Carmustin-Wafer in der multimodalen Therapie des Glioblastoma multiforme

Zusammenfassung

Ziel: Retrospektive Analyse über Nutzen und Risiken der Carmustin-Therapie in der multimodalen Therapie des Glioblastoma multiforme.

Material und Methoden: Patienten mit Glioblastoma multiforme wurden zwischen 2008 und 2011 unter Einsatz von Carmustin operiert. Es wurden unerwünschte Ereignisse protokolliert und retrospektiv die Sterbedaten eingeholt.

Ergebnisse: Von 88 operierten Patienten wurde bei 30 Carmustin-Wafer implantiert. 69 unerwünschte Ereignisse traten in beiden Therapiegruppen im postoperativen Verlauf bis zum Versterben der Patienten oder bis zum Untersuchungszeitpunkt auf. Die durchschnittliche Überlebenszeit in der Gruppe der mit Carmustin therapierten Patienten lag bei 385 Tagen versus 343 Tage ohne Carmustin-Therapie (p = 0,41).

Schlussfolgerung und klinische Relevanz: Durch den Einsatz von Carmustin konnte kein Überlebensvorteil, jedoch auch keine erhöhte Toxizität innerhalb des multimodalen Ansatzes für dieses Patientenkollektiv nachgewiesen werden. Trotz des zu erwartenden Nutzens für weniger als 20% aller Glioblastompatienten scheint es sinnvoll, die multimodale Therapie mit Carmustin-Wafern bei selektierten Patientengruppen weiter prospektiv zu erforschen.

Summary

Objective: Retrospective analysis to evaluate benefits and risks of carmustin implants during multimodal therapy of Glioblastoma multiforme.

Materials and methods: Patients with Glioblastoma multiforme were operated between 2008 and 2011 using carmustin. Dates of death were registered retrospectively and adverse events were recorded.

Results: 88 patients were operated during the study. 30 patients received Carmustin. 69 adverse events were recorded. There was no statistical difference between treatment arms. Median survival of all patients was 357 days (minimum 4 days, maximum 1 296 days). Patients receiving Carmustin lived 385 days versus 343 days without Carmustin (p = 0.41).

Conclusion and clinical Relevance: Implantation of Carmustin did not prolong survival, nor did it increase toxicity in this collective. In spite of benefits for less than 20 % of all patients with Glioblastoma multiforme, prospective studies with well selected patient collectives should be conducted.

