This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

Ten-Year Results

Gianni Bonadonna, MD; Milvia Zambetti, MD; Pinuccia Valagussa

JAMA. 1995;273(7):542-547.

Abstract
Objective.
—To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes.

Design.
—A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years.

Setting.
—The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology.

Patients.
—A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P=.08).

Main Outcome Measure.
—Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method.

Results.
—Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P=.002) and total survival was 58% vs 44% (P=.002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients.

Conclusions.
—Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF.

(JAMA. 1995;273:542-547)

Author Affiliations
From the Division of Medical Oncology, Department of Medicine, Istituto Nazionale Tumori, Milan, Italy.

Footnotes
Reprint requests to Istituto Nazionale Tumori, Via Venezian 1, Milan 20133, Italy (Dr Bonadonna).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Role of Anthracyclines in the Treatment of Early Breast Cancer
Gianni et al.
JCO 2009;27:4798-4808.
ABSTRACT | FULL TEXT  

Anthracyclines in Early-Stage Breast Cancer: Is It the End of an Era?
Robson and Verma
The Oncologist 2009;14:950-958.
ABSTRACT | FULL TEXT  

Intensive Dose-Dense Compared With Conventionally Scheduled Preoperative Chemotherapy for High-Risk Primary Breast Cancer
Untch et al.
JCO 2009;27:2938-2945.
ABSTRACT | FULL TEXT  

Phase III Trial Evaluating the Addition of Paclitaxel to Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil, As Adjuvant or Primary Systemic Therapy: European Cooperative Trial in Operable Breast Cancer
Gianni et al.
JCO 2009;27:2474-2481.
ABSTRACT | FULL TEXT  

Anthracyclines and Early Breast Cancer: The End of an Era?
Gianni and Valagussa
JCO 2009;27:1155-1157.
FULL TEXT  

Molecular profiling including epidermal growth factor receptor and p21 expression in high-risk breast cancer patients as indicators of outcome
Somlo et al.
Ann Oncol 2008;19:1853-1859.
ABSTRACT | FULL TEXT  

Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00
Fountzilas et al.
Ann Oncol 2008;19:853-860.
ABSTRACT | FULL TEXT  

Inflammatory breast cancer in Tunisia in the era of multimodality therapy
Labidi et al.
Ann Oncol 2008;19:473-480.
ABSTRACT | FULL TEXT  

Lessons From the Initial Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil Studies in Operable Breast Cancer
Bonadonna et al.
JCO 2008;26:342-344.
FULL TEXT  

Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313)
Linden et al.
JCO 2007;25:656-661.
ABSTRACT | FULL TEXT  

Increased Dose Density Is Feasible: A Pilot Study of Adjuvant Epirubicin and Cyclophosphamide followed by Paclitaxel, at 10- or 11-Day Intervals with Filgrastim Support in Women with Breast Cancer
Fornier et al.
Clin. Cancer Res. 2007;13:223-227.
ABSTRACT | FULL TEXT  

Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer
Poole et al.
NEJM 2006;355:1851-1862.
ABSTRACT | FULL TEXT  

Sequential gemcitabine and cisplatin followed by docetaxel as first-line treatment of advanced urothelial carcinoma: a multicenter phase II study of the Hellenic Oncology Research Group
Boukovinas et al.
Ann Oncol 2006;17:1687-1692.
ABSTRACT | FULL TEXT  

Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era.
Colozza et al.
The Oncologist 2006;11:111-125.
ABSTRACT | FULL TEXT  

Multicycle Dose-Intensive Chemotherapy for Women With High-Risk Primary Breast Cancer: Results of International Breast Cancer Study Group Trial 15-95
International Breast Cancer Study Group
JCO 2006;24:370-378.
ABSTRACT | FULL TEXT  

Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, and Fluorouracil and Its Effects on Tumor Response as Preoperative Therapy
Gianni et al.
Clin. Cancer Res. 2005;11:8715-8721.
ABSTRACT | FULL TEXT  

Dose Density in Breast Cancer: A Simple Message?
Lin et al.
JNCI J Natl Cancer Inst 2005;97:1712-1714.
FULL TEXT  

Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group
Fountzilas et al.
Ann Oncol 2005;16:1762-1771.
ABSTRACT | FULL TEXT  

Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group
Campone et al.
Ann Oncol 2005;16:1343-1351.
ABSTRACT | FULL TEXT  

Conceptual and Practical Implications of Breast Tissue Geometry: Toward a More Effective, Less Toxic Therapy
Norton
The Oncologist 2005;10:370-381.
ABSTRACT | FULL TEXT  

Phase II Study of Feasibility of Dose-Dense FEC Followed by Alternating Weekly Taxanes in High-Risk, Four or More Node-Positive Breast Cancer
Dang et al.
Clin. Cancer Res. 2004;10:5754-5761.
ABSTRACT | FULL TEXT  

Conventional Adjuvant Chemotherapy Versus Single-Cycle, Autograft-Supported, High-Dose, Late-Intensification Chemotherapy in High-Risk Breast Cancer Patients: A Randomized Trial
Leonard et al.
JNCI J Natl Cancer Inst 2004;96:1076-1083.
ABSTRACT | FULL TEXT  

High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support Compared With Standard-Dose Chemotherapy in Breast Cancer Patients With 10 or More Positive Lymph Nodes: First Results of a Randomized Trial
Zander et al.
JCO 2004;22:2273-2283.
ABSTRACT | FULL TEXT  

Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer
Bonadonna et al.
JCO 2004;22:1614-1620.
ABSTRACT | FULL TEXT  

A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer
Cresta et al.
Ann Oncol 2004;15:433-439.
ABSTRACT | FULL TEXT  

Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study
Felip et al.
Ann Oncol 2003;14:1549-1554.
ABSTRACT | FULL TEXT  

Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group
Martin et al.
Ann Oncol 2003;14:833-842.
ABSTRACT | FULL TEXT  

Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741
Citron et al.
JCO 2003;21:1431-1439.
ABSTRACT | FULL TEXT  

A randomized phase II study of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer
Paridaens et al.
Ann Oncol 2003;14:433-440.
ABSTRACT | FULL TEXT  

Randomized Trial Comparing Six Versus Three Cycles of Epirubicin-Based Adjuvant Chemotherapy in Premenopausal, Node-Positive Breast Cancer Patients: 10-Year Follow-Up Results of the French Adjuvant Study Group 01 Trial
Fumoleau et al.
JCO 2003;21:298-305.
ABSTRACT | FULL TEXT  

Radical and Simple Mastectomy
Badwe et al.
NEJM 2002;347:2170-2171.
FULL TEXT  

Multimodal treatment with primary single-agent epirubicin in operable breast cancer: 5-year experience of the Michelangelo Cooperative Group
Bonadonna et al.
Ann Oncol 2002;13:1049-1058.
ABSTRACT | FULL TEXT  

Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy
Niyikiza et al.
Molecular Cancer Therapeutics 2002;1:545-552.
ABSTRACT | FULL TEXT  

Progress in Systemic Chemotherapy of Primary Breast Cancer: an Overview
Hortobagyi
J Natl Cancer Inst Monogr 2001;2001:72-79.
ABSTRACT | FULL TEXT  

Doxorubicin Followed by Sequential Paclitaxel and Cyclophosphamide versus Concurrent Paclitaxel and Cyclophosphamide: 5-Year Results of a Phase II Randomized Trial of Adjuvant Dose-dense Chemotherapy for Women with Node-positive Breast Carcinoma
Fornier et al.
Clin. Cancer Res. 2001;7:3934-3941.
ABSTRACT | FULL TEXT  

Phase II Study of Sequential Administration of Docetaxel Followed by Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer
Khayat et al.
JCO 2001;19:3367-3375.
ABSTRACT | FULL TEXT  

Theoretical Concepts and the Emerging Role of Taxanes in Adjuvant Therapy
Norton
The Oncologist 2001;6:30-35.
ABSTRACT | FULL TEXT  

Benefit of a High-Dose Epirubicin Regimen in Adjuvant Chemotherapy for Node-Positive Breast Cancer Patients With Poor Prognostic Factors: 5-Year Follow-Up Results of French Adjuvant Study Group 05 Randomized Trial
JCO 2001;19:602-611.
ABSTRACT | FULL TEXT  

Intensification of Adjuvant Chemotherapy: 5-Year Results of a Randomized Trial Comparing Conventional Doxorubicin and Cyclophosphamide With High-Dose Mitoxantrone and Cyclophosphamide With Filgrastim in Operable Breast Cancer With 10 or More Involved Axillary Nodes
Fumoleau et al.
JCO 2001;19:612-620.
ABSTRACT | FULL TEXT  

Long-Term Cardiac Sequelae in Operable Breast Cancer Patients Given Adjuvant Chemotherapy With or Without Doxorubicin and Breast Irradiation
Zambetti et al.
JCO 2001;19:37-43.
ABSTRACT | FULL TEXT  

Treating young patients with breast cancer
Dixon and Hortobagyi
BMJ 2000;320:457-458.
FULL TEXT  

Initial Paclitaxel Improves Outcome Compared With CMFP Combination Chemotherapy as Front-Line Therapy in Untreated Metastatic Breast Cancer
Bishop et al.
JCO 1999;17:2355-2355.
ABSTRACT | FULL TEXT  

Epirubicin Plus Tamoxifen Versus Tamoxifen Alone in Node-Positive Postmenopausal Patients With Breast Cancer: A Randomized Trial of the International Collaborative Cancer Group
Wils et al.
JCO 1999;17:1988-1988.
ABSTRACT | FULL TEXT  

Phase I Trial of Multiple Cycles of High-Dose Chemotherapy Supported by Autologous Peripheral-Blood Stem Cells
Schilder et al.
JCO 1999;17:2198-2198.
ABSTRACT | FULL TEXT  

Engraftment of MDR1 and NeoR Gene-Transduced Hematopoietic Cells After Breast Cancer Chemotherapy
Moscow et al.
Blood 1999;94:52-61.
ABSTRACT | FULL TEXT  

5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk Node-Positive Breast Cancer: A Phase II Study
Hudis et al.
JCO 1999;17:1118-1118.
ABSTRACT | FULL TEXT  

Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables
Tjeerdsma et al.
Heart 1999;81:419-423.
ABSTRACT | FULL TEXT  

Multicycle High-Dose Chemotherapy and Filgrastim-Mobilized Peripheral-Blood Progenitor Cells in Women With High-Risk Stage II or III Breast Cancer: Five-Year Follow-Up
Basser et al.
JCO 1999;17:82-82.
ABSTRACT | FULL TEXT  

Sequential Dose-Dense Doxorubicin, Paclitaxel, and Cyclophosphamide for Resectable High-Risk Breast Cancer: Feasibility and Efficacy
Hudis et al.
JCO 1999;17:93-93.
ABSTRACT | FULL TEXT  

Adjuvant Drug Treatment for Resectable Breast Cancer
Hudis and Norton
The Oncologist 1997;2:351-358.
ABSTRACT | FULL TEXT  

Assessing Differences in Clinical Trials Comparing Surgical vs Nonsurgical Therapy: Using Common (Statistical) Sense
Howard et al.
JAMA 1997;278:1432-1436.
ABSTRACT  

Sequential Adriamycin and CMF in Metastatic Breast Cancer
Zambetti et al.
The Oncologist 1997;2:223-227.
ABSTRACT | FULL TEXT  

Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil for Breast Cancer
Michaelson
JAMA 1995;274:796-796.
ABSTRACT  

Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil for Breast Cancer-Reply
Bonadonna et al.
JAMA 1995;274:796-797.
ABSTRACT  

Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil in Node-Positive Breast Cancer -- The Results of 20 Years of Follow-Up
Bonadonna et al.
NEJM 1995;332:901-906.
ABSTRACT | FULL TEXT  

SEQUENTIAL DOXORUBICIN/CMF IMPROVES SURVIVAL IN NODE- POSITIVE BREAST CANCER
JWatch General 1995;1995:1-1.
FULL TEXT