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Dose-response effect of adjuvant cyclophosphamide, methotrexate, 5-fluorouracil (CMF) in node-positive breast cancer. International Breast Cancer Study Group. 1998

M Colleoni, and K Price, and M Castiglione-Gertsch, and A Goldhirsch, and A Coates, and J Lindtner, and J Collins, and R D Gelber, and B Thürlimann, and C M Rudenstam
European Institute of Oncology, Milan, Italy.

There is evidence in the literature of a relationship between dose and response to adjuvant chemotherapy for breast cancer, although published results are conflicting. We therefore retrospectively analysed the role of dose response in patients included in four adjuvant trials of the International Breast Cancer Study Group (IBCSG, formerly the Ludwig Breast Cancer Study Group (trials I, II, III and V), all using 'classical' cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). A total of 1385 node-positive patients were treated with oral cyclophosphamide, and intravenous methotrexate plus 5-fluorouracil (CMF) for at least six 4 week courses. 1350 of these were included in 6 month landmark treatment outcome analyses. A total of 1029 patients were premenopausal, 321 were postmenopausal; 800 had one to three and 550 more than three involved axillary nodes at surgery. The median follow-up ranged from 12 years for trial V to 15 years for trials I-III. Patients were grouped according to three prospectively defined dose levels based on the percentage of the protocol prescribed dose that was actually administered (level I > or = 85%, level II 65-84%, level III < 65%). Patients who received dose level II had a higher disease-free (P = 0.07) and overall survival (P = 0.03) than those who received a higher (level I) or lower (level III) percentage. The 10 year overall survival was 60% for dose level II, 56% for dose level I, 51% for dose level III. The results were generally consistent within trial, menopausal status, and oestrogen receptor status groups. The results within nodal groups showed a large difference among the dose levels for the group with one to three positive nodes (P = 0.02), but no difference for the group with four or more positive nodes. Our results indicate that the dose-response effect remains a crucial factor in adjuvant chemotherapy of breast cancer. Reductions larger than 35% in the dose administered of oral CMF adversely influenced the outcome of breast cancer patients and should be avoided. The better outcome of the intermediate dose group indicates the need to investigate other aspects involved in the cytotoxicity of adjuvant CMF chemotherapy.

UI MeSH Term Description Entries
D008207 Lymphatic Metastasis Transfer of a neoplasm from its primary site to lymph nodes or to distant parts of the body by way of the lymphatic system. Lymph Node Metastasis,Lymph Node Metastases,Lymphatic Metastases,Metastasis, Lymph Node
D008727 Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D001943 Breast Neoplasms Tumors or cancer of the human BREAST. Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D002986 Clinical Trials as Topic Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries. Clinical Trial as Topic
D003520 Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. (+,-)-2-(bis(2-Chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-Oxide Monohydrate,B-518,Cyclophosphamide Anhydrous,Cyclophosphamide Monohydrate,Cyclophosphamide, (R)-Isomer,Cyclophosphamide, (S)-Isomer,Cyclophosphane,Cytophosphan,Cytophosphane,Cytoxan,Endoxan,NSC-26271,Neosar,Procytox,Sendoxan,B 518,B518,NSC 26271,NSC26271
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005260 Female Females
D005472 Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid. 5-FU,5-FU Lederle,5-FU Medac,5-Fluorouracil,5-Fluorouracil-Biosyn,5-HU Hexal,5FU,Adrucil,Carac,Efudex,Efudix,Fluoro-Uracile ICN,Fluoroplex,Fluorouracil Mononitrate,Fluorouracil Monopotassium Salt,Fluorouracil Monosodium Salt,Fluorouracil Potassium Salt,Fluorouracil-GRY,Fluorouracile Dakota,Fluorouracilo Ferrer Far,Fluoruracil,Fluracedyl,Flurodex,Haemato-FU,Neofluor,Onkofluor,Ribofluor,5 FU Lederle,5 FU Medac,5 Fluorouracil,5 Fluorouracil Biosyn,5 HU Hexal,Dakota, Fluorouracile,Fluoro Uracile ICN,Fluorouracil GRY,Haemato FU
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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