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5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial

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Abstract

The study was designed to compare an anthracycline-containing regimen to a regimen combining both anthracycline and paclitaxel as adjuvant therapy for high-risk breast cancer patients. In this multicenter, randomized phase-III trial, node-positive early breast cancer patients were randomly assigned to receive either 6 cycles of FEC (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, day 1, every 3 weeks) or 4 cycles of EP (epirubicin 90 mg/m2 and paclitaxel 175 mg/m2, day 1, every 3 weeks). The primary endpoint was overall survival (OS). Secondary endpoints included toxicity and event-free survival (EFS). From 1996 to 2001, 1055 patients were enrolled. At a median follow-up of 12.8 years, 335 deaths had been recorded. The 10-year OS was 73 % (95 % CI 69–77) in the FEC arm and 74 % (95 % CI 70–78) in the EP arm (p = 0.405). The 10-year EFS was 51 % (95 % CI 45–56) in the FEC arm and 49 % (95 % CI 44–55) in the EP arm (p = 0.572). No difference in the hazard of death was observed (HR for EP 0.85, 95 % CI 0.68–1.06, p = 0.15). Patients treated with FEC experienced more frequently nausea and vomiting, stomatitis, and leukopenia as compared to patients treated with EP. Toxicities which occurred more frequently with EP were anemia, fever, myalgias, and neurotoxicity. Our study failed to demonstrate a superiority of an adjuvant treatment with four EP as compared to six FEC in node-positive breast cancer patients.

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Abbreviations

FEC:

5-Fluorouracil, epirubicin, and cyclophosphamide

PE:

Epirubicin and paclitaxel

OS:

Overall survival

EFS:

Event-free survival

HR:

Hazard ratio

ER:

Estrogen receptors

PgR:

Progesteron receptors

AC:

Doxorubicin and cyclophosphamide

DFS:

Disease free survival

EBCTCG:

Early Breast Cancer Trialists’ Collaborative Group

References

  1. Holmes FA, Walters RS, Theriault R, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN (1991) Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797–1805

    Article  PubMed  CAS  Google Scholar 

  2. Gianni L, Munzone E, Capri G, Villani F, Spreafico C, Tarenzi E, Fulfaro F, Caraceni A, Martini C, Laffranchi A et al (1995) Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. J Natl Cancer Inst 87:1169–1175

    Article  PubMed  CAS  Google Scholar 

  3. Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C et al (1995) Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688–2699

    PubMed  CAS  Google Scholar 

  4. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  PubMed  CAS  Google Scholar 

  5. French Adjuvant Study Group (2001) 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. J Clin Oncol 19:602–611

    Google Scholar 

  6. Van der Hage JA, Van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L (2001) Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 19:4224–4237

    PubMed  Google Scholar 

  7. Mouridsen HT, Andersen M, Dombernowsky P et al. (1999) Adjuvant anthracycline in breast cancer: improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol 18(68a); (abstr 254)

  8. Henderson IC, Berry DA, Dimetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  9. Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G (2009) Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trail in Operable breast cancer. J Clin Oncol 27:2474–2481

    Article  PubMed  CAS  Google Scholar 

  10. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23:3686–3696

    Article  PubMed  CAS  Google Scholar 

  11. Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM, GEICAM 9906 Study Investigators (2008) Randomized phase 3 trial of Fluorouracil, Epirubicin, and Cuclophosphamide alone or followed by Paclitaxel for early breast cancer. J Natl Cancer Inst 100:805–814

    Article  PubMed  CAS  Google Scholar 

  12. Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM (2005) Post-operative 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. Ann Oncol 16:1762–1771

    Article  PubMed  CAS  Google Scholar 

  13. Jm Albert, Buzdar AU, Guzman R, Allen PK, Strom EA, Perkins GH, Woodward WA, Hoffman KE, Tereffe W, Hunt KK, Buchholz TA, Oh JL (2011) Prospective randomized trial of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus paclitaxel and FAC (TFAC) in patients with operable breast cancer: impact of taxane chemotherapy on locoregional control. Breast Cancer Res Treat 128:421–427

    Article  CAS  Google Scholar 

  14. Burnell M, Levine MN, Chapman JAW, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O’Brien P, Shepherd LE (2010) Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high risk node-nagative breast cancer. J Clin Oncol 28:77–82

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Santaballa A, Rodríguez CA, Crespo C, Abad M, Domínguez S, Florián J, Llorca C, Méndez M, Godes M, Cubedo R, Murias A, Batista N, García MJ, Caballero R, de Alava E (2010) Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat 123:149–157

    Article  PubMed  CAS  Google Scholar 

  16. Early Breast Cancer Trialists’ Cooperative Group (EBCTCG), Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K (2012) Comparison between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432–444

    Article  CAS  Google Scholar 

  17. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with Trastuzumab for all HER-2 overespressors and random assignment to trastuzumab or not in HER-2 non-overespressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649

    Article  PubMed  CAS  Google Scholar 

  18. Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2015) Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol 33:2353–2360

