correlate well with improvements in survival.

In the study, according to Katharina Pachmann, M.D., professor of experimental oncology and hematology, breast cancer patients undergoing neoadjuvant chemotherapy gave blood samples in which epithelial antigen-positive cells were isolated. Such cells are detected in most breast cancer patients but are rarely found in normal subjects. The investigators measured the levels of cirulating tumor cells before and during primary chemotherapy with several different cytotoxic agents.

Paclitaxel (taxol) produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells. In three different paclitaxel-containing regimens, circulating cell numbers massively increased, whereas tumor size decreased. These cells remained in the circulation for at least five months after surgery.

The tumor shrinks, but more cells are found in the circulation. This corresponds with a high pathologic complete response during paclitaxel treatment, but in the end, this is not reflected in improved survival. These cells are alive in the circulation. What this study has shown, so far, that in three different paclitaxel (taxol) containing regimens, as the tumor collapses (a clinical response, not cure), it produces the greatest release of circulating tumor cells. The study has not looked at any other combination regimens. (5)

The results of these kinds of study are coming out slowly and quietly (now that Taxol is off-patent) and indicate that taxol containing regimens didn't prolong survival over other more conventional and less expensive cytotoxic drugs. Even before the advent of the CellSearch technique, it had been observed in various "cell death" assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from taxane therapy, even in cases where the majority of the cells are being killed by taxanes. It may indeed give clincial response (tumor shrinkage), sometimes impressive, however, these are mostly short-lived and relapses after a response to taxanes (Taxol) are often dramatic. (6)

With these cells being alive in the circulation, it may mean that a patient with invasive breast cancer without lymph node involvement (where systemic treatment "may" benefit), or a patient with invasive breast cancer that involves lymph nodes (where systemic treatment is "usually" recommended), would need additional (anti-estrogen) treatment, such as Tamoxifen (it may be given alone or in addition to chemotherapy, if given).

It has been shown that Tamoxifen treatment will reduce circulating tumor cells in some patients, but not all. So they develop a drug called Herceptin. Why? It has been shown that Herceptin treatment will reduce circulating tumor cells in patients with HER2-negative tumors, but less pronounced in HER2-positive tumors.

Does Herceptin really work on these circulating tumor cells? A study from the Dana Farber Cancer Institute identified central nervous system metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. (7)

In 2006, another report that CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen. Central Nervous System Relapse in Patients With Breast Cancer Is Associated With Advanced Stages, With CK-19 mRNA-positive Circulating Occult Tumor Cells and With Her2/neu-positive tumors.

by gdpawel on Wed, 2009-06-10 11:28
During the past years it has been frequently observed that patients with breast cancer treated with a taxane-containing chemotherapy regimen, either in the adjuvant setting or in the metastatic setting, presenting central nervous system (CNS) involvement as the only evidence of disease progression. More studies were therefore interested to evaluate the incidence of CNS metastases in patients with early and advanced breast cancer treated with a taxane-containing chemotherapy regimen and to identify predictive factors for CNS relapse.

Recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen. There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab (Herceptin).

In the present study it was also possible to confirm the initial clinical observation that breast cancer patients who receive a taxane-containing chemotherapy regimen have a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS.

Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

Furthermore, the detection of cytokeratin 19 (CK-19) and of mRNA-positive circulating tumor cells (CTCs) in the peripheral blood and the bone marrow of patients with breast cancer is correlated with increased incidence of relapse.

The aforementioned data suggest that taxanes may not penetrate well into the CNS, and therefore the CNS may represent tumor 'sanctuary' sites for taxane-containing chemotherapy regimens. A difference in the incidence of CNS relapses between patients with breast cancer and other solid tumors treated with taxanes was observed. (8)

The percentage of patients that must respond to a drug before it is approved by the FDA varies from as high as 80% to as low as 20%. Thereafter, it is used routinely for all patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean it will help all patients with the same diagnosis. The response rate for Taxol for FDA approval was 30%.

