Growth Factor Allows Effective Dose-Intensive Regimen in Advanced Breast Cancer Patients

A dose-intensive outpatient regimen of doxorubicin and CMF (cyclophosphamide,methotrexate, and fluorouracil) with growth factor support provedto be effective and well tolerated in women with advanced breastcancer, Mark L. Graham, MD, said at the San Antonio Breast CancerSymposium.

The regimen produced partial or complete responses in 20 of 34women with stage II, III, or IV disease. The therapy caused someproblems with mucositis and cardiotoxicity, but was generallywell tolerated. However, the use of granulocyte colony-stimulatingfactor (G-CSF, filgrastim; Neupogen) added $8,000 to $9,000 tothe cost of chemotherapy.

The regimen was evaluated by North Carolina investigators as ameans of dealing with patients who present with stage IIb (T3N0),stage III, or stage IV breast cancer. The incidence of those stagesis twice the national average in North Carolina, said Dr. Graham,a medical oncologist at the University of North Carolina Schoolof Medicine, Chapel Hill.

The patients were treated with neoadjuvant or adjuvant chemotherapyregimens. The neoadjuvant regimen began with doxorubicin at adose of 75 to 90 mg/m²/d every 2.5 weeks for 10 weeks (fourcycles). Growth factor support began on day 4 and continued fora minimum of 7 days at a dose of 4 to 6.2 mcg/kg/d. Chemotherapywas followed by definitive surgery. After surgery, patients receivedfour cycles of CMF over 10 weeks. Growth factor support startedon day 3 and continued for a minimum of 7 days after the plateletcount exceeded 7,500.

Among patients who had definitive surgery first, acute adjuvantdoxorubicin began immediately after surgery. CMF then followed.

Eleven patients received doxorubicin as adjuvant therapy, and23 received neoadjuvant therapy. The target dose was 36 mg/m²/wk,which was achieved in 95% of the patients. All 34 patients finishedthe four doxorubicin cycles, and 18 finished the cycles withinthe 10-week schedule. Analysis of CMF dose objectives has notbeen completed, Dr. Graham said.

Overall, 20 of 34 patients had clinical responses, including 9partial responses and 11 clinical complete responses (see table).Five patients had complete responses with respect to breast, lymphnodes, and pathology. Of 23 patients who received neoadjuvantdoxorubicin, 9 were converted from mastectomy candidates to conservativesurgery.

Patients required G-CSF support an average of 8.7 days per doxorubicincycle and 9 days per CMF cycle.

Doxorubicin Toxicity

The doxorubicin regimen was associated with grade 3 mucositisin 30% of patients. The toxicity typically occurred during thelast two cycles, Dr. Graham said. Grade 3 hand-foot syndrome occurredin 20% of patients. Nausea and vomiting posed minor problems.Growth factor support minimized neutropenia to 4 of 136 cyclesof therapy.

Doxorubicin was associated with a decrease in ejection fractionfrom a mean of 65% to 56%. Some patients with lower ejection fractionsat baseline had losses of pumping activity in the low and below-normalranges, but only one patient had symptoms of heart failure, hesaid.

Toxicity data are incomplete for the CMF regimen. Anemia requiringtransfusion has occurred in about a quarter of 29 evaluable patients,and 3 patients have developed thrombocytopenia.