Abstract
Purpose
This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.
Methods
Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1–3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.
Results
Seventeen patients received 39 cycles of treatment: median 2, (range 1–5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60–90%) and age: 52 (range 24–75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1–59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02–3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2–5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.
Conclusions
The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.
Similar content being viewed by others
References
Wong ET, Hess KR, Gleason MJ (1999) Outcomes and prognostic factors in recurrent giloma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578
Boogerd W, Hart AA, Tjahja IS (1997) Treatment and outcome of brain metastasis as first site of distant metastasis from breast cancer. J Neurooncol 35:161–167
Logothetis CJ, Samuels ML, Trindade A (1982) The management of brain metastases in germ cell tumors. Cancer 49:12–18
Vlasveld LT, Beynen JH, Boogerd W, Bokkel Huinink WW, Rodenhuis S (1990) Complete remission of brain metastases of ovarian cancer following high-dose carboplatin: a case report and pharmacokinetic study. Cancer Chemother Pharmacol 25:382–383
Bernardo G, Cuzzoni Q, Strada MR, Bernardo A, Brunetti G, Jedrychowska I, Pozzi U, Palumbo R (2002) First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest 20:293–302
Boogerd W, van der Sande JJ, van Zandwijk N (1999) Teniposide sometimes effective in brain metastases from non-small cell lung cancer. J Neurooncol 41:285–289
Boogerd W, Dalesio O, Bais EM, van der Sande JJ (1992) Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 69:972–980
Buckner JC (1991) The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Cancer Metastasis Rev 10:335–341
Cormio G, Gabriele A, Maneo A, Zanetta G, Bonazzi C, Landoni F (1998) Complete remission of brain metastases from ovarian carcinoma with carboplatin. Eur J Obstet Gynecol Reprod Biol 78:91–93
Groen HJ, Smit EF, Haaxma-Reiche H, Postmus PE (1993) Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 29A:1696–1699
Mastronardi L, Puzzilli F, Couldwell WT, Farah JO, Lunardi P (1998) Tamoxifen and carboplatin combinational treatment of high-grade gliomas. Results of a clinical trial on newly diagnosed patients. J Neurooncol 38:59–68
Mastronardi L, Puzzilli F, Ruggeri A (1998) Tamoxifen as a potential treatment of glioma. Anticancer Drugs 9:581–586
Hofmann J, Doppler W, Jakob A, Maly K, Posch L, Uberall F, Grunicke HH (1988) Enhancement of the antiproliferative effect of cis- diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C. Int J Cancer 42:382–388
Romanelli S, Perego P, Pratesi G, Carenini N, Tortoreto M, Zunino F (1998) In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol 41:385–390
Ma J, Maliepaard M, Nooter K, Boersma AW, Verweij J, Stoter G, Schellens JH (1998) Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro. Cancer Chemother Pharmacol 41:307–316
Green S, Weiss G (1992) Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239–253
Loos WJ, Stoter G, Verweij J, Schellens JH (1996) Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine. J Chromatogr B Biomed Sci Appl 678:309–315
Lien EA, Solheim E, Ueland PM (1991) Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51:4837–4844
Lien EA, Wester K, Lonning PE, Solheim E, Ueland PM (1991) Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients. Br J Cancer 63:641–645
Couldwell WT, Hinton DR, Surnock AA, DeGiorgio CM, Weiner LP, Apuzzo MLJ, Masri L, Law RE, Weiss MH (1996) Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 2:619–622
Mende S, Bleichner F, Stoeter P, Meuret G (1983) Successful treatment of brain metastases in breast cancer with blood-brain barrier-impervious cytostatics and hormones. Onkologie 6:58–61
Pors H, von Eyben FE, Sorensen OS, Larsen M (1991) Longterm remission of multiple brain metastases with tamoxifen. J Neurooncol 10:173–177
Baker SD, Heidman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF (1996) Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37:195–202
