Summary:
Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, taxol 175 mg/m2 day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m2 (three patients), 50 mg/m2 (three patients), 60 mg/m2 (five patients) and 70 mg/m2 (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m2. Cmax of Idarubicin and idarubicinol were 7.7±2.0 and 26.3±9.7 ng/ml at 40 mg/m2 and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m2. AUCt0–264 of idarubicin and idarubicinol increased from 423.2±111.6 and 2581±606 hng/ml at 40 mg/m2 to 732.8±140.2 and 4590±1258 hng/ml at 70 mg/m2. Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete crossresistance between the two drugs.
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References
Stadtmauer EA, O'Neill A, Goldstein LJ et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hemopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000; 342: 1069–1076.
Lotz J-P, Curè H, Janvier M et al. High-dose chemotherapy (HD-CT) with hematopoietic stem cell transplantation (HSCT) for metastatic breast cancer (MBC): results of the French Protocol PEGASE 04. Proc Am Soc Clin Oncol 1999; 18: 43a (abstr. 161).
Crump M, Gluck S, Stewart D et al. A randomized trial of high-dose chemotherapy (HDC) with autologous peripheral blood stem cell support (ASCT) compared to standard therapy in women with metastatic breast cancer: a National Cancer Institute of Canada (NCIC) clinical trial group study. Proc Am Soc Clin Oncol. 2001; 20: (abstr. 82).
Berg J, Wiklund T, Erikstein B et al. Tailored fluorouracil, epirubicin and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomized trial. Scandinavian Breast Group 9401 study. Lancet 2000; 356: 1384–1391.
Teicher B, Cucchi C, Lee J et al. Alkylating agents. In vitro studies of cross-resistance patterns in human tumor cell lines. Cancer Res 1986; 46: 4379–4383.
Conte PF, Gennari A, Donati S et al. Gemcitabine plus epirubicin plus taxol (GET) in advanced breast cancer: a phase II study. Breast Cancer Res Treat 2001; 68: 171–179.
Bengala C, Pazzagli I, Innocenti F et al. High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin–paclitaxel-containing regimens in metastatic breast cancer (MBC). Ann Oncol 2001; 12: 69–74.
Villani F, Galimberti M, Comazzi R, Crippa F . Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin). Eur J Cancer Clin Oncol 1989; 25 (1): 13–18.
Kuffel MJ, Reid J, Ames MM . Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with tumor cells in culture. Cancer Chemother Pharmacol 1992; 30: 51–57.
Lionetto R, Pronzato P, Conte PF et al. Idarubicin in advanced breast cancer: a phase II study. Cancer Treat Rep 1986; 70: 1439–1440.
Martoni A, Piana E, Guaraldi M et al. Comparative phase II study of idarubicin versus doxorubicin in advanced breast cancer. Oncology 1990; 47: 427–432.
Toffoli G, Sorio R, Aita P et al. Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients. Clin Cancer Res 2000; 6: 2279–2287.
Miller AB, Hoogstraten B, Staquet M, Winkler A . Reporting results of cancer treatment. Cancer 1981; 47: 207–214.
Fogli S, Danesi R, Innocenti F et al. An improved HPLC method for therapeutic drug monitoring of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites in human plasma. Ther Drug Monitor 1999; 21: 367–375.
Bennis S, Faure P, Chapey C et al. Cellular pharmacology of lipophilic anthracyclines in human tumor cells in culture selected for resistance to doxorubicin. Anticancer Drugs 1997; 8: 610–617.
Berman E, McBride M . Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells. Blood 1992; 79: 3267–3273.
Toffoli G, Corona G, Simone F et al. Cellular pharmacology of idarubicinol in multidrug-resistant LoVo cell lines. Int J Cancer 1996; 67: 129–137.
Cersosimo RJ . Idarubicin: an anthracycline antineoplastic agent. Clin Pharmaeol 1992; 11: 152–167.
Nitiss JL, Wang JC . Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol Pharmacol 1990; 25: 445–448.
Eksborg S, Bjorkholm M, Hast R, Fagerlund E . Plasma pharmacokinetics of idarubicin and its 13-dihydro metabolite –a comparison of bolus versus 2 h infusion during a 3 day course. Anticancer Drugs 1997; 8: 42–47.
Pea F, Damiani D, Michieli M et al. Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia. Eur J Clin Pharmacol 1999; 55: 361–368.
Boogerd W, Tjahja IS, van de Sandt MM, Beijnen JH . Penetration of idarubicin into malignant brain tumor tissue. J Neurooncol 1999; 44: 65–69.
Rose M, Lee FA, Gollekeri A et al. The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function. Bone Marrow Transplant 2000; 26: 133–139.
Acknowledgements
We acknowledge the dedicated work of the nurses of the Division of Medical Oncology and the excellent technical support of Dr MG Bulleri and Bruno Fiori, Laboratory of Cryopreservation, St Chiara Hospital. The study was supported by a Grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC).
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Bengala, C., Danesi, R., Guarneri, V. et al. High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine–epirubicin–paclitaxel in metastatic breast cancer: a dose finding study. Bone Marrow Transplant 31, 275–280 (2003). https://doi.org/10.1038/sj.bmt.1703827
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DOI: https://doi.org/10.1038/sj.bmt.1703827
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