Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without prior gliadel implantation (carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas.

PURPOSE Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol. METHODS AND MATERIALS Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months. RESULTS Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2-7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2-20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2-20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27-229), whereas it was 68 mL (10-362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group. CONCLUSION In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival.

[1]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[2]  J. Herman,et al.  Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. , 1999, Cancer research.

[3]  E. Pan,et al.  A retrospective study of the safety of BCNU wafers with concurrent temozolomide and radiotherapy and adjuvant temozolomide for newly diagnosed glioblastoma patients , 2008, Journal of Neuro-Oncology.

[4]  W. Mark Saltzman,et al.  Chemotherapeutic Drugs Released from Polymers: Distribution of 1,3-bis(2-chloroethyl)-l-nitrosourea in the Rat Brain , 1996, Pharmaceutical Research.

[5]  S. Piantadosi,et al.  Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas , 1995, The Lancet.

[6]  J. Herman,et al.  Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. , 2000, Cancer research.

[7]  G. Reifenberger,et al.  MGMT promoter methylation in malignant gliomas: ready for personalized medicine? , 2010, Nature Reviews Neurology.

[8]  S. Gerson.  MGMT: its role in cancer aetiology and cancer therapeutics , 2004, Nature Reviews Cancer.

[9]  L. Recht,et al.  Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas , 2003, Cancer.

[10]  M. McGirt,et al.  Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. , 2009, Journal of neurosurgery.

[11]  M. J. van den Bent,et al.  MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  J. Villemure,et al.  Metabolic disposition and elimination studies of a radiolabelled biodegradable polymeric implant in the rat brain. , 1994, Biomaterials.

[13]  M. Sanson,et al.  Up-front temozolomide in elderly patients with glioblastoma , 2010, Journal of Neuro-Oncology.

[14]  R. McLendon,et al.  Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. , 2001, Neuro-oncology.

[15]  M. Dolan,et al.  Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. , 1992, Journal of the National Cancer Institute.

[16]  M. Christmann,et al.  MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. , 2007, DNA repair.

[17]  S. Goodman,et al.  Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. , 2002, Journal of the National Cancer Institute.

[18]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Brian J. Smith,et al.  Treatment of adults with newly diagnosed glioblastoma multiforme or anaplastic astrocytoma with surgