French Trial Ended Due to Deaths Among Patients on Docetaxel-Doxorubicin Regimen
A breast cancer chemotherapy regimen that involved simultaneous administration of docetaxel and doxorubicin suppressed white blood cell activity in 40 percent of patients and led to two treatment-related deaths, concludes a report on the European RAPP-01 clinical trial published in the May 18 Journal of the American Medical Association.
The first death occurred in March 2000, when a 49-year-old patient became ill with abdominal pain 7 days after receiving the doxorubicin-plus-docetaxel regimen under study. She developed febrile neutropenia 2 days later and subsequently died. An autopsy was not performed, and the steering committee concluded that the death was "not specifically attributable" to docetaxel and decided to continue the trial. In January 2001, a second woman developed febrile neutropenia. She went into septic shock 6 days after her fourth cycle of doxorubicin and docetaxel but later recovered. In January 2003, a 39-year-old woman fell ill 6 days after first receiving the regimen. She died a week later from septic shock. The investigators ended the trial and switched the remaining patients in the docetaxel arm to the standard regimen of doxorubicin and cyclophosphamide.
Investigators have long known that combining docetaxel with doxorubicin can drop white cell counts, according to Dr. Jennifer Low, a senior investigator in the NCI's Cancer Therapy Evaluation Program. Hence, the report underscores the importance of providing prophylaxis. "Febrile neutropenia is a serious risk with any doxorubicin-docetaxel regimen," said Dr. Low. "Prophylaxis - especially the use of growth factors - is used in all of the current trials with this regimen to help prevent febrile neutropenia and reduce the risk of septic death."
Because the trial was terminated early, the investigators were unable to determine if the docetaxel regimen extended survival. "At this time the doxorubicin-docetaxel regimen should not be recommended outside of carefully designed clinical trials," write the authors, who hail from several French research institutions including the Centre Rene Huguenin, Centre Leon Berard, and the Sainte Catherine Institute Breast Clinic.
While the docetaxel regimen caused less nausea and vomiting than the standard therapy, it was responsible for 72 of the 87 severe adverse events (82.8 percent) reported to the French Medicines Agency. Most of these events (87.5 percent) were related to febrile neutropenia.
One hundred twenty-six of 311 women (40.5 percent) receiving doxorubicin-docetaxel developed neutropenia accompanied by fever. In contrast, only 22 of 316 women (7 percent) taking the standard doxorubicin-cylcophosphamide therapy developed febrile neutropenia. The rates of neutropenia in the docetaxel arm were so high because, unlike similar studies conducted in the United States, the French trial did not employ prophylaxis for neutropenia. Patients received granulocyte-colony stimulating factor (G-CSF) only after their white cell count had already dropped.
Studies of doxorubicin-docetaxel combinations that employ prophylactic antibiotics or G-CSF report substantially lower rates of febrile neutropenia, according to Dr. Low. The Breast Cancer International Research Group 001 trial documented neutropenia in 24 percent of patients who received docetaxel, while the corresponding figure for the National Surgical Adjuvant Breast and Bowel Project B-27 trial was 21 percent.
Because the major risk from neutropenia is blood-borne infection, the antibiotic ciprofloxacin is sometimes given prophylactically to patients receiving docetaxel. But, said Dr. Low, "Most physicians now prefer using hematopoeitic colony-stimulating factors" because it boosts white cell production and is more effective than antibiotics.
By Brian Vastag