High-dose doxorubicin, etoposide, and cyclophosphamide with stem cell reinfusion in patients with metastatic or high-risk primary breast cancer. City of Hope Bone Marrow Oncology Team.
BACKGROUND
Chemotherapy with a doxorubicin-containing regimen results in high overall response rates in the treatment of metastatic adenocarcinoma of the breast; the combination of doxorubicin, etoposide, and cyclophosphamide has produced a response rate of 84% in untreated patients with stage IV disease. Recent data suggest that selected groups of patients with metastatic disease treated with high-dose chemotherapy and stem cell support may enjoy unmaintained, long-term remission. This study was designed to establish the feasibility of administering the combination of high-dose infusional doxorubicin, etoposide, and cyclophosphamide followed by autologous stem cell rescue in patients with responsive metastatic, or high-risk primary breast cancer.


METHODS
Criteria for patient enrollment included the presence of high-risk primary breast cancer (stage II with > or = 10 involved axillary nodes or stages III A or B) or stage IV disease in complete or partial response; Karnofsky performance status of 80% or more; no prior radiation therapy to the left side of the chest; exposure to a 150-mg/m2 or smaller cumulative dose of doxorubicin, and a ventricular ejection fraction of 55% or more. Chemotherapy consisted of escalating doses of doxorubicin given by a 96-hour continuous intravenous infusion, followed by 60 mg/kg of etoposide and 100 mg/kg cyclophosphamide, both given intravenously. On Day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused.


RESULTS
Thirty-five patients were treated in this study. There were no treatment-related deaths. No patient had a decrease in cardiac ejection fraction below 50% as a consequence of high-dose chemotherapy. Two patients suffered grade 3 mucositis at the highest level of doxorubicin (200 mg/m2). Of 21 patients treated for primary high-risk breast cancer, 19 are recurrence free, with a median follow-up of more than 8 months (> or = 4-36 months). Five of fourteen patients with stage IV disease remain progression free at greater than or equal to 5, 7, 9, 15, and 42 months. For patients with stage IV breast cancer, the median progression-free survival after high-dose chemotherapy was 9 months; the median overall survival had been reached at 22 months.


CONCLUSIONS
The phase II dose of doxorubicin in this combination therapy has been established at 165 mg/m2, with dose-limiting toxicity defined as mucositis. Further trials to define the role of this safe and effective high-intensity regimen in the treatment of breast cancer are indicated.
Somlo
G
G
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA 91010.
Doroshow
J H
JH
Forman
S J
SJ
Leong
L A
LA
Margolin
K A
KA
Morgan
R J
RJ
Raschko
J W
JW
Akman
S A
SA
Ahn
C
C
Nagasawa
S
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery*; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D012074:Remission Induction; D012307:Risk Factors; D018805:Sepsis / Q000209:etiology; D033581:Stem Cell Transplantation; D013318:Stroke Volume / Q000187:drug effects; D015996:Survival Rate; D014182:Transplantation, Autologous
D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide