Researchers Sound Warning About Chemotherapy Solvent
September 23, 2009
Orlando - Researchers at Northwestern University Feinberg School of Medicine are now warning that Cremophor EL (polyethoxylated castor oil)–containing paclitaxel-associated anaphylaxis may be a greater concern than oncology nurses and pharmacists may have previously thought.
A review of case reports for Cremophor EL–containing paclitaxel-induced hypersensitivity has found that 109 patients have experienced fatal reactions. In addition, 22% of the fatalities occurred despite prophylaxis before paclitaxel therapy, and 15% experienced life-threatening respiratory arrest.
"It can happen when patients are appropriately treated in advanced. I think it is an issue that people need to know about, and it is important to know that even with prophylaxis there is some risk," lead study investigator Charles Bennett, MD, told The Oncology Pharmacist. "So patients should be considered for an alternative formulation of paclitaxel, which does not have hypersensitivity associated with it."
The new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University identified 287 unique cases of hypersensitivity reactions submitted to the US Food and Drug Administration (FDA) Adverse Event Report System between 1997 and 2007. The researchers found 109 (38%) deaths in patients who received Cremophor EL–containing paclitaxel, a solvent-administered taxane chemotherapy. The findings from the study were presented at the annual meeting of the American Society of Clinical Oncology.
Adverse event reports generally only represent from 1% to 10% of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher, according to Dr Bennett. The severe allergic reactions are believed to be caused by Cremophor EL, the chemical solvent, which is a derivative of castor oil. This chemical is used to dissolve some insoluble drugs before they can be injected into the bloodstream.
Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor EL–containing paclitaxel to prevent recurrence. Both of these patients had received medications before chemotherapy administration to reduce the risk of hypersensitivity reactions. "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," said Dr Bennett.
Cremophor EL–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 US product labeling for Cremophor EL–containing paclitaxel includes a black-box warning, alerting clinicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.
In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor EL–based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prophylactic medications to prevent the reactions.
For the report, Dr Bennett and his colleagues reviewed adverse event reports submitted to regulatory agencies in the United States, Europe, and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.
"We were surprised by the number of deaths and number of adverse events. It was very clear in many of these cases that the hypersensitivity started within minutes of when the intravenous drip was started. It was surprising that some had received prophylaxis," explained Dr Bennett, RADAR program coordinator and professor of hematology/oncology at Northwestern's Feinberg School of Medicine, Chicago, Illinois. "Despite how serious it is, the reporting on this has been poor and there is probably more out there that we have not heard about. We reviewed the quality of the reporting and the reporting was rather poor. So it is disturbing."
He said clinicians should be aware of the potential alternative therapy for these patients, a recently FDA-approved Cremophor EL–free nanoparticle paclitaxel formulation (paclitaxel protein-bound particles for injectable suspension/albumin-bound).
-John Schieszer
