Introduction and objective:
Gliomas are a highly heterogenous group of tumours of the nervous system. They are characterized by a varied course of disease. Depending on the cancer stage, they affect overall survival and progression-free survival. In view of the varied disease course, an individualized chemotherapeutic regimen is the most significant treatment.The aim of the study is to present up-to-date information on the most important cytostatic drugs used in the treatment of glioma.

Review methods:
A review of previous knowledge and the latest scientific reports was undertaken using the publication databases PubMed, Web of Science and Scopus, focusing mainly on articles from the last five years. The key words and their combinations used for the search were consistent with the MeSH browser: glioma, cytostatic agents, temozolomide, procarbazine, lomustine, vincristine, bevacizumab.

Brief description of the state of knowledge:
In the treatment of gliomas, temozolomide, lomustine, procarbazine, vincristine and bevacizumab are used. Combination therapy based on multi-drug regimens or chemotherapy combined with radiation therapy is also often used. Current therapies include cytostatic drugs, such temozolomide (TMZ), combination therapy with vincristine (VCR), lomustine (CNNU) and procarbazine, which is referred to as PCV therapy. The review includes the most important and recent information of chemotherapeutic drugs used in the treatment of gliomas i.e.: temozolomide, lomustine, procarbazine, vincristine and bevacizumab. The review contains information about the mechanisms of action, current scientific studies on combination therap, and potential adverse effects of the described drugs.

The latest results of drug interaction studies confirm the need for further research into combination therapy regimens using both newl-discovered therapeutics and combinations of already known drugs.

Taal W, Bromberg JE, van den Bent MJ. Chemotherapy in glioma. CNS Oncol. 2015; 4(3): 179–92. doi: 10.2217/cns.15.2.
Ostrom QT, Gittleman H, Stetson L, et al. Epidemiology of gliomas. Cancer Treat Res. 2015; 163: 1–14. doi: 10.1007/978-3-319-12048-5_1.
Wang W, Shi G, Ma B, et al. Chemotherapy for Adults with Malignant Glioma: A Systematic Review and Network Meta-Analysis. Turk Neurosurg. 2017; 27(2): 174–181. doi: 10.5137/1019-5149.JTN.15462-15.0.
Chen X, Zhang M, Gan H, et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat Commun. 2018; 9(1): 2949. doi: 10.1038/s41467-018-05373-4.
Choi S, Yu Y, Grimmer MR, et al. Temozolomide-associated hypermutation in gliomas. Neuro Oncol. 2018; 20(10): 1300–1309. doi: 10.1093/neuonc/noy016.
Kaina B, Christmann M. DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas. DNA Repair (Amst). 2019; 78: 128–141. doi: 10.1016/j.dnarep.2019.04.007.
Kim IH, Park CK, Heo DS, et al. Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial. J Neurooncol. 2011; 103(3): 595–602. doi: 10.1007/s11060-010-0427-y.
Xu X, Stockhammer F, Schmitt A, et al. Therapeutical doses of temozolomide do not impair the function of dendritic cells and CD8+ T cells. Int J Oncol. 2012; 40(3): 764–72. doi: 10.3892/ijo.2011.1269.
Ellsworth S, Balmanoukian A, Kos F, et al. Sustained CD4+ T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide. Oncoimmunology. 2014; 3(1): e27357. doi: 10.4161/onci.27357.
Matsuda M, Yamamoto T, Ishikawa E, et al. Profile Analysis of Chemotherapy-induced Nausea and Vomiting in Patients Treated with Concomitant Temozolomide and Radiotherapy: Results of a Prospective Study. Neurol Med Chir (Tokyo). 2015; 55(9): 749–55. doi: 10.2176/nmc.oa.2014-0413.
Charakterystyka Produktu Leczniczego Avastin: [access: 25.04.2021].
Kim MM, Umemura Y, Leung D. Bevacizumab and Glioblastoma: Past, Present, and Future Directions. Cancer J. 2018; 24(4): 180–186. doi: 10.1097/PPO.0000000000000326.
Chinot OL, de La Motte Rouge T, Moore N, et al. AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther. 2011; 28(4): 334–40. doi: 10.1007/s12325-011-0007-3.
Jahangiri A, De Lay M, Miller LM, et al. Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res. 2013; 19(7): 1773–83. doi: 10.1158/1078-0432.CCR-12-1281.
Tamura R, Tanaka T, Miyake K, et al. Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget. 2016; 7(32): 52423–52435. doi: 10.18632/oncotarget.9387.
Ghiaseddin A, Peters KB. Use of bevacizumab in recurrent glioblastoma. CNS Oncol. 2015; 4(3): 157–69. doi: 10.2217/cns.15.8.
van den Bent MJ, Klein M, Smits M, et al. Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol. 2018; 19(9): 1170–1179. doi: 10.1016/S1470-2045(18)30362-0.
Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8): 709–22. doi: 10.1056/NEJMoa1308345.
Platten M. EGFRvIII vaccine in glioblastoma-InACT-IVe or not ReACTive enough? Neuro Oncol. 2017; 19(11): 1425–1426. doi: 10.1093/neuonc/nox167.
van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013; 31(3): 344–50. doi: 10.1200/JCO.2012.43.2229.
Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 2020; 87: 102029. doi: 10.1016/j.ctrv.2020.102029.
Gurgul A. Substancje pochodzenia roślinnego w terapii nowotworów. Postępy Fitoter. 2017; 18(3): 203–208.
De Witt M, Gamble A, Hanson D, et al. Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Mol Med. 2017; 23: 50–56. doi: 10.2119/molmed.2017.00011.
Brings A, Lehmann ML, Foerster KI, et al. Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers. Br J Clin Pharmacol. 2019; 85(7): 1528–1537. doi: 10.1111/bcp.13934.
Diouf B, Evans WE. Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy: Progress Continues. Clin Pharmacol Ther. 2019; 105(2): 315–317. doi: 10.1002/cpt.1209.
Hafazalla K, Sahgal A, Jaja B, et al. Procarbazine, CCNU and vincristine (PCV) versus temozolomide chemotherapy for patients with low-grade glioma: a systematic review. Oncotarget. 2018; 9(72): 33623–33633. doi: 10.18632/oncotarget.25890.
Parasramka S, Talari G, Rosenfeld M, et al. Procarbazine, lomustine and vincristine for recurrent high-grade glioma. Cochrane Database Syst Rev. 2017; 7(7): CD011773. doi: 10.1002/14651858.CD011773.pub2.
Goernera R, Bogdahn U, Hau P. Procarbazine--a traditional drug in the treatment of malignant gliomas. Curr Med Chem. 2008; 15(14): 1376–87. doi: 10.2174/092986708784567707.
Kim SH, Yoo H, Chang JH, et al. Procarbazine and CCNU Chemo-therapy for Recurrent Glioblastoma with MGMT Promoter Methylation. J Korean Med Sci. 2018; 33(24): e167. doi: 10.3346/jkms.2018.33.e167.
Armand JP, Ribrag V, Harrousseau JL, Abrey L. Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors. Ther Clin Risk Manag. 2007; 3(2): 213–24. doi: 10.2147/tcrm.2007.3.2.213.
Wang R, Zhang C, Zheng C, et al. Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression. Bioorg Chem. 2019; 83: 461–467. doi: 10.1016/j.bioorg.2018.11.011.
Jutras G, Bélanger K, Letarte N, et al. Procarbazine, lomustine and vincristine toxicity in low-grade gliomas. Curr Oncol. 2018; 25(1): e33-e39. doi: 10.3747/co.25.3680.
Solimando DA Jr, Waddell JA. Procarbazine, Lomustine, and Vincristine (PCV) Regimen for Central Nervous System Tumors. Hosp Pharm. 2017; 52(2): 98–104. doi: 10.1310/hpj5202-98.
Donovan LE, Lassman AB. Chemotherapy Treatment and Trials in Low-Grade Gliomas. Neurosurg Clin N Am. 2019; 30(1): 103–109. doi: 10.1016/
Keogh RJ, Aslam R, Hennessy MA, et al. One year of procarbazine lomustine and vincristine is poorly tolerated in low grade glioma: a real world experience in a national neuro-oncology centre. BMC Cancer. 2021; 21(1): 140. doi: 10.1186/s12885-021-07809-5.
Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med. 2016; 374(14): 1344–1355. doi: 10.1056/nejmoa1500925.
Mondesir J, Willekens C, Touat M, de Botton S. IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016; 7: 171–80. doi: 10.2147/JBM.S70716.
Han S, Liu Y, Cai SJ, et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020; 122(11): 1580–1589. doi: 10.1038/s41416-020-0814-x.
Li F, He X, Ye D, et al. NADP(+)-IDH Mutations Promote Hyper-succinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol Cell. 2015; 60(4): 661–75. doi: 10.1016/j.molcel.2015.10.017.
Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 2016; 18(1) 16–26. doi: 10.1093/neuonc/nov136.
Krell D, Assoku M, Galloway M, et al. Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. PLoS One. 2011; 6(5): e19868. doi: 10.1371/journal.pone.0019868.
Miller JJ, Shih HA, Andronesi OC, Cahill DP. Isocitrate dehydrogenase-mutant glioma: Evolving clinical and therapeutic implications. Cancer. 2017; 123(23): 4535–4546. doi: 10.1002/cncr.31039.
Pientka FK, Hu J, Schindler SG, et al. Oxygen sensing by the prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartmentalisation on HIF-1 signalling. J Cell Sci. 2012; 125(Pt 21): 5168–76. doi: 10.1242/jcs.109041.
Tom MC, Cahill DP, Buckner JC, et al. Management for Different Glioma Subtypes: Are All Low-Grade Gliomas Created Equal? Am Soc Clin Oncol Educ Book. 2019; 39: 133–145. doi: 10.1200/EDBK_238353.
Irfan N, Samuel E, Rafi Ranjha F, et al. Toxicity Profile of Procarbazine Lomustine and Vincristine Chemotherapy in Low-Grade Glioma – Retrospective Review. Cureus. 2020; 12(10): e11070. doi: 10.7759/cureus.11070.
Buckner JC, Gesme D Jr, O’Fallon JR, et al. Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities. J Clin Oncol. 2003; 21(2): 251–5. doi: 10.1200/JCO.2003.06.023.
McDuff SGR, Dietrich J, Atkins KM, et al. Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV. Cancer Med. 2020; 9(1): 3–11. doi: 10.1002/cam4.2686.
Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015; 372(26): 2499–508. doi: 10.1056/NEJMoa1407279.
Nama N, Barker MK, Kwan C, et al. Vincristine-induced peripheral neurotoxicity: A prospective cohort. Pediatr Hematol Oncol. 2020; 37(1): 15–28. doi: 10.1080/08880018.2019.1677832.
Park SH, Kim MJ, Jung HH, et al. One-Year Outcome of Multiple Blood-Brain Barrier Disruptions With Temozolomide for the Treatment of Glioblastoma. Front Oncol. 2020; 10: 1663. doi: 10.3389/fonc.2020.01663.
Journals System - logo
Scroll to top