Orlando, Fla. (May 18, 2005) - The chemotherapy regimen of doxorubicin plus docetaxel, used to treat women with medium risk breast cancer in a clinical trial, was associated with serious complications including to 2 deaths, resulting in the premature termination of the trial, according to a study in the May 18 issue of JAMA .
Combinations of certain chemotherapy drugs have proven superior to some single agents alone in advanced or metastatic breast cancer, according to background information in the article. Uncertainties remain regarding the optimal schedule of administration of combination regimens, as well as safety and cost issues, and whether some drugs should be used outside of clinical trials.
Etienne G. C. Brain, M.D., of the René Huguenin Cancer Centre, Saint-Cloud, France and colleagues describe the adverse events associated with the chemotherapy in a breast cancer trial. The randomized multicenter study compared the effectiveness of 2 chemotherapy regimens.
The trial included 627 women aged 18-70 years, who had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (3 or less) or no positive axillary lymph nodes, but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Patients received doxorubicin (trade name Adriamycin) plus docetaxel (Taxotere), or doxorubicin plus cyclophosphamide, given postoperatively for 4 courses.
Doses were: Doxorubicin, 50 mg/m 2 , plus docetaxel, 75 mg/m 2 , or doxorubicin, 60 mg/m 2 , plus cyclophosphamide, 600 mg/m 2 , given postoperatively for 4 courses.
The trial was halted prematurely when 2 deaths related to drug toxicity and 1 case of bowel perforation with peritonitis (inflammation of the membrane of the abdomen) occurred among patients with febrile neutropenia (very low level of white blood cells accompanied by fever, a condition that indicates the patient may have a potentially life-threatening infection), all in the doxorubicin-docetaxel group.
The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8 percent) than with the doxorubicin-cyclophosphamide regimen (7.1 percent). The follow-up has been too short (24 months) to analyze the primary end point, which was the disease-free survival rate at 5 years.
"The rate of toxic death has decreased far below 0.10 percent in more recent trials," the authors write. "We observed a much higher rate of toxic death (0.63 percent) with the doxorubicin-docetaxel regimen. The higher rate of febrile neutropenia observed with doxorubicin-docetaxel than with doxorubicin-cyclophosphamide in our trial may have induced severe immunosuppression and contributed to the high rate of toxic death, which was 3 times as much as that observed in [another trial], in which 3 of 7 deaths were attributable to sequential docetaxel immunosuppression among 1,584 patients (0.19 percent)."
"In conclusion, this study shows that the doxorubicin-docetaxel combination is associated with an increased risk of severe sepsis and life-threatening complications. Clinicians should be aware of the potential toxicity of the doxorubicin-docetaxel regimen and consider the preventive use of granulocyte colony-stimulating factor (G-CSF) and/or antibiotics (neither of which was recommended at the time of our trial) in both the adjuvant and metastatic settings. At this time the doxorubicin-docetaxel regimen should not be recommended outside of carefully designed clinical trials," the authors conclude.
René Huguenin Cancer Centre was the sponsor of the RAPP-01 trial. This work was also supported in part by AventisÂOncology France and the Ligue Régionale Contre le Cancer du Département des Yvelines. AventisÂOncology France supplied the docetaxel.
Abstract: Life-Threatening Sepsis Associated With Adjuvant Doxorubicin Plus Docetaxel for Intermediate-Risk Breast Cancer. Etienne G. C. Brain , MD et al. JAMA. 2005;293:2367-2371.
Edited by J. Strax, May 18, 2005