    Article  PubMed  CAS  Google Scholar 

  19. Sparano JA, O’Neill A, Gray RJ et al. (2012) 10-year update of E2197: phase III doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN + and high-risk LN- breast cancer and the comparison of the prognostic utility of the 21-gene recurrence score (RS) with clinicopathologic features. J Clin Oncol (suppl; abstr 1021)

  20. Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N (2010) Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 362:2053–2065

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Bianco AR, Del Mastro L, Gallo C, Perrone F, Matano E, Pagliarulo C, De Placido S (1991) Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 63:799–803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Goldhirsh A, Gelber RD, Castiglione M (1990) The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol 1:183–188

    Google Scholar 

Download references

Acknowledgments

This paper is dedicated to the memory of Dr. Marco Venturini, leader of the GONO-MIG group, who designed the study. We thank the following investigators who contributed to enrolling study patients: Eugenio Villa, MD, Oncologia Medica, Ospedale San Raffaele, Milano, Italy; Marco Danova, MD, Internal Medicine and Medical Oncology, Ospedale Civile, Vigevano, Azienda Ospedaliera di Pavia, Pavia, Italy; Donatella Grasso, MD, Oncologia Medica, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Federico Cappuzzo, MD, Istituto Toscano Tumori, Livorno, Italy; Domenico Guarneri, MD, Dipartimento di Oncologia Medica, Ospedale Giovanni Borea, Sanremo, Italy; Stefano Banducci, MD, Oncologia Medica, Ospedale San Leopoldo Mandic, Merate, Italy; Enrichetta Valle, MD, Oncologia Medica 2, Ospedale di Businco, Cagliari, Italy; Franco Testore, MD, Oncologia Ospedale Cardinal Massaia, Asti, Italy; Rita Ceccherini, MD, Centro Sociale Oncologico ASS 1 Triestina, Trieste, Italy; Pietro Gallotti, MD, Istituto clinico Beato Matteo, Vigevano, Italy.

Funding

This work was partially supported by Bristol Myers Squibb. Bristol Myers Squibb had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, IRCCS AOU San Martino –IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Largo R. Benzi 10, 16132, Genoa, Italy

    Lucia Del Mastro, Alessia Levaggi, Claudia Bighin, Loredana Miglietta, Simona Pastorino & Paolo Pronzato

  2. Department of Medical Oncology, AOU Pisana, Osp. S. Chiara, Via Roma 67, 56100, Pisa, Italy

    Andrea Michelotti & Elisabetta Landucci

  3. Medical Oncology, Azienda Ospedaliera “Carlo Poma”, Strada Lago Paiolo 10, 46100, Mantua, Italy

    Giovanna Cavazzini & Francesca Adami

  4. Medical Oncology, Ospedale Civile, Via De Nicola 14, 07100, Sassari, Italy

    Tiziana Scotto & Margherita Piras

  5. Department of Gynecology and Obstetrics, Ospedale S. Anna, Via Ventimiglia 3, 10126, Turin, Italy

    Saverio Danese

  6. Department of Medical Oncology, Ospedale S. Croce e Carle, Via M. Coppino 26, 12100, Cuneo, Italy

    Ornella Garrone

  7. Breast Unit, AOU Città della Salute e delle Scienze, Via Cherasco 23, 10126, Turin, Italy

    Antonio Durando & Valeria Accortanzo

  8. Medical Oncology, Ospedale San Lazzaro, Via P. Belli 26, 12051, Alba, Cuneo, Italy

    Federico Castiglione

  9. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Via Gattamelata 64, 35128, Padua, Italy

    PierFranco Conte

  10. Epidemiology Unit, IRCCS AOU San Martino –IST, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132, Genoa, Italy

    Paolo Bruzzi

Authors
  1. Lucia Del Mastro
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  2. Alessia Levaggi
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  4. Giovanna Cavazzini
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  9. Ornella Garrone
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  13. Loredana Miglietta
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  16. Federico Castiglione
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  19. Paolo Bruzzi
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Corresponding author

Correspondence to Lucia Del Mastro.

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Conflict of interest

Employment or Leadership Position: None. Consultant or Advisory Role: Lucia Del Mastro Pfizer, Novartis, Takeda; Paolo Pronzato Celgene, Eisai, Genomic Health; Andrea Michelotti Roche, Novartis, Eisai, Astrazeneca, Teva, Celgene, Takeda, Amgen; Paolo Bruzzi Novartis, Merck Sharp & Dohme, Bristol Myers Squibb. Stock Ownership: None. Honoraria: None. Research Funding: None. Expert Testimony: None. Patents, Royalties, and Licenses: None. Travel, Accommodations: Andrea Michelotti and Lucia Del Mastro Takeda; Andrea Michelotti Roche, Novartis, Eisai, Astrazeneca, Teva, Celgene, Takeda, Amgen. Other Remuneration: None. All remaining authors have declared no conflicts of interest.

Ethical standards

The study was conducted according to current laws of the countries in which the study was performed.

Ethical approval

The primary study was approved by the appropriate institutional and/or national ethics committee. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the primary study.

Additional information

Trial registration: http://clinicaltrials.gov, NCT02450058.

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Del Mastro, L., Levaggi, A., Michelotti, A. et al. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat 155, 117–126 (2016). https://doi.org/10.1007/s10549-015-3655-1

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