Taxol (Paclitaxel) is known as a taxane type of chemotherapy drug. Taxol is given into a vein, but in order for the body to absorb the drug, it must first be dissolved in a solution. The compound wouldn't dissolve very much in any solution. It was discovered that something Taxol would dissove in the might work in a reasonably safe intravenous solution in humans. It was an elixir made of castor oil and marketed as Cremophor EL. It was the only answer. However, this castor-oil carrier is suspected as the culprit behind the misery which includes nausea, vomiting, joint pain, appetite loss, brittle hair and tingling sensations in hands and feet (neuropathy). (9)

The American Cancer Society has mentioned that the solution can cause dangerous allergic reactions in many people, so patients "must" first take other drugs like steroids and antihistamines in "hopes" to prevent a bad reaction. The solution can also leach chemicals from regular plastic tubes used to deliver medication, so Taxol must be given through special tubing.

A new drug for breast cancer (Abraxane) is a new form of Taxol (Paclitaxel). Abraxane does not need to be dissolved in the castor oil solution and does not require special equipment to be given to patients. However, more of the women on Abraxane had numbness and tingling in their hands and feet. And more suffered nausea and vomiting, diarrhea, muscle and joint pain and anemia.

Taxol (Paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients. Side effects of Taxol (Paclitaxel) include severe allergic reactions, cardiovascular problems (such as changes in blood pressure), infections developing from white blood cell deficiencies, complete hair loss (apolecia), joint and muscle pain, irritation at the Taxol and other chemotherapy drugs injection site, low red blood cell count, mouth or lip sore, numbness or burning in the hands and feet, and stomach upset/diarrhea. (10)

There is a molecular basis for the peripheral pain caused by Taxol. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling, researchers at Yale School of Medicine reported in a study published in the Proceedings of the National Academy of Sciences. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms. These serious side effects limit the drug's effectiveness. Peripheral pain becomes worse with continued use and increased dosages lead to persistent and irreversible pain.

The binding protein is called neuronal calcium sensor (NCS-1). When paclitaxel (taxol) binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme (calpain) that degrades proteins, especially NCS-1. Calcium signals are needed for nerves to be stimulated and to respond and the loss of NCS-1 makes it more difficult to generate any calcium signals. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses. (11)

Taxol actually causes cancer cell microtentacles to grow longer and allows tumor cells to reattach faster, which may have important treatment implications for breast cancer patients. Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that microtentacles, or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body.

Microtentacles are microtubule-based protrusions that occur in detached cells. These protrusions are unusual in that they are not actin-based. The function of microtentacles may be to aid in metastasis. Breast cancer cells that have microtentacles travel more slowly in blood vessels than breast cancer cells that do not have microtentacles. The microtentacles may allow these cells to latch on to blood vessel walls and invade other tissues.

Chemotherapy designed to kill dividing cancer cells seems to make the tentacles grow further and faster. If you take a cell that doesn't have very many tentacles and actually treat it with the tubulin stabilizer, Paclitaxel (Taxol), that causes this cell to generate more tentacles. So, at the same time you're actually reducing the ability of the tumor cell to divide, you can be increasing its ability to reattach in a distant site. This research will also play a role in other major cancers: lung, colon, ovarian, and prostate.

They feel that more research is needed into how chemotherapies that slow down cell division affect metastasis. The timing of giving these drugs can be particularly important. If you treat people with taxol before surgery to shrink the primary tumor, levels of circulating tumor cells go up 1,000 to 10,000 fold, potentially increasing metastasis. (12)

Sources:

(1) National Cancer Institute
(2) American Journal Clinical Oncology 2002;63:6-15
(3) Am J Oncology Rev 1(3):169-170, '02
(4) J Clin Oncol 21(6): 959-962, '03
(5) Oncol News Int'l, Vol 14, #5, May '05
(6) Cell Function Analysis
(7) Cancer 2003 Jun 15;97(12):2972-7
(8) Breast Cancer Res. 2006;8(4)2006 BioMed Central, Ltd.
(9) Office of Research, Florida State University
(10) Bionumerik
(11) PNAS 104: 11103-11108 June 20, 2007
(12) Oncogene (2010) 29, 3217–3227; doi:10.1038/onc.2010.68

The Human ATP-Binding Cassette (ABC) Transporter Superfamily [url]http://www.ncbi.nlm.nih.gov/books/NBK31/

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