Advertisement

Breast Cancer Research and Treatment

, Volume 131, Issue 1, pp 127–135 | Cite as

A GINECO randomized phase II trial of two capecitabine and weekly paclitaxel schedules in metastatic breast cancer

  • Alain LortholaryEmail author
  • Anne-Claire Hardy-Bessard
  • Thomas Bachelot
  • Gaëtan de Rauglaudre
  • Jérôme Alexandre
  • Hugues Bourgeois
  • Dominique Jaubert
  • Désiré Paraiso
  • Rémy Largillier
Clinical trial

Abstract

To determine whether capecitabine schedule adaptation improves the tolerability of capecitabine–paclitaxel combination therapy for metastatic breast cancer (MBC), patients with anthracycline-pretreated HER2-negative MBC were randomized to either arm A (21-day cycles: capecitabine 1,000 mg/m2 twice daily, days 1–14; paclitaxel 60 mg/m2, days 1, 8, and 15) or arm B (28-day cycles: capecitabine 1,000 mg/m2 twice daily, days 1–5, 8–12, and 15–19; paclitaxel 80 mg/m2, days 1, 8, and 15). The primary endpoint was the incidence of dose reductions or delays >1 week for grade 3/4 toxicity. Secondary endpoints were efficacy and safety. All 130 randomized patients were evaluable for safety. Dose reduction or delay for grade 3/4 toxicity occurred in 39% of patients in arm A and 34% in arm B during cycles 1–6. In arm A, there were significantly more toxicity-related dose reductions (cycles 1–6: 82 vs. 67%, respectively; P = 0.05) and discontinuations (29 vs. 8%, respectively). Grade 3 diarrhea occurred in 12 and 0%, respectively, and grade 3 hand-foot syndrome in 12 versus 9%, respectively (grade 4 not applicable). There were no detectable differences in efficacy. Weekday capecitabine dosing with weekly paclitaxel may improve tolerability without a detrimental effect on efficacy, and merits further evaluation in patients suited to combination chemotherapy.

Keywords

Capecitabine Combination therapy Metastatic breast cancer Weekly paclitaxel 

Notes

Acknowledgments

The authors would like to thank Nicolas Gane, Data Management at the study office of ARCAGY-GINECO (the sponsor of the study), Paris. We also thank the following investigators who participated in the trial: Dr P.L. Etienne (Clinique Armoricaine de Radiologie, Saint Brieuc); Dr P. Dalivoust (Hôpital Saint-Joseph, Marseille); Dr C. El Kouri and Dr J.F. Ramee (Centre Catherine de Sienne, Nantes); Dr J.M. Ferrero and Dr W. Lescaut (Centre Antoine Lacassagne, Nice); Dr J.P. Guastalla and Dr I. Ray-Coquard (Centre Léon Bérard, Lyon); Dr S. Kirscher (Institut Sainte Catherine, Avignon); Dr L. Chauvenet (Hôpital Hôtel-Dieu, Paris); and Dr G. Sadki-Benaoudia (Centre Hospitalier Robert Ballanger, Aulnay sous Bois). This work and third-party medical writing assistance for this article were supported by Roche France.

Conflict of interest

The authors declared no conflict of interest.

References

  1. 1.
    O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20:2812–2823PubMedCrossRefGoogle Scholar
  2. 2.
    Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF (2011) Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol 22:1094–1101PubMedCrossRefGoogle Scholar
  3. 3.
    Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V, Breast Cancer Investigators of the Hellenic Oncology Research Group (2010) Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol 21:48–54PubMedCrossRefGoogle Scholar
  4. 4.
    Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, duBois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P (2009) Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol 27:1753–1760Google Scholar
  5. 5.
    Lück HJ, duBois A, Schrader I, Huober J, Heilmann V, Fasching PA, Stähle A, Jackisch C, Marth C, Richter B, von Minckwitz G (2007) Final results of the AGO breast cancer study group MAMMA-3 trial: first-line capecitabine + paclitaxel vs epirubicin + paclitaxel for high-risk metastatic breast cancer [abstract]. Breast Cancer Res Treat 106(1):S67 Abstract 1076Google Scholar
  6. 6.
    Gradishar WJ, Meza LA, Amin B, Samid D, Hill T, Chen YM, Lower EE, Marcom PK (2004) Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study. J Clin Oncol 22:2321–2327PubMedCrossRefGoogle Scholar
  7. 7.
    Susnjar S, Bosnjak S, Radulovic S, Stevanovic J, Gajic-Dobrosavljevic M, Kreacic M (2007) Dose-finding study of capecitabine in combination with weekly paclitaxel for patients with anthracycline-pretreated metastatic breast cancer. J BUON 12:189–196PubMedGoogle Scholar
  8. 8.
    Gick U, Rochlitz C, Mingrone W, Pestalozzi B, Rauch D, Ballabeni P, Lanz D, Hess V, Aebi S (2006) Efficacy and tolerability of capecitabine with weekly paclitaxel for patients with metastatic breast cancer: a phase II report of the SAKK. Oncology 71:54–60PubMedCrossRefGoogle Scholar
  9. 9.
    Uhlmann C, Ballabeni P, Rijken N, Brauchli P, Mingrone W, Rauch D, Pestalozzi BC, Rochlitz C, Aebi S, Swiss Group for Clinical Cancer Research; Swiss Institute for Applied Cancer Research (2004) Capecitabine with weekly paclitaxel for advanced breast cancer: a phase I dose-finding trial. Oncology 67:117–122PubMedCrossRefGoogle Scholar
  10. 10.
    Di Costanzo F, Gasperoni S, Papaldo P, Bilancia D, Manzione L, Landucci E, Mazzoni F, Cognetti F, Gruppo Oncologico Italiano di Ricerca clinica; Gruppo Oncologico del Lazio (2006) Weekly paclitaxel plus capecitabine in advanced breast cancer patients: dose-finding trial of GOIRC and GOL. Ann Oncol 17:79–84PubMedCrossRefGoogle Scholar
  11. 11.
    Susnjar S, Bosnjak SM, Radulovic S (2008) Severe skin toxicity observed with the combination of capecitabine and weekly paclitaxel in metastatic breast cancer patients. Support Care Cancer 16:1415–1418PubMedCrossRefGoogle Scholar
  12. 12.
    Bari M, Rosario D’Andrea M, Azzarello G, Pappagallo GL, Sartori D, Iop A, Gaion F, Rosetti F, Silvestri B, Bonura S, D’Alessio A, Vinante O (2005) Salvage therapy with capecitabine plus weekly paclitaxel in heavily pretreated advanced breast cancer. Am J Cancer 4:307–313CrossRefGoogle Scholar
  13. 13.
    Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O’Shaughnessy JA (2006) Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 24:4384–4390PubMedCrossRefGoogle Scholar
  14. 14.
    Elza-Brown K, Dees E, Wolff A, Carducci M, Donehower R (2000) A phase I study of capecitabine and weekly paclitaxel in advanced solid tumors [abstract]. Proceedings of ASCO 19: Abstract 921JGoogle Scholar
  15. 15.
    Zielinski C, Gralow J, Martin M (2010) Optimising the dose of capecitabine: confused, clarified, or confirmed? Ann Oncol 21:2145–2152PubMedCrossRefGoogle Scholar
  16. 16.
    Traina TA, Theodoulou M, Feigin K, Patil S, Tan KL, Edwards C, Dugan U, Norton L, Hudis C (2008) Phase I study of a novel capecitabine schedule based on the Norton–Simon mathematical model in patients with metastatic breast cancer. J Clin Oncol 26:1797–1802PubMedCrossRefGoogle Scholar
  17. 17.
    Levy E, Pierga J, Largillier R, Tubiana M, Dieras V, Antoine E, Oudard S, Brain E, Ady-Vago N, Milano G (2008) Randomized study evaluating an alternative schedule of capecitabine (X) as monotherapy for metastatic breast cancer (MBC): safety and pharmacokinetic (PK) results [abstract]. Proceedings of ASCO Breast Cancer Symposium:Abstract 188Google Scholar
  18. 18.
    Pentheroudakis G, Pappas P, Golfinopoulos V, Fountzilas G, Nikolaidou M, Boumba VA, Vougiouklakis T, Nikiforidis L, Tzamakou E, Siarabi O, Marselos M, Pavlidis N (2007) Weekday on-weekend off oral capecitabine: a phase I study of a continuous schedule better simulating protracted fluoropyrimidine therapy. Cancer Chemother Pharmacol 60:733–739PubMedCrossRefGoogle Scholar
  19. 19.
    Ngan SY, Michael M, Mackay J, McKendrick J, Leong T, Lim Joon D, Zalcberg JR (2004) A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer 91:1019–1024PubMedGoogle Scholar
  20. 20.
    Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019PubMedGoogle Scholar
  21. 21.
    Stockler M, Sourjina T, Grimison P, Gebski V, Byrne M, Harvey V, Francis P, Nowak AK, Van Hazel G, Forbes J, ANZ Breast Cancer Trials Group (2007) A randomized trial of capecitabine (C) given intermittently (IC) rather than continuously (CC) compared to classical CMF as first-line chemotherapy for advanced breast cancer (ABC) [abstract]. J Clin Oncol 25(18s):1031Google Scholar
  22. 22.
    Wardley AM, Pivot X, Morales-Vasquez F, Zetina LM, de Fátima Dias Gaui M, Reyes DO, Jassem J, Barton C, Button P, Hersberger V, Torres AA (2010) Randomized phase II trial of first-line trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J Clin Oncol 28:976–983PubMedCrossRefGoogle Scholar
  23. 23.
    Steger GG, Greil R, Jakesz R, Lang A, Mlineritsch B, Melbinger-Zeinitzer E, Marth C, Samonigg H, Kubista E, Gnant M (2009) A randomized phase III study comparing epirubicin, docetaxel, and capecitabine (EDC) to epirubicin and docetaxel (ED) as neoadjuvant treatment for early breast cancer—first results of the Austrian Breast and Colorectal Cancer Study Group-Trial 24 (ABCSG-24) [abstract]. EJC Suppl 7:Abstract 4LBAGoogle Scholar
  24. 24.
    Joensuu H, Kellokumpu-Lehtinen P-L, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Bono P, Lindman H, On behalf of the FinXX Study Investigators (2010) FinXX final 5-year analysis: results of the randomised, open-label, phase III trial in medium-to-high-risk early breast cancer [abstract]. Cancer Res 70(24):S4-1CrossRefGoogle Scholar
  25. 25.
    Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, Jassem J, Köstler WJ, Krainer M, Menard S, Petit T, Petruzelka L, Possinger K, Schmid P, Stadtmauer E, Stockler M, Van Belle S, Vogel C, Wilcken N, Wiltschke C, Zielinski CC, Zwierzina H, Central European Cooperative Oncology Group (CECOG) (2009) Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 20:1771–1785PubMedCrossRefGoogle Scholar
  26. 26.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  27. 27.
    Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol 28:3239–3247PubMedCrossRefGoogle Scholar
  28. 28.
    Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2–negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29:1252–1260PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Alain Lortholary
    • 1
    Email author
  • Anne-Claire Hardy-Bessard
    • 2
  • Thomas Bachelot
    • 3
  • Gaëtan de Rauglaudre
    • 4
  • Jérôme Alexandre
    • 5
  • Hugues Bourgeois
    • 6
  • Dominique Jaubert
    • 7
  • Désiré Paraiso
    • 8
  • Rémy Largillier
    • 9
  1. 1.Centre Catherine de SienneNantes Cedex 2France
  2. 2.Clinique Armoricaine de RadiologieSaint BrieucFrance
  3. 3.Centre Léon BérardLyonFrance
  4. 4.Clinique Sainte CatherineAvignonFrance
  5. 5.Université Paris Descartes, AP-HP, Hôpitaux Universitaire Paris Centre, Site Hôpital Hôtel-DieuParisFrance
  6. 6.Centre Jean BernardLe MansFrance
  7. 7.Clinique TivoliBordeauxFrance
  8. 8.Centre Hospitalier de L’Agglomération MontargoiseAmillyFrance
  9. 9.Centre Antoine LacassagneNiceFrance

Personalised recommendations