Evaluation of toxicity of carmustine with or without bevacizumab in patients with recurrent or progressive high grade gliomas
An increased incidence in hematologic toxicity has been reported with the addition of bevacizumab to lomustine for patients with recurrent or progressive high grade gliomas (HGG). Data regarding incidence of toxicity with combination bevacizumab and carmustine is limited. The purpose of this study is to compare toxicity of single agent carmustine and carmustine plus bevacizumab for patients with HGGs.
This single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with age ≥ 18 years who received carmustine between January 2003 and May 2017.
Sixty-five patients with HGGs collectively received 110 doses of BCNU during the specified time period. Sixteen patients received single agent BCNU (30 doses); 49 patients received combination bevacizumab with BCNU (80 doses). There was no significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, leukopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Rates of grade 3 and 4 neutropenia (20% vs 13.8%, p = 0.55) and thrombocytopenia (23.3% vs 23.8%, p = 1) did not differ between single agent BCNU versus combination therapy. When stratified based on dose ( < 150 mg/m2, 150 mg/m2, > 150 mg/m2), there was no statistically significant difference between the two groups with respect to grade 3 and 4 neutropenia or thrombocytopenia.
This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. The addition of bevacizumab to carmustine did not increase incidence or grade of hematologic toxicity when compared to single agent carmustine.
KeywordsHigh grade glioma Carmustine BCNU Nitrosurea Bevacizumab Glioblastoma
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by PY and SNR. The first draft of the manuscript was written by PY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.National Comprehensive Cancer Network (2019) Central nervous system cancers (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed August 8, 2019
- 2.Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff R-O (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. https://doi.org/10.1016/S1470-2045(09)70025-7 CrossRefGoogle Scholar
- 3.Gorlia T, Stupp R, Brandes AA, Rampling RR, Fumoleau P, Dittrich C, Campone MM, Twelves CC, Raymond E, Hegi ME, Lacombe D, van den Bent MJ (2012) New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur J Cancer 48:1176–1184. https://doi.org/10.1016/j.ejca.2012.02.004 CrossRefGoogle Scholar
- 4.Nabors LB, Portnow J, Baehring J, Brem H, Brown P, Butowski N, Chamberlain MC, Fenstermaker RA, Friedman A, Gilbert MR, Hattangadi-Gluth J, Holdhoff M, Junck L, Kaley T, Lawson R, Loeffler JS, Lovely MP, Moots PL, Mrugala MM, Newton HB, Parney I, Raizer JJ, Recht L, Shonka N, Shrieve DC, Sills AK Jr, Swinnen LJ, Tran D, Tran N, Vrionis FD, Weiss S, Wen PY, McMillian N, Engh AM (2015) Central nervous system cancers, version 1.2018. J Natl Compr Cancer Netw 13:1191–1202CrossRefGoogle Scholar
- 5.Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330 CrossRefGoogle Scholar
- 6.Avastin (Bevacizumab) (2014) Prescribing information. Genentech Inc, San Francisco, CAGoogle Scholar
- 7.Gliadel (Carmustine Wafers) (2013) Prescribing information. In: Arbor Pharmaceuticals L (ed). Atlanta, GAGoogle Scholar
- 8.Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH (2012) NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48:2192–2202. https://doi.org/10.1016/j.ejca.2012.04.011 CrossRefGoogle Scholar
- 9.BiCNU (carmustine for injection) (2007) Prescribing information. In: Company B-MS (ed). Princeton, NJGoogle Scholar
- 10.Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15:943–953. https://doi.org/10.1016/s1470-2045(14)70314-6 CrossRefGoogle Scholar
- 11.Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ (2017) Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377:1954–1963. https://doi.org/10.1056/NEJMoa1707358 CrossRefGoogle Scholar
- 12.Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. https://doi.org/10.1200/jco.2009.26.3541 CrossRefGoogle Scholar
- 13.Rahman R, Hempfling K, Norden AD, Reardon DA, Nayak L, Rinne ML, Beroukhim R, Doherty L, Ruland S, Rai A, Rifenburg J, LaFrankie D, Alexander BM, Huang RY, Wen PY, Lee EQ (2014) Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. Neuro-oncology 16:1523–1529. https://doi.org/10.1093/neuonc/nou118 CrossRefGoogle Scholar
- 16.van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268–1274. https://doi.org/10.1200/jco.2008.17.5984 CrossRefGoogle Scholar