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A Phase I Study of High-dose BCNU, Etoposide and Escalating-dose Thiotepa (BTE) with Hematopoietic Progenitor Cell Support in Adults with Recurrent and High-risk Brain Tumors

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Abstract

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500–800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n=18) or both PBPC and marrow (n=4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5×109/l was 10 days (range 8–30 days). Platelet engraftment >20×109/l occurred after 11 days (range 9–65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho=−0.78, p=0.001) and platelet engraftment (rho=−0.76, p=0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

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Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, Columbia University College of Physicians and Surgeons, NY, USA

    Kyriakos P. Papadopoulos, Elizabeth Kaufman, Linda T. Vahdat, David G. Savage, Karen H. Antman & Charles S. Hesdorffer

  2. Department of Neurology, Columbia University College of Physicians and Surgeons, NY, USA

    Casilda Balmaceda & Michael Fetell

  3. Department of Neuro-Surgery, Columbia University College of Physicians and Surgeons, NY, USA

    Jeffrey Bruce & Michael Sisti

  4. Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, NY, USA

    Steven Isaacson

  5. Department of Neuro-Radiology, Columbia University College of Physicians and Surgeons, NY, USA

    Robert De LaPaz

  6. Department of Biostatistics, Columbia University College of Physicians and Surgeons, NY, USA

    Andrea Troxel

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  1. Kyriakos P. Papadopoulos
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  2. Casilda Balmaceda
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  3. Michael Fetell
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  4. Elizabeth Kaufman
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  5. Linda T. Vahdat
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  6. Jeffrey Bruce
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  7. Michael Sisti
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  8. Steven Isaacson
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  9. Robert De LaPaz
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  10. David G. Savage
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  11. Andrea Troxel
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  12. Karen H. Antman
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  13. Charles S. Hesdorffer
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Papadopoulos, K.P., Balmaceda, C., Fetell, M. et al. A Phase I Study of High-dose BCNU, Etoposide and Escalating-dose Thiotepa (BTE) with Hematopoietic Progenitor Cell Support in Adults with Recurrent and High-risk Brain Tumors. J Neurooncol 44, 155–162 (1999). https://doi.org/10.1023/A:1006391619009

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  • DOI: https://doi.org/10.1023/A:1006391619009

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