Schlüsselwörter

Carmustin - Glioblastom - multimodale Therapie - Überlebenszeit

Keywords

Carmustin - glioblastoma - multimodal therapy - survival

• Literatur

• 1 See SJ, Gilbert MR. Chemotherapy in adults with gliomas. Ann Acad Med Singapore 2007; 36 (05) 364-6.
• 2 Kunwar S. et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma”. Neuro-Oncology 2010; 12 (08) 871-81.
• 3 Stupp R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352 (10) 987-96.
• 4 Fleming AB, Saltzman WM. Pharmacokinetics of the carmustine implant. Clinical Pharmacokinetics 2002; 41 (06) 403-19.
• 5 Brem H. et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995; 345: 1008-12.
• 6 Westphal M. et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-Oncology 2003; 05 (02) 79-88.
• 7 Miglierini P, Bouchekoua M, Rousseau B, Dam PHieu, Malhaire JP, Pradier O. Impact of the peroperatory application of Gliadel wafers in combination with TZM and radiotherapy in patients with GBM: Efficacy and toxicity. Clin Neurol and Neurosurg 2012; 114 (09) 1222-5.
• 8 Salvati M, D’elia A, Frati A, Brogna C, Santoro A, Delfini R. Safety and feasibility oft he adjunct of local chemotherapy with biodegradable carmustine wafers tot he standard multimodal approach to high grade gliomas at first diagnosis. J Neurosurg Sc 2011; 55 (01) 1-6.
• 9 Limentani SA, Asher A, Heafner M, Kim JW, Fraser R. A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combanation with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. J Neuro-Oncology 2005; 72: 241-4.
• 10 De Bonis P. et al. Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. Acta Neurochir (Wien) 2012; 154 (08) 1371-8.
• 11 Noël G, Schott R, Froelich S, Gaub MP, Boyer P, Fischer-Lokou D, Dufour P, Kehrli P, Maitrot D. Retrospective comparison of cheotherapy followed by adjuvant chemotherapy, with or without prior Gliadel implantation (Carmustine) after initial surgery in patients with newly diagnosed highgrade gliomas. Int J Radiation Oncology Biol Phys 2012; 82 (02) 749-55.
• 12 Grossman SA, Reinhard C, Colvin OM, Chasin M, Brundrett R, Tamargo RJ, Brem H. The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg 1992; 76 (04) 640-7.
• 13 Nagpal S. The role of BCNU polymer wafers (Gliadel) in the treatment of malignant glioma. Neurosurg Clin 2012; 23: 289-95.
• 14 Whittle IR, Lyles S, Walker M. Gliadel therapy given for first resection of malignant glioma: a single centre study oft he potential use of gliadel. Brit J Neurosurg 2003; 17 (04) 352-4.
• 15 Menei P, Metellus P, Parot-Schinkel E, Loiseau H, Capelle L, Jacquet G, Guyotat J. Biodegradable Carmustine wafers (Gliadel) alone or in combination with chemoradiotherapy: the french experience. Ann Surg Oncol 2010; 17: 1740-6.
• 16 Stummer W. et al. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article. J Neurosurg 2011; 114 (03) 613-23.
• 17 d’Avella D, DellaPuppa A. Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastomas. Acta Neurochir 2012; 154: 1379-81.
• 18 Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Chemotherapy wafers for high grade glioma (Review). The Cochrane Collaboration. John Wiley & Sons; 2011
• 19 Attenello FJ, Mukherjee D, Datoo G, McGirt MJ, Bohan E, Weingart JD, Olivi A, Quinones-Hinojosa A, Brem H. Use of Gliadel wafer in the surgical treatment of malignant glioma: A 10-year institutional experience. Annals of surgical Oncology 2008; 15 (10) 2887-93.
• 20 Barr JG, Grundy PL. The effect of NICE technology appraisal 121 (Gliadel+TMZ) on survival in high-grade glioma. Br J Neurosurg 2012; 26 (06) 812-22.
• 21 Muntasser H, Liaquat I, Barlow A, Whittle I. Gliadel wafers acting as a lattice for bacterial growth: a case illustration. Acta Neurochir 2011; 153: 2099-100.
• 22 Bock HC. et al. First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience. Neurosurg Rev 2010; 33 (04) 441-9.
• 23 Smith KA. et al. Prospective trial of gross-total resection with gliadel followed by early postoperative gamma knife radiosurgery and conformal fractionated radiotherapy as the initial treatment for patients with radiographic suspected newly dianogsed GBM. J Neurosurg 2008; 109 Suppl: 106-17.
• 24 Dörner L, Ulmer S, Rohr A, Mehdorn HM, Nabavi A. Space-occupying cyst development in the resection cavity of malignant gliomas following Gliadel implantation – incidence, therapeutiv strategies, and outcome. J Clin Neurosc 2011; 18: 347-51.
• 25 Sabel M, Giese A. Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Curr Med Res Opin 2008; 24 (11) 3239-57.
• 26 Gallego JM, Barcia JA, Barcia-Mariño C. Fatal outcome related to carmustine implants in GBM. Acta Neurochir (Wien) 2007; 149 (03) 261-5.
• 27 Valtonen S. et al. Interstitial Chemotherapy with Carmustine-loaded Polymers for High-grade Gliomas: A Randomized Double-blind Study. Neurosurgery 1997; 41 (01) 44-8.
• 28 Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. uActa Neurochir 2006; 148: 269-75.
• 29 Dixit S, Hingorani M, Achawal S, Scott I. The sequential use of carmustine wafers and post-operative radiotherapy with concomitant TMZ followed by adjuvant TMZ: a clinical review. Brit J Neurosurg 2011; 25 (04) 459-69.
• 30 Pegg AE, Dolan ME, Moschel RC. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol 1995; 51: 167-223.
• 31 Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS. O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 1999; 05 (04) 807-14.
• 32 Cao VT. et al. The correlation and prognostic significance of MGMT promoter methylation and MGMT Protein in GBM. Neurosurg 2009; 65: 866-75.
• 33 Lechapt-Zalcman E. et al. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer 2012; 118 (18) 4545-54.
• 34 Belanich M. et al. Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res 1996; 56 (04) 783-8.