Breast Cancer Research and Treatment

, Volume 70, Issue 3, pp 163–169

Phase I/II study of gemcitabine in association with vinorelbine for metastatic breast cancer

  • G. Mariani
  • P. Tagliabue
  • P. Zucchinelli
  • C. Brambilla
  • R. Demicheli
  • E. Villa
  • A. Marchianò
  • P. Valagussa
  • G. Bonadonna
  • L. Gianni
Article

Abstract

Background. Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination.

Patients and methods. Fifty-three patients with metastatic breast cancer were treated. In the dose-finding phase, seven cohorts of patients (22 women) received increasing doses to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination. Patients recruited in the phase II portion of the study (31 women) received the dose level immediately below the one defined as MTD (i.e., G 1200 mg/m2, V 30 mg/m2, on day 1 and day 8, every 3 weeks).

Results. Dose escalation was discontinued at G 1400 mg/m2 and V 30 mg/m2 because of toxic death due to thrombocytopenia and CNS hemorrage. No other limiting toxicities were observed, and tolerability was similar at all dose levels studied in the escalation portion of the study. The main toxicity was granulocytopenia of grade 3/4 in 36 and 48% of the patients on phase I and II respectively, without episodes of neutropenic fever. Thrombocytopenia was uncommon. Other side effects were usually mild to moderate. In 46 evaluable patients, the response rate was 24% (complete response 7%, partial response 17%). Disease stabilization was observed in further 17%. The median duration of response was 12 months (range 5–14) and the median survival was 20 months (range 1 to 45+).

Conclusions. G and V, on day 1 and 8 of 3-weekly cycles, can safely be administered to patients with metastatic breast cancer at the dose of 1200 and 30 mg/m2, respectively. The antitumor activity of G and V in combination was similar to that reported when using either drug as single agent.

gemcitabine vinorelbine chemotherapy metastatic breast cancer phase I/II study 

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References

  1. 1.
    Harris JR, Morrow M, Norton L: Cancer of the breast. Management of metastatic disease. In: De Vita VT Jr, Hellman S, Rosenberg SA (eds) Cancer Principles and Practice of Oncology. Lippincott, Philadelphia, 1997, pp 1602-1606Google Scholar
  2. 2.
    Fellous A, Ohayon R, Vacassin T, Binet S, Lataste H, Krikorian A, Couzinier JP, Meininger V: Biochemical effects of Navelbine on tubulin and associated proteins. Semin Oncol 16(suppl 4): 9-14, 1989Google Scholar
  3. 3.
    Fumoleau P, Delozier T, Extra JM, Canobbio L, Delgado FM, Hurteloup P, Hortobagyi GN, Abeloff MD: Vinorelbine (Navelbine) in the treatment of breast cancer: the European experience. Semin Oncol 22(suppl 5): 22-29, 1995Google Scholar
  4. 4.
    Hertel LW, Kroin JS, Misner JW, Tustin JM: Synthesis of 2-deoxy-2',2'-difluoro-D-ribose and 2-deoxy-2',2'-difluoro-Dribofuranosyl nucleosides. J Org Chem 53: 2406-2409, 1988Google Scholar
  5. 5.
    Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB: Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res 50: 4417-4422, 1990Google Scholar
  6. 6.
    Lüftner D, Flath B, Akrivakis C, Grunewald R, Mergenthaler HG, Possinger K: Gemcitabine for palliative treatment in metastatic breast cancer. J Cancer Res Clin Oncol 124: 527-531, 1998Google Scholar
  7. 7.
    Blackstein M, Vogel CL, Ambinder R, Cowan J, Pearce P, Iglesias J, Dorr FA: Phase II study of gemcitabine in patients with metastatic breast cancer. Proc. ASCO (American Society of Clinical Oncology) 15: 117 (abstract 135), 1996Google Scholar
  8. 8.
    Possinger K: Gemcitabine in advanced breast cancer. Anticancer Drugs 6(suppl 6): 55-60, 1995Google Scholar
  9. 9.
    Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL: Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 13: 2731-2736, 1995Google Scholar
  10. 10.
    Spielmann M, Pouillart P, Espie M, Llombart-Cussac A, Namer M, Kalla S, Ferrero JM, Cuvier C, Fumoleau P, Ponzio A, Kayitalire L: Activity of gemcitabine in metastatic breast cancer (MBC) patients previously treated with anthracycline-containing regimens. Breast Cancer Res Treat 41: 236 (abstract 143), 1996Google Scholar
  11. 11.
    Sledge GW Jr: Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: The Eastern Cooperative Oncology Group experience. Semin Oncol 22(suppl 12): 123-125, 1995Google Scholar
  12. 12.
    Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C: Paclitaxel by three-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, 1995Google Scholar
  13. 13.
    Terenziani M, Demicheli R, Brambilla C, Ferrari L, Moliterni A, Zambetti M, Caraceni A, Martini C, Bonadonna G: Vinorelbine: an active non cross-resistant drug in advanced breast cancer. Results from a phase II study. Breast Cancer Res Treat 39: 285-291, 1996Google Scholar
  14. 14.
    Krajnik G, Wein R, Greil R, Marhold F, Mohn-Staudner A, Kummer F, Malayeri R, Zochbauer-Muller S, Huber H, Pirker R: Vinorelbine/gemcitabine in advanced non-small cell lung cancer (NSCLC): a phase I trial. Euro J Cancer, 34,(12): 1977-1980, 1998Google Scholar
  15. 15.
    Camps-Herrero C, Martinez NE, Berrocal Jaime A: Secondline treatment with gemcitabine and vinorelbine in non-smallcell lung cancer (NSCLC) cisplatin failures: a pilot study. Lung Cancer 27: 47-53, 2000Google Scholar
  16. 16.
    Krajnik G, Mohn-Staudner A, Thaler J, Griel R, Schmeikal S, Marhold F, Deutsch J, Preiss P, Malayeri R, Schafer-Prokop C, Wein W, Huber H, Pirker R: Vinorelbine-gemcitabine in advanced non-small cell lung cancer (NSCLC): an AASLC phase II trial. Ann Oncol 11: 993-998, 2000Google Scholar
  17. 17.
    Hainsworth JD, Burris HA, Litchy S, Erland JB, Hon JK, Brierre JE, Greco FA: Gemcitabine and vinorelbine in the second-line treatment of non-small cell lung carcinoma patients. AMinnie Pearl Cancer Research Network phase II trial. Cancer 15, 88(6): 1353-1358, 2000Google Scholar
  18. 18.
    Nicolaides C, Dimopoulos MA, Samantas E, Bafaloukos D, Kalofonos C, Fountzilas G, Razi E, Kosmidis P, Pavlidis N: Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer progression after first-line taxane-based chemotherapy. A phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 11: 873-875, 2000Google Scholar
  19. 19.
    Valenza R, Leonardi V, Gebbia V, Agostara B: Gemcitabine and vinorelbine in pretrated advanced breast cancer: a pilot study. Ann Oncol 11: 495-496, 2000Google Scholar
  20. 20.
    Borchmann P, Schnell R, Diehl V, Engert A: New drugs in the treatment of Hodgkin's disease. Ann Oncol 9(suppl 5): 103-108, 1998Google Scholar
  21. 21.
    Delord JP, Raymond E, Chaouche M, Ruffie P, Ducreux M, Faivre S, Boige V, Le Chevalier T, Rixe O, Baudin E, Pautier P, Rodier JM, Chouaki N, Escudier B, Kayitalire L, Armand JP: A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies. Ann Oncol 11: 73-79, 2000Google Scholar
  22. 22.
    Caristi N, Maisano R, Spadaro P, Toscano G, Scimone A, Pergolizzi A, Gnani A, Cascinu S: Gemcitabine and vinorelbine combination in patients older than 70 years or unresponsive to a cisplatin chemotherapy in advanced bladder cancer. Proc ASCO 19: 362a (abstract 1429), 2000Google Scholar
  23. 23.
    Lilenbaum R, Cano R, Schwartz M, Siegel L, Lutzky J, Lewis M, Krill E, Barreras L, Davila E: Gemcitabine and vinorelbine in advanced non-small cell lung carcinoma. A phase II study Cancer 88(3): 557-562, 2000Google Scholar
  24. 24.
    Lorusso V, Carpagnano F, Frasci G, Panza N, Di Rienzo G, Cisternino ML, Napoli G, Orlando S, Cinieri S, Brunetti C, Palazzo S, De Lena M: Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non-small cell lung cancer. J Clin Oncol 18(2): 405-411, 2000Google Scholar
  25. 25.
    Zambetti M, Demicheli R, De Candis D, Antonelli G, Giacobone A, Terenziani M, Laffranchi A, Garbagnati F, Biasi S, Bonadonna G: Five-days infusion fluorouracil plus vinorelbine i.v. in metastatic pretreated breast cancer patients. Breast Cancer Res Treat 44: 255-260, 1997Google Scholar
  26. 26.
    Zambetti M, Mariani G, Demicheli R, Verderio P, Potepan P, Garbagnati F: Five-days infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel. Breast Cancer Res Treat 62(2): 135-139, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • G. Mariani
    • 1
  • P. Tagliabue
    • 1
  • P. Zucchinelli
    • 2
  • C. Brambilla
    • 1
  • R. Demicheli
    • 1
  • E. Villa
    • 2
  • A. Marchianò
    • 1
  • P. Valagussa
    • 1
  • G. Bonadonna
    • 1
  • L. Gianni
    • 1
  1. 1.Istituto Nazionale TumoriMilanItaly
  2. 2.Ospedale San RaffaeleMilanItaly

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