Background Adjuvant combination chemotherapy with cyclophosphamide,methotrexate, and fluorouracil was administered after radicalmastectomy for primary breast cancer with histologically positiveaxillary lymph nodes to assess whether it would improve treatmentoutcome as compared with surgery alone. Here we report a 20-yearfollow-up of this investigation.
Methods In 1973 we began a trial involving 386 women who wererandomly assigned to receive either no further treatment afterradical mastectomy (179 women) or 12 monthly cycles of adjuvantcombination chemotherapy (207 women). All patients were admittedto the Istituto Nazionale Tumori in Milan, Italy. Adjuvant chemotherapywas delivered in the outpatient clinic of the Division of MedicalOncology.
Results After a median follow-up of 19.4 years, the patientsgiven adjuvant combination chemotherapy had significantly betterrates of relapse-free survival (unadjusted relative risk ofrelapse, 0.71; 95 percent confidence interval, 0.56 to 0.90;P = 0.004; adjusted relative risk, 0.65; 95 percent confidenceinterval, 0.51 to 0.83; P<0.001) and total survival (unadjustedrelative risk of death, 0.78; 95 percent confidence interval,0.62 to 0.99; P = 0.04; adjusted relative risk, 0.76; 95 percentconfidence interval, 0.60 to 0.97; P = 0.03). With the exceptionof postmenopausal women, a benefit from adjuvant chemotherapywas evident in all subgroups of patients.
Conclusions The long-term results of this trial of adjuvantcombination chemotherapy confirm our preliminary observationsof the effectiveness of the treatment in women with node-positivebreast cancer.
Source Information
From the Division of Medical Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy, where reprint requests should be addressed to Dr. Bonadonna.
Adjuvant Chemotherapy in Breast Cancer
Del Mastro L., Costantini M., Bianco A. R., Newman M. D., Evans R. A., Bonadonna G., Valagussa P., Henderson I. C.
Extract |
Full Text
N Engl J Med 1995;
333:596-597, Aug 31, 1995.
Correspondence
This article has been cited by other articles:
Jenkins, P., Freeman, S.
(2008). Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer. Ann Oncol
0: mdn560v1-mdn560
[Abstract][Full Text]
Balducci, L., Al-Halawani, H., Charu, V., Tam, J., Shahin, S., Dreiling, L., Ershler, W. B.
(2007). Elderly Cancer Patients Receiving Chemotherapy Benefit from First-Cycle Pegfilgrastim. The Oncologist
12: 1416-1424
[Abstract][Full Text]
Courneya, K. S., Segal, R. J., Mackey, J. R., Gelmon, K., Reid, R. D., Friedenreich, C. M., Ladha, A. B., Proulx, C., Vallance, J. K.H., Lane, K., Yasui, Y., McKenzie, D. C.
(2007). Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial. JCO
25: 4396-4404
[Abstract][Full Text]
Petersen, R. P., Pham, D., Burfeind, W. R., Hanish, S. I., Toloza, E. M., Harpole, D. H. Jr, D'Amico, T. A.
(2007). Thoracoscopic Lobectomy Facilitates the Delivery of Chemotherapy after Resection for Lung Cancer. Ann. Thorac. Surg.
83: 1245-1250
[Abstract][Full Text]
Touw, I. P., Bontenbal, M.
(2007). Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy?. JNCI J Natl Cancer Inst
99: 183-186
[Full Text]
Griggs, J. J., Culakova, E., Sorbero, M. E.S., van Ryn, M., Poniewierski, M. S., Wolff, D. A., Crawford, J., Dale, D. C., Lyman, G. H.
(2007). Effect of Patient Socioeconomic Status and Body Mass Index on the Quality of Breast Cancer Adjuvant Chemotherapy. JCO
25: 277-284
[Abstract][Full Text]
Walshe, J. M., Denduluri, N., Swain, S. M.
(2006). Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer. JCO
24: 5769-5779
[Abstract][Full Text]
Dittrich, C., Petruzelka, L., Vodvarka, P., Gneist, M., Janku, F., Kysela, T., Melemed, A., Latz, J., Simms, L., Krejcy, K.
(2006). A Phase I Study of Pemetrexed (ALIMTA) and Cyclophosphamide in Patients with Locally Advanced or Metastatic Breast Cancer. Clin. Cancer Res.
12: 7071-7078
[Abstract][Full Text]
Lohrisch, C., Paltiel, C., Gelmon, K., Speers, C., Taylor, S., Barnett, J., Olivotto, I. A.
(2006). Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer. JCO
24: 4888-4894
[Abstract][Full Text]
Wardley, A.
(2006). Capecitabine: Expanding Options for the Treatment of Patients with Early or Locally Advanced Breast Cancer. The Oncologist
11: 20-26
[Abstract][Full Text]
Roche, H., Kerbrat, P., Bonneterre, J., Fargeot, P., Fumoleau, P., Monnier, A., Clavere, P., Goudier, M.-J., Chollet, P., Guastalla, J.-P., Serin, D., On behalf of the French Adjuvant Study Group,
(2006). Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial. Ann Oncol
17: 1221-1227
[Abstract][Full Text]
Neugut, A. I., Matasar, M., Wang, X., McBride, R., Jacobson, J. S., Tsai, W.-Y., Grann, V. R., Hershman, D. L.
(2006). Duration of Adjuvant Chemotherapy for Colon Cancer and Survival Among the Elderly. JCO
24: 2368-2375
[Abstract][Full Text]
Petrek, J. A., Naughton, M. J., Case, L. D., Paskett, E. D., Naftalis, E. Z., Singletary, S. E., Sukumvanich, P.
(2006). Incidence, Time Course, and Determinants of Menstrual Bleeding After Breast Cancer Treatment: A Prospective Study. JCO
24: 1045-1051
[Abstract][Full Text]
Gilbert, S. G., Banna, G. L., Santoro, A., Gounaris, I. G., Katsumata, M., Drebin, J. A., Greene, M. I., Mastrianni, D. M., Mano, M., Cameron, D., Gelber, R. D., the HERA Trial Study Team, , Bryant, J., Romond, E., Perez, E. A., Hortobagyi, G. N., Barron, H.
(2006). Trastuzumab in breast cancer.. NEJM
354: 640-644
[Full Text]
International Breast Cancer Study Group,
(2006). Multicycle Dose-Intensive Chemotherapy for Women With High-Risk Primary Breast Cancer: Results of International Breast Cancer Study Group Trial 15-95. JCO
24: 370-378
[Abstract][Full Text]
Gluck, S.
(2005). Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin. The Oncologist
10: 780-791
[Abstract][Full Text]
Kris, M. G.
(2005). How Today's Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow's Standards of Care. The Oncologist
10: 23-29
[Abstract][Full Text]
Hershman, D., McBride, R., Jacobson, J. S., Lamerato, L., Roberts, K., Grann, V. R., Neugut, A. I.
(2005). Racial Disparities in Treatment and Survival Among Women With Early-Stage Breast Cancer. JCO
23: 6639-6646
[Abstract][Full Text]
Parulekar, W. R., Day, A. G., Ottaway, J. A., Shepherd, L. E., Trudeau, M. E., Bramwell, V., Levine, M., Pritchard, K. I.
(2005). Incidence and Prognostic Impact of Amenorrhea During Adjuvant Therapy in High-Risk Premenopausal Breast Cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5. JCO
23: 6002-6008
[Abstract][Full Text]
Demicheli, R., Miceli, R., Moliterni, A., Zambetti, M., Hrushesky, W. J. M., Retsky, M. W., Valagussa, P., Bonadonna, G.
(2005). Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol
16: 1449-1457
[Abstract][Full Text]
Griggs, J. J., Sorbero, M. E. S., Lyman, G. H.
(2005). Undertreatment of Obese Women Receiving Breast Cancer Chemotherapy. Arch Intern Med
165: 1267-1273
[Abstract][Full Text]
Lyman, G. H., Lyman, C. H., Agboola, O., for the Anc Study Group,
(2005). Risk Models for Predicting Chemotherapy-Induced Neutropenia. The Oncologist
10: 427-437
[Abstract][Full Text]
Pierce, L. J.
(2005). The Use of Radiotherapy After Mastectomy: A Review of the Literature. JCO
23: 1706-1717
[Full Text]
Sano, H. S, Waddell, J A., A Solimando, D. Jr, Doulaveris, P., Myhand, R.
(2005). Study of the effect of standardized chemotherapy order forms on prescribing errors and anti-emetic cost. J Oncol Pharm Pract
11: 21-30
[Abstract]
Bonadonna, G., Moliterni, A., Zambetti, M., Daidone, M. G., Pilotti, S., Gianni, L., Valagussa, P.
(2005). 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ
330: 217-
[Abstract][Full Text]
Bonadonna, G., Zambetti, M., Moliterni, A., Gianni, L., Valagussa, P.
(2004). Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer. JCO
22: 1614-1620
[Abstract][Full Text]
Lyman, G. H., Dale, D. C., Crawford, J.
(2003). Incidence and Predictors of Low Dose-Intensity in Adjuvant Breast Cancer Chemotherapy: A Nationwide Study of Community Practices. JCO
21: 4524-4531
[Abstract][Full Text]
Giordano, S. H.
(2003). Update on Locally Advanced Breast Cancer. The Oncologist
8: 521-530
[Abstract][Full Text]
Weiss, R. B., Woolf, S. H., Demakos, E., Holland, J. F., Berry, D. A., Falkson, G., Cirrincione, C. T., Robbins, A., Bothun, S., Henderson, I. C., Norton, L.
(2003). Natural History of More Than 20 Years of Node-Positive Primary Breast Carcinoma Treated With Cyclophosphamide, Methotrexate, and Fluorouracil-Based Adjuvant Chemotherapy: A Study by the Cancer and Leukemia Group B. JCO
21: 1825-1835
[Abstract][Full Text]
Moliterni, A., Menard, S., Valagussa, P., Biganzoli, E., Boracchi, P., Balsari, A., Casalini, P., Tomasic, G., Marubini, E., Pilotti, S., Bonadonna, G.
(2003). HER2 Overexpression and Doxorubicin in Adjuvant Chemotherapy for Resectable Breast Cancer. JCO
21: 458-462
[Abstract][Full Text]
Fumoleau, P., Kerbrat, P., Romestaing, P., Fargeot, P., Bremond, A., Namer, M., Schraub, S., Goudier, M.-J., Mihura, J., Monnier, A., Clavere, P., Serin, D., Seffert, P., Pourny, C., Facchini, T., Jacquin, J.-P., Sztermer, J.-F., Datchary, J., Ramos, R., Luporsi, E.
(2003). 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. JCO
21: 298-305
[Abstract][Full Text]
Climent, J., Martinez-Climent, J. A., Blesa, D., Garcia-Barchino, M. J., Saez, R., Sanchez-Izquierdo, D., Azagra, P., Lluch, A., Garcia-Conde, J.
(2002). Genomic Loss of 18p Predicts an Adverse Clinical Outcome in Patients with High-Risk Breast Cancer. Clin. Cancer Res.
8: 3863-3869
[Abstract][Full Text]
Morrow, T., Siegel, M., Boone, S., Lawless, G., Carter, W.
(2002). Chemotherapy Dose Intensity Determination as a Quality of Care Measure for Managed Care Organizations in the Treatment of Early-Stage Breast Cancer. American Journal of Medical Quality
17: 218-224
[Abstract]
Hamilton, A., Love, R. R.
(2002). Ethical Issues Surrounding the Conduct of Off-Shore Clinical Research. JCO
20: 3934-3936
[Full Text]
Niyikiza, C., Baker, S. D., Seitz, D. E., Walling, J. M., Nelson, K., Rusthoven, J. J., Stabler, S. P., Paoletti, P., Calvert, A. H., Allen, R. H.
(2002). Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy. Molecular Cancer Therapeutics
1: 545-552
[Abstract][Full Text]
Ferreira Filho, A. F., Di Leo, A., Paesmans, M., Beauduin, M., Vindevoghel, A., Michel, J., Focan, C., Awada, A., Cardoso, F., Dolci, S., Bartholomeus, S., Piccart, M. J.
(2002). The feasibility of classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for pre- and post-menopausal node-positive breast cancer patients in a Belgian multicentric trial: a study of consistency in relative dose intensity (RDI) and cumulative doses across institutions. Ann Oncol
13: 416-421
[Abstract][Full Text]
Wilson-Royalty, M., Lawless, G., Palmer, C., Brown, R.
(2001). Predictors for chemotherapy-related severe or febrile neutropenia: a review of the clinical literature. J Oncol Pharm Pract
7: 141-147
[Abstract]
Antman, K. H.
(2001). Overview of the Six Available Randomized Trials of High-Dose Chemotherapy With Blood or Marrow Transplant in Breast Cancer. J Natl Cancer Inst Monogr
2001: 114-116
[Full Text]
Goldhirsch, A., Glick, J. H., Gelber, R. D., Coates, A. S., Senn, H.-J.
(2001). Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. JCO
19: 3817-3827
[Full Text]
Menard, S., Valagussa, P., Pilotti, S., Gianni, L., Biganzoli, E., Boracchi, P., Tomasic, G., Casalini, P., Marubini, E., Colnaghi, M. I., Cascinelli, N., Bonadonna, G.
(2001). Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node-Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables. JCO
19: 329-335
[Abstract][Full Text]
Wolff, A. C., Davidson, N. E.
(2000). Primary Systemic Therapy in Operable Breast Cancer. JCO
18: 1558-1569
[Abstract][Full Text]
Antman, K. H., Heitjan, D. F., Hortobagyi, G. N.
(1999). High-Dose Chemotherapy for Breast Cancer. JAMA
282: 1701-1703
[Full Text]
Antman, K. H.
(1999). Critique of the High-Dose Chemotherapy Studies in Breast Cancer: A Positive Look at the Data. JCO
17: 30-34
[Full Text]
Liberman, L., Cody, H. S. III, Hill, A. D. K., Rosen, P. P., Yeh, S. D. J., Akhurst, T., Morris, E. A., Abramson, A. F., Borgen, P. I., Dershaw, D. D.
(1999). Sentinel Lymph Node Biopsy after Percutaneous Diagnosis of Nonpalpable Breast Cancer. Radiology
211: 835-844
[Abstract][Full Text]
Acuna, L. R., Langhi, M., Perez, J., Acuna, J. R., Machiavelli, M., Lacava, J., Vallejo, C., Romero, A., Fasce, H., Ortiz, E., Grasso, S., Amato, S., Rodriguez, R., Barbieri, M., Leone, B.
(1999). Vinorelbine and Paclitaxel as First-Line Chemotherapy in Metastatic Breast Cancer. JCO
17: 74-74
[Abstract][Full Text]
Basser, R. L., To, L. B., Collins, J. P., Begley, C. G., Keefe, D., Cebon, J., Bashford, J., Durrant, S., Szer, J., Kotasek, D., Juttner, C. A., Russell, I., Maher, D. W., Olver, I., Sheridan, W. P., Fox, R. M., Green, M. D.
(1999). 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. JCO
17: 82-82
[Abstract][Full Text]
Esteva, F. J., Hortobagyi, G. N.
(1998). Integration of Systemic Chemotherapy in the Management of Primary Breast Cancer. The Oncologist
3: 300-313
[Abstract][Full Text]
Foote, M.
(1998). The Importance of Planned Dose of Chemotherapy on Time: Do We Need to Change Our Clinical Practice?. The Oncologist
3: 365-368
[Full Text]
Baker, J. P., Jones, S. E.
(1998). Rationalisation of chemotherapy services in the University Hospital Birmingham National Health Science Trust. J Oncol Pharm Pract
4: 10-14
[Abstract]
Hudis, C. A., Norton, L.
(1997). Adjuvant Drug Treatment for Resectable Breast Cancer. The Oncologist
2: 351-358
[Abstract][Full Text]
Overgaard, M., Hansen, P. S., Overgaard, J., Rose, C., Andersson, M., Bach, F., Kjaer, M., Gadeberg, C. C., Mouridsen, H. T., Jensen, M.-B., Zedeler, K., The Danish Breast Cancer Cooperative Group 82b Tri,
(1997). Postoperative Radiotherapy in High-Risk Premenopausal Women with Breast Cancer Who Receive Adjuvant Chemotherapy. NEJM
337: 949-955
[Abstract][Full Text]
Mayer, R. J., Schnipper, L. E., Broder, S., Hughes-Davies, T.H., Rand, T. S., Cole, P., Rodu, B., Corey, S., Suit, H., Isselbacher, K., Chabner, B., Feldman, A., Atkins, R. N., Arlen, P. A., Noxon, C. L., Wilcken, N., Bailar, J. C., Gornik, H. L.
(1997). Winning the War on Cancer. NEJM
337: 935-938
[Full Text]
Schrag, D., Kuntz, K. M., Garber, J. E., Weeks, J. C.
(1997). Decision Analysis -- Effects of Prophylactic Mastectomy and Oophorectomy on Life Expectancy among Women with BRCA1 or BRCA2 Mutations. NEJM
336: 1465-1471
[Abstract][Full Text]
Gamel, J. W., Edwards, M. J.
(1996). Parametric Models of Therapeutic Efficacy in Breast Cancer. NEJM
334: 1270-1271
[Full Text]
Carbone, D. P, Minna, J. D
(1995). Chemotherapy for non-small cell lung cancer. BMJ
311: 889-890
[Full Text]
Del Mastro, L., Costantini, M., Bianco, A. R., Newman, M. D., Evans, R. A., Bonadonna, G., Valagussa, P., Henderson, I. C.
(1995). Adjuvant Chemotherapy in Breast Cancer. NEJM
333: 596-597
[Full Text]
(1995). Breast Cancer: Long-Term Follow-up of Adjuvant Chemotherapy . . .. Journal Watch Dermatology
1995: 13-13
[Full Text]
(1995). BREAST CANCER: LONG-TERM FOLLOW-UP OF ADJUVANT CHEMOTHERAPY. JWatch General
1995: 2-2
[Full Text]
Henderson, I. C.
(1995). Paradigmatic Shifts in the Management of Breast Cancer. NEJM
332: 951-952
[Full Text]
