A dose-intensive outpatient regimen of doxorubicin(Drug information on doxorubicin) and CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil)) with growth factor support proved to be effective and well tolerated in women with advanced breast cancer, Mark L. Graham, MD, said at the San Antonio Breast Cancer Symposium.
The regimen produced partial or complete responses in 20 of 34 women with stage II, III, or IV disease. The therapy caused some problems with mucositis and cardiotoxicity, but was generally well tolerated. However, the use of granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim); Neupogen) added $8,000 to $9,000 to the cost of chemotherapy.
The regimen was evaluated by North Carolina investigators as a means of dealing with patients who present with stage IIb (T3N0), stage III, or stage IV breast cancer. The incidence of those stages is twice the national average in North Carolina, said Dr. Graham, a medical oncologist at the University of North Carolina School of Medicine, Chapel Hill.
The patients were treated with neoadjuvant or adjuvant chemotherapy regimens. The neoadjuvant regimen began with doxorubicin at a dose of 75 to 90 mg/m²/d every 2.5 weeks for 10 weeks (four cycles). Growth factor support began on day 4 and continued for a minimum of 7 days at a dose of 4 to 6.2 mcg/kg/d. Chemotherapy was followed by definitive surgery. After surgery, patients received four cycles of CMF over 10 weeks. Growth factor support started on day 3 and continued for a minimum of 7 days after the platelet count exceeded 7,500.
Among patients who had definitive surgery first, acute adjuvant doxorubicin began immediately after surgery. CMF then followed.
Eleven patients received doxorubicin as adjuvant therapy, and 23 received neoadjuvant therapy. The target dose was 36 mg/m²/wk, which was achieved in 95% of the patients. All 34 patients finished the four doxorubicin cycles, and 18 finished the cycles within the 10-week schedule. Analysis of CMF dose objectives has not been completed, Dr. Graham said.
Overall, 20 of 34 patients had clinical responses, including 9 partial responses and 11 clinical complete responses (see table). Five patients had complete responses with respect to breast, lymph nodes, and pathology. Of 23 patients who received neoadjuvant doxorubicin, 9 were converted from mastectomy candidates to conservative surgery.
Patients required G-CSF support an average of 8.7 days per doxorubicin cycle and 9 days per CMF cycle.
The doxorubicin regimen was associated with grade 3 mucositis in 30% of patients. The toxicity typically occurred during the last two cycles, Dr. Graham said. Grade 3 hand-foot syndrome occurred in 20% of patients. Nausea and vomiting posed minor problems. Growth factor support minimized neutropenia to 4 of 136 cycles of therapy.
Doxorubicin was associated with a decrease in ejection fraction from a mean of 65% to 56%. Some patients with lower ejection fractions at baseline had losses of pumping activity in the low and below-normal ranges, but only one patient had symptoms of heart failure, he said.
Toxicity data are incomplete for the CMF regimen. Anemia requiring transfusion has occurred in about a quarter of 29 evaluable patients, and 3 patients have developed thrombocytopenia.