Background. Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. Patients and methods. The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 or 125 mg/m2) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated.
Results. Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0-2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed.
Conclusions. In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.
1. WHO Classification of tumours of the central nervous system. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. Lyon: IARC Press; 2007.
2. CBTRUS, Central Brain Tumor Registry of the United States. 2007-2008. Primary brain tumors in the United States. Statistical report. 2000-2004 years of data collected. Available from: http://www.cbtrus.org/reports/2007-2008/2007report.pdf. Accessed on 10 November 2013.
3. Kase M, Minajeva A, Niinepuu K, Kase S, Vardja M, Asser T, et al. Impact of CD133 positive stem cell proportion on survival in patients with glioblastoma multiforme. Radiol Oncol 2013; 47: 405-10.
4. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin 2007; 25: 867-90.
5. Smrdel U, Kovac V, Popovic M, Zwitter M. Glioblastoma patients in Slovenia from 1997 to 2008. Radiol Oncol 2014; 48: 72-9.
6. Zakelj MP, Zadnik V, Zagar T, Zakotnik B. Survival of cancer patients, diagnosed in 1991-2005 in Slovenia. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2009. p. 229.
7. Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 2010; 60: 166-93.
8. Podergajs N, Brekka N, Radlwimmer B, Herold-Mende C, Talasila KM, Tiemann K, et al. Expansive growth of two glioblastoma stem-like cell lines is mediated by bFGF and not by EGF. Radiol Oncol 2013; 47: 330-7.
9. Stupp R, Mason PW, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-96.
10. Stupp R, Hegi EM, Mason PW, van den Bent MJ, Taphoorn JBM, Janzer CR, et al. 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 2009; 10: 459-66
11. Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 2005; 63: 47-55.
12. Blamek S, Larysz D, Miszczyk L, Idasiak A, Rudnik A, Tarnawski R. Hypofractionated stereotactic radiotherapy for large or involving critical organs cerebral arteriovenous malformations. Radiol Oncol 2013; 47: 50-6.
13. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 2005; 23: 8863-9.
14. Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 2008; 112: 2046-51.
15. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse: Temodal Brain Tumor Group. J Clin Oncol 1999; 17: 2762-71. [Erratum in J Clin Oncol 1999; 17: 3693.]
16. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999; 17: 2572-8.
17. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000; 83: 588-93.
18. Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, Ermani M. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology 2004; 63: 1281-4.
19. Schmidt F, Fischer J, Herrlinger U, Dietz K, Dichgans J, Weller M. PCV chemotherapy for recurrent glioblastoma. Neurology 2006; 66: 587-9.
20. Loscalzo J, Kohane I, Barabasi AL. Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol 2007; 3: 124.
21. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27: 740-5.
22. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27: 4733-40.
23. Cloughesy T, Vredenburgh JJ, Day B, Das A, Friedman HS. Updated safety and survival of patients with relapsed glioblastoma treated with bevacizumab in the BRAIN study. [Abstract]. J Clin Oncol 2010; 28(Suppl 15 ): No. 2008.
24. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 2007; 25: 4714-21.
25. Vredenburgh JJ, Desjardins AHJE, Marcello J, Reardon DA, Quinn JA, Rich JN, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007; 25: 4722-9.
26. Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 2008; 112: 2267-73.
27. Guiu S, Taillibert S, Chinot O, Taillandier L, Honnorat J, Dietrich PY, et al. [Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. [French]. Rev Neurol (Paris) 2008, 164: 588-94.
28. Ali SA, McHayleh WM, Ahmad A, Sehgal R, Braffet M, Rahman M, et al. Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J Neurosurg 2008; 109: 268-72.
29. Desjardins A, Reardon DA, Herndon JE, Marcello J, Quinn JA, Rich JN, et al. Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas. Clin Cancer Res 2008; 14: 7068-73.
30. Kang TY, Jin T, Elinzano H, Peereboom D. Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J Neurooncol 2008; 89: 113-8.
31. Poulsen HS, Grunnet K, Sorensen M, Olsen P, Hasselbalch B, Nelausen K, et al. Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours. Acta Oncol 2009; 48: 52-8.
32. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, et al. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 2009; 91: 329-36.
33. NCCN clinical practical guidelines in oncology. Central nervous system cancer. Version 2.2013. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed on 4 November 2013.
34. Stupp R, Tonn JC, Brada M, Pentheroudakis G. High grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl 5): v190-3.
35. Xu T, Chen J, Lu Y, Wolff JEA. Effectstof bevacizumab plus irinotecan on response and survival in patients with recurrent malignant glioma: a systematic review and survival-gain analysis. BMC Cancer 2010, 10: 252.