Stewart DJ, Lu K, Benjamin RS, Leavens ME, Luna M, Yap HY, Loo TL (1983) Concentration of vinblastine in human intracerebral tumor and other tissues. J Neurooncol 1:139–144
Donelli MG, Zucchetti M, D’Incalci M (1992) Do anticancer agents reach the tumor target in the human brain? Cancer Chemother Pharmacol 30:251–260
Vertosick FT, Selker RG, Pollack IF, Arena V (1992) The treatment of intracranial malignant gliomas using orally administered tamoxifen therapy: preliminary results in a series of “failed” patients. Neurosurgery 30:897–903
Zhang W, Hinton DR, Surnock AA, Couldwell WT (1996) Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen, and hypericin: corroborating clinical response in vitro: case report. Neurosurgery 38:587–591
Couldwell WT, Weiss MH, DeGiorgio CM, Weiner LP, Hinton DR, Ehresmann GR, Conti PS, Apuzzo MLJ (1993) Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 32:485–490
Lunardi P, Osman FJ, Mastronardi L, Puzzili F, LoBianco FM (1996) Intravenous administration of high doses of carboplatin in multimodal treatment of high grade gliomas: a phase II study. Acta Neurochir (Wien) 138:215–220
Lee JS, Pisters KM, Komaki R, Glisson BS, Khuri FR, Schea R, Fossella FV (1997) Paclitaxel/carboplatin chemotherapy as primary treatment of brain metastases in non-small cell lung cancer: a preliminary report. Semin Oncol 24:S12
Colleoni M, Graiff C, Nelli P, Vicario G, Sgarbossa G, Pancheri F, Manente P (1997) Activity of combination chemotherapy in brain metastases from breast and lung adenocarcinoma. Am J Clin Oncol 20:303–307
Multani PS, Supko JG, Batchelor TT, Goodman A, Seiden MV (1998) Effective treatment of leptomeningeal metastases from ovarian cancer with topotecan: case report. Cancer Therapeutics 1:33–36
Friedman AH, Ashley DM, Kerby T, Colvin OM, Fields S, Zilisch J, Graden D, Provenzale J, Friedman HS (1998) Topotecan treatment of adults with primary malignant glioma. Proc Am Soc Clin Oncol 17:390a
Schmidt F, Reiger J, Wischhusen J, Naumann U, Weller M (2009) Giloma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA change. Eur J Pharm 412:25
Groves MD, Glantz MJ, Chamberlain MC, Baumgartner KE, Conrad CA, Hus S, Wefel JS, Gilbert MR, Ictech S, Hunter KU, Forman AD, Puduvalli VK, Colman H, Hess KR, Yung WK (2009) A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neurology 10:208–215
Blaney SM, Phillips PC, Packer RJ, Heideman RL, Berg SL, Adamson PC, Alen JC, Sallan SE, Jakacki RI, Lange BJ, Reaman GH, Horowitz ME, Poplack DG, Ballis FM (1996) Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78:527–531
Sung C, Blaney SM, Cole DE, Balis FM, Dedrick RL (1994) A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid. Cancer Res 54:5118–5122
Kaufmann SH, Peereboom D, Buckwalter CA, Svingen PA, Grochow LB, Donehower RC, Rowinsky EK (1996) Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 88:734–741
Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen TL, Peereboom C, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA, Donehower RC (1996) Sequences of topotecan and cisplatin: phase I pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 14:3074–3084
Rowinsky EK, Kaufmann SH (1997) Topotecan in combination chemotherapy. Semin Oncol 24:S20-11–S20-26
Cloughesy T, Filka E, Kuhn J, Nelson G, Kabbinavar F, Friedman H, Miller L, Elfring G (2003) Two studies evaluating irinotecan treatment for recurrent malignant glioma using an every-3-week regimen. Cancer 97:2381–2386
Fetell M, Grossman S, Fisher J, Erlanger B, Rowinsky E, Stockel J, Piantadosi S (1997) Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to breain tumor therapy central nervous system consortium. J Clin Oncol 15:3121–3128
Acknowledgments
This work was supported in part by NCI Cancer Center Support Grant CA 33572, and by GlaxoSmithKline, Inc. This study has been reported in part in Proc. Amer. Soc. Clin. Oncol. 21:2102, 2002, and in Proc Society for Neurooncology in Neuro-Oncology 3:378, 2001.
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Morgan, R.J., Synold, T., Mamelak, A. et al. Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors. Cancer Chemother Pharmacol 66, 927–933 (2010). https://doi.org/10.1007/s00280-010-1242-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-010-1242-z