Breast Cancer Research and Treatment

, Volume 78, Issue 1, pp 29–36 | Cite as

The Combination of Gemcitabine and Vinorelbine is an Active Regimen as Second-Line Therapy in Patients with Metastatic Breast Cancer Pretreated with Taxanes and/or Anthracyclines: a Phase I–II Study

  • Alessandro Morabito
  • Gianfranco Filippelli
  • Sergio Palmeri
  • Stefano Cascinu
  • Francesco Ferraù
  • Vittorina Zagonel
  • Domenico Gattuso
  • Vincenzo Catalano
  • Barbara Capaccetti
  • Vittorio Franciosi
  • Vincenzo Accurso
  • Fedele Scinto
  • Giampietro Gasparini


Purpose. To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes.

Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m2 and vinorelbine was given at the fixed dose of 25 mg/m2, both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m2 per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30–70) and median performance status (PS, ECOG score), 1 (range 0–2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively.

Results. The optimal schedule for the combination was gemcitabine 800 mg/m2 and vinorelbine 25 mg/m2. The maximum tolerated dose of gemcitabine was 1000 mg/m2, with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3–9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28–57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone.

Conclusions. The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline – based schedules or with combinations of anthracyclines and taxanes.

gemcitabine metastatic breast cancer vinorelbine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Winer EP, Morrow M, Osborne CK, Harris JR: Cancer of the breast. Management of patients with metastatic breast cancer. In: De Vita VT Jr, Hellman S, Rosenberg SA (eds) Cancer Principles and Practice of Oncology. Lippincott, Philadelphia, pp 1699-1706, 2001Google Scholar
  2. 2.
    Abrams JS, Vena DA, Baltz J, Adams J, Montello M, Christian M, Onetto N, Desmond-Hellmann S, Canetta R, Friedman MA: Paclitaxel activity in heavily pre-treated breast cancer: A National Cancer Institute Treatment Referral Center Trial. J Clin Oncol 13(8): 2056-2065, 1995Google Scholar
  3. 3.
    Vogel CL: Current status of salvage chemotherapy for refractory advanced breast cancer. Oncology 10(Suppl 6): 7-15, 1996Google Scholar
  4. 4.
    Budman DR: Vinorelbine (Navelbine). A third generation vinca alkaloid. Cancer Invest 15: 475-490, 1997Google Scholar
  5. 5.
    Carmichel J, Walling J: Advanced breast cancer: investigational role of gemcitabine. Eur J Cancer 33(Suppl 1): S27-S30, 1997Google Scholar
  6. 6.
    Binet S, Chaineau E, Fellous A, Lataste H, Krikorian A, Couzinier JP, Meninger V: Immunofluorescence study of the action of navelbine, vincristine and vinblastine on mitotic axonal microtubules. Int J Cancer 46: 262-266, 1990Google Scholar
  7. 7.
    Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, Garcia-Giralt E, Keiling R, Namer M, Closon MT: Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 11: 1245-1252, 1993Google Scholar
  8. 8.
    Garcia-Conde J, Lluch A, Martin M, Casado A, Gervasio H, De Oliveira C, De Pablo JL, Gorostiaga J, Giron GC, Cervantes A: Phase II trial of weekly i.v. vinorelbine in firstline advanced breast cancer chemotherapy. Ann Oncol 5: 854-857, 1994Google Scholar
  9. 9.
    Bruno S, Puerto VL, Mickiewicz E, Hegg R, Texeira LC, Gaitan L, Martinez L, Fernandez O, Otero J, Kesselring G: Phase II trial of weekly i.v. vinorelbine as a single agent in first-line advanced breast cancer. Am J Clin Oncol 18: 392-396, 1995Google Scholar
  10. 10.
    Romero A, Rabinovich MG, Vallejo CT, Perez JE, Rodriguez R, Cuevas MA, Machiavelli M, Lacava JA, Langhi M, Romero Acuna L: Vinorelbine as first-line chemotherapy for metastatic breast carcinoma.J Clin Oncol 12: 336-341, 1994Google Scholar
  11. 11.
    Abeloff MD: Vinorelbine (Navelbine) in the treatment of breast cancer: a summary. Semin Oncol 22(Suppl 5): 1-4, 41-44, 1995Google Scholar
  12. 12.
    Degardin M, Bonneterre J, Hecquet B, Pion JM, Adenis A, Horner D, Demaille A: Vinorelbine (Navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 5: 424-426, 1994Google Scholar
  13. 13.
    Weber BL, Vogel C, Jones S, Harvey H, Hutchins L, Bigley J, Hohneker J: Intravenous vinorelbine as first-line and secondline therapy in advanced breast cancer. J Clin Oncol 13: 2722-2730, 1995Google Scholar
  14. 14.
    Conti F, Vici P: Vinorelbine in the treatment of breast cancer: current status and prospectives for the future. Clin Ter 149: 61-74, 1998Google Scholar
  15. 15.
    Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G: Vinorelbine is an active antiproliferative agent in pre-treated advanced breast cancer patient: a phase II study. J Clin Oncol 12: 2094-2101, 1994Google Scholar
  16. 16.
    Livingston RB, Ellis GK, Gralow JR, Williams MA, White R, McGuirt C, Adamkiewicz BB, Long CA: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15: 1395-1400, 1997Google Scholar
  17. 17.
    Hertel LW, Boder GB, Kroin JS, Rzel 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
  18. 18.
    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
  19. 19.
    Arning M, Blatter J: Gemcitabine in solid tumors: present status and further development. Oncologie 20: 297-304, 1997Google Scholar
  20. 20.
    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
  21. 21.
    Herbst R, Dang N, Lynch C, Teicher B, Strauss G, Elias A, Anderson I, Salgia R, Jacobs C, Skarin A: Phase I study of combination weekly gemcitabine and vinorelbine in patients with lung cancer. Proc Am Soc Clin Oncol 17: 488a (bstract 1877), 1998Google Scholar
  22. 22.
    Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47: 207-214, 1981Google Scholar
  23. 23.
    Buyse M, Piedbois P: On the relationship between response to treatment and survival time. Statist Med 15: 2797-2812, 1996Google Scholar
  24. 24.
    Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU: Long-term follow up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996Google Scholar
  25. 25.
    Esteva FJ, Valero V, Pusztai L, Boehnke-Michaud L, Buzdar AU, Hortobagy GN: Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. Oncologist 6: 133-146, 2001Google Scholar
  26. 26.
    Grindey GB, Hertel LW, Plunkett W: Cytotoxicity and antitumor activity of 2′,2′-difluorodeoxycytidine (Gemcitabine). Cancer Invest 8: 313-318, 1990Google Scholar
  27. 27.
    Binet S, Fellous A, Lataste H, Krikorian A, Couzinier JP, Meininger V: In situ analysis of the action of navelbine on various types of microtubules using immunofluorescence. Semin Oncol 16(Suppl 4): 5-8, 1989Google Scholar
  28. 28.
    Haider K, Kornek G, Kwasny W, Weinlander G, Valencak J, Lang F, Puribauer F, Kovats E, Depisch D, Scheithauer W: Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor. Breast Cancer Res Treat 55: 203-211, 1999Google Scholar
  29. 29.
    Mariani G, Tagliabue P, Zucchinelli P, Brambilla C, Demicheli R, Villa E, Marchianò A, Valagussa P, Bonadonna G, Gianni L: Phase I/II study of gemcitabine in association with vinorelbina for metastatic breast cancer. Breast Cancer Res Treat 70: 163-169, 2001Google Scholar
  30. 30.
    Gokmen E, Karabulut B, Sezgin C, Sanal S: A phase II study of Gemcitabine (G) and Vinorelbine (V) in patients with advanced breast cancer (ABC). Proc Ann Soc Clin Oncol 19: 110a (abstract 427), 2000Google Scholar
  31. 31.
    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 progressing after first-line taxane-based chemotherapy: a phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 11: 873-875, 2000Google Scholar
  32. 32.
    Valenza R, Leonardi V, Gebbia V, Agostara B: Gemcitabine and vinorelbine in pre-treated advanced breast cancer: a pilot study. Ann Oncol 11: 495-496, 2000Google Scholar
  33. 33.
    Stathopoulus GP, Rigatos SK, Pergantas N, Tsavdarides D, Athanasiadis I, Malamos NA, Stathopoulos JG: Phase II trial of biweekly administration of vinorelbine and gemcitabine in pre-treated advanced breast cancer. J Clin Oncol 20: 37-41, 2002Google Scholar
  34. 34.
    O'shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Hazel GV, Verms S, Leonard R: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pre-treated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20: 2812-2823, 2002Google Scholar
  35. 35.
    Fox SB, Gasparini G, Harris AL: Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol 2: 278-289, 2001Google Scholar
  36. 36.
    Gasparini G: Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2: 733-740, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Alessandro Morabito
    • 1
  • Gianfranco Filippelli
    • 2
  • Sergio Palmeri
    • 3
  • Stefano Cascinu
    • 4
  • Francesco Ferraù
    • 5
  • Vittorina Zagonel
    • 6
  • Domenico Gattuso
    • 1
  • Vincenzo Catalano
    • 7
  • Barbara Capaccetti
    • 1
  • Vittorio Franciosi
    • 4
  • Vincenzo Accurso
    • 3
  • Fedele Scinto
    • 6
  • Giampietro Gasparini
    • 1
  1. 1.Division of OncologyAzienda Ospedaliera 'San Filippo Neri'RomeItaly
  2. 2.ASL1PaolaItaly
  3. 3.University of PalermoItaly
  4. 4.Azienda OspedalieraParmaItaly
  5. 5.Ospedale 'Contrada Sirina'TaorminaItaly
  6. 6.Ospedale FatebenefratelliRomeItaly
  7. 7.Ospedale 'S. Salvatore'PesaroItaly

Personalised recommendations