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Mitoxantrone plus vinorelbine with granulocyte-colony stimulating factor (G-CSF) support in advanced breast cancer patients. A dose and schedule finding study

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Summary

Mitoxantrone (MTZ) and vinorelbine (VNR) have shown a good efficacy in advanced breast cancer. We conducted a phase I-II trial to determine the MTDs and best schedule of these drugs, in advanced breast cancer patients, when granulocyte-colony stimulating factor (G-CSF) support was given. The starting dose-intensity level was MTZ 3 mg/m2/week + VNR 15 mg/m2/week; dose was escalated at each step by 1 mg/m2/week for MTZ and 5 mg/m2/week for VNR, until dose limiting toxicity (DLT) developed in 33% or more of the patients at the first course. G-CSF 5 µg/kg/day d 3–13 was administered at each cycle from dose level 2 on. For each dose step we planned 3 different schedules (a = total dose of MTZ on day 1; b = total dose d 1 and 8; c = weekly schedule). At the time of this analysis (December 1993) 43 patients with locoregionally advanced or metastatic breast cancer have entered this study, 23 of whom had received prior chemotherapy other than adjuvant. Toxicity has been primarily hematologic. Non hematologic toxicity never caused interruption of dose escalation.

Overall 8 patients developed DLT at the first course. Dose escalation was stopped at level 3 in patients receiving schedules a or b, and in those receiving schedule c the dose was escalated until level 5. The MTD was MTZ 6 mg/m2 and VNR 30 mg/m2 weekly. Age, dose level, and PS were found to be correlated with neutrophil and platelet nadirs, but dose level was the only independent variable predictive of myelotoxicity at multiple regression analysis.

Forty-one patients were evaluable for response. Five complete and 16 partial responses were recorded for a 51% [35–67] overall response rate. This was 67% (12/18) in chemotherapy naive patients as compared to 39% (9/23) in those who had been pretreated.

Seven of 21 (33%) patients receiving dose level 1 and 2 responded as compared to 14/20 (70%) patients who received higher dose-intensity (p = 0.02). Dose level and pretreatment were the only variables significantly associated with response rate at multiple logistic analysis.

The median TTP was 9.5 months for the entire group. It was significantly better in patients who received a dose level > 2 (15 vs. 7; p = 0.015). However, the chemotherapy dose level did not significantly predict outcome after correction for pretreatment (yes vs. no), at multivariate Cox analysis.

In conclusion, G-CSF support allows us to achieve a high dose-intensity of MTZ and VNR. Weekly administration of mitoxantrone is recommended to achieve the maximum dose level.

Dose escalation seems to provide a significant gain in terms of response rate, although the low number of patients enrolled and the short follow-up prevents us from drawing any conclusion on its effects on TTP and survival. Further controlled trials of this combination in unpretreated patients with advanced breast cancer are needed to determine whether dose escalation can really improve prognosis.

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References

  1. De Carli A, La Vecchia C: Cancer mortality in Italy, 1988. Tumori 78: 69–74, 1992

    Google Scholar 

  2. Mick R, Begg CB, Antman K, Korzun AH, Frei E: Diverse prognosis in metastatic breast cancer: Who should be offered alternative initial therapies? Breast Cancer Res Treat 13: 33–38, 1989

    Google Scholar 

  3. A'Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67: 801–805, 1993

    Google Scholar 

  4. Bennett JM, Muss HB, Doroshow JH, Wolff S, Krementz ET, Cartwright K, Dukart G, Reisman A, Schock I: A randomized multicenter trial comparing mitoxantrone, cyclophsphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast cancer. J Clin Oncol 6: 1611–1620, 1988

    Google Scholar 

  5. Henderson IC, Hayes DF, Gelman R: Dose-response in the treatment of breast cancer: a critical review. J Clin Oncol 6: 1501–1515, 1988

    Google Scholar 

  6. Leonard RCF, Cornbleet MA, Kaye SB, Soukop M, White G, Hutcheon AW, Robinson S, Kerr ME, Smyth JF: Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast. J Clin Oncol 5: 1056–1063, 1987

    Google Scholar 

  7. Neidhart JA, Gochnour D, Roach R, Hoth D, Young D: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4: 672–677, 1986

    Google Scholar 

  8. Canobbio L, Pastorino G, Gasparini G: Phase II study of navelbine in advanced breast cancer patients. (Abstract) Second International Congress on Neo-adjuvant chemotherapy, Paris, France, February 19–20, 1988 (Abstr C38)

  9. Mickiewicz E, Fernandez O, Bruno S, Delgado C, Teixeira L, Martinez L, Lira-Puerto V, Noguera C, Solidoro A, Otero J, Hegg R, Delgado FM: Phase II trial of navelbine in advanced breast cancer. (Abstract) Proceedings of the Sixth European Conference on Clinical Oncology, Florence. Eur J Cancer 27 (suppl. 2): S 66, 1991

    Google Scholar 

  10. Lluch A, Garcia Conde J, Casado A, Martin M, Diaz Rubio E, Oliveira C, Gervasio MH, De Pablo JL, Garcia Giron JL, Gorostiaga J, Martinez A, Delgado FM: Phase II trial with navelbine in advanced breast cancer previously untreated. (Abstract) Proc Am Soc Clin Oncol 11: 72, 1992

    Google Scholar 

  11. Fumoleau P, Delgado FM, Delozier T, Mounier A, Delgado MA, Kerbrat P, Garcia-Giralt E, Keiling R, Namer M, Closon MT, Goudier MJ, Chollet P, Lecourt L, Montcuquet P: Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 7: 1245–1252, 1993

    Google Scholar 

  12. Ferrero JM, Wendling JL, Hoch M, Frenay M, Francois E, Namer M: Mitoxantrone-vinorelbine as first-line chemotherapy in metastatic breast cancer. A pilot study. (Abstract) Proc Am Soc Clin Oncol 12: 108, 1993

    Google Scholar 

  13. Kayitalire L, Spielmann M, Brain E, Sari C, Le Cesne A, Toussaint C, Gottfried M, Janin N, Le Chevalier T, Tursz T: Salvage chemotherapy with combination of mitoxantrone and vinorelbine in anthracycline resistant advanced breast cancer. (Abstract) Proc Am Soc Clin Oncol 12: 90, 1993

    Google Scholar 

  14. Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, Yagoda A, Fain K, Moore MA, Clarkson B, Oettgen HF, Alton K, Welte K, Souza L: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 318: 1414–1422, 1988

    Google Scholar 

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

    Google Scholar 

  16. Pearson ES, Hartley HO: Biometrika tables for statisticians. (3rd ed.) Cambridge, England: Cambridge University Press, Vol. 1, 1966

    Google Scholar 

  17. Fisher RA: The significance of deviations from expectation in a Poisson series. Biometrics 17-24, 1950

  18. Kaplan ES, Meier P: Non parametric estimation for incomplete observations. J Am Stat Assoc 53: 557–580, 1958

    Google Scholar 

  19. Mantel N: Evaluation of survival data and two new-rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163–170, 1966

    Google Scholar 

  20. Cox DR: Regression models and life tables. J R Stat Soc 187-120, 1972

  21. Wilkinson, Leland. Systat: The system for statistics. SYSTAT INC., Evanston, IL, 1988

    Google Scholar 

  22. Brosio C, Cinat G, Mickiewicz E, Cabalar M, Alvarez A, Piris N, Giglio R, Dodyk R, Andrade P, Ezcurdia L: Granulocytic colony stimulating factor support in weekly chemotherapy with vinorelbine. (Abstract) Proc Am Soc Clin Oncol 12: 144, 1993

    Google Scholar 

  23. Brown T, Tangen C, Fleming T, McDonald J: A phase II trial of taxol and granulocyte colony stimulating factor in patients with adenocarcinoma of the pancreas. (Abstract) Proc Am Soc Clin Oncol 12: 200, 1993

    Google Scholar 

  24. Malfetano J, Brown L, Abrams J, Homesley H, Beningno B, Braly P, Bean L, Malta E, Dziem G: Filgrastim (r-met-huG-CSF) as an adjunct to cyclophosphamide and carboplatin chemotherapy in advanced ovarian carcinoma. (Abstract) Proc Am Soc Clin Oncol 12: 265, 1993

    Google Scholar 

  25. Masuda N, Fukuoka M, Kusunoky Y, Matsui K, Kudoh S, Negoro S, Takifuji N, Nakagawa K, Hirashima T, Tamanoi M, Nitta T, Yana H, Takada M: Phase I study of irinotecan (CPT-11) and cisplatin (CDDP) plus G-CSF for advanced non-small cell lung cancer. (Abstract) Proc Am Soc Clin Oncol 2: 327, 1993

    Google Scholar 

  26. Johnson D, Levitt M, Mason B, Belani C, Kerr R, Bean L, Malta E, Tomita D: A phase II trial of filgrastim (r-metHuG-CSF) as an adjunct to cisplatin and etoposide chemotherapy in locally advanced or metastatic non-small cell lung carcinoma. (Abstract) Proc Am Soc Clin Oncol 12: 338, 1993

    Google Scholar 

  27. Maugard-Louboutin C, Chastang C, Chevallier B, Kerbrat P, Roche H, Tresca P, Delgado M, Fumoleau P: Dose-effect relationship of granulocyte colony stimulating factor (G-CSF): PE 2601 in patients with advanced breast carcinoma treated by intensive chemotherapy. (Abstract) Proc Am Soc Clin Oncol 12: 90, 1993

    Google Scholar 

  28. Crawford J, Orer H, Johnson D: Granulocyte-colony stimulating factor: Prevention of chemotherapy induced febrile neutropenia in patients with small cell lung cancer. A randomized double-blind placebo controlled trial. (Abstract) Proc Am Soc Clin Oncol 9: 884, 1990

    Google Scholar 

  29. deVries EGE, Biesma B, Willemse PHB, Mulder NH, Stern AC, Aalders JG, Vellenga E: A double-blind placebo-controlled study with granulocyte-macrophage colony stimulating factor during chemotherapy for ovarian carcinoma. Cancer Res 51: 116–122, 1991

    Google Scholar 

  30. Gianni AM, Bregni M, Siena S, Orazi A, Stern AC, Gandola L, Bonadonna G: Recombinant human granulocyte-macrophage colony stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma. J Clin Oncol 8: 768–778, 1990

    Google Scholar 

  31. Tapler J, Hamm JT, Shulman L, Ritch P, Nemunaitis J, Young DC, Felser J, Resta D, Gaynes L, Millenson M, Strauss G, Linch T, Skarin A, Schnipper LE, Elias AD: Combination cytokine therapy with recombinant human interleukin 3 (IL-3) and granulocyte colony stimulating factor (G-CSF) after ‘ICE’ chemotherapy for lung cancer: sequential and simultaneous schedules. (Abstract) Proc Am Soc Clin Oncol 12: 333, 1993

    Google Scholar 

  32. Sledge GW, Antman KH: Progress in chemotherapy for metastatic breast cancer. Seminars in Oncology 3: 317–332, 1992

    Google Scholar 

  33. Mulder NH, Mulder POM, Sleijfer DT, Willemse PH, Van der Ploegh E, Dolsma WV, de Vries EG: Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer. Eur J Cancer 29A: 668–671, 1993

    Google Scholar 

  34. Ferguson JE, Dodwell DJ, Seymour AM, Richards MA, Howell A: High-dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer. Br J Cancer 67: 825–829, 1993

    Google Scholar 

  35. Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert D, Focan-Henrard D, Lemaire M, Lobelle JP, Longree L, Ries F: Dose-response relationship of epirubcin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol 7: 1253–1263, 1993

    Google Scholar 

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Authors and Affiliations

  1. VII Division of General Surgery, University Federico II-Naples, Postale 105, 84014, Nocera Inferiore, SA, Italy

    G. Frasci, N. Della Volpe, A. Imbriani & G. Persico

  2. Division of Emergency Surgery Hospital of Nocera Inferiore, Postale 105, 84014, Nocera Inferiore, SA, Italy

    F. Salzano

  3. Division of General Surgery Hospital of Cava dei Tirreni, Postale 105, 84014, Nocera Inferiore, SA, Italy

    L. Cremone

  4. Division of Medical Oncology A National Cancer Institute of Naples, Postale 105, 84014, Nocera Inferiore, SA, Italy

    G. Comella & P. Comella

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  1. G. Frasci
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Frasci, G., Comella, G., Comella, P. et al. Mitoxantrone plus vinorelbine with granulocyte-colony stimulating factor (G-CSF) support in advanced breast cancer patients. A dose and schedule finding study. Breast Cancer Res Tr 35, 147–156 (1995). https://doi.org/10.1007/BF00668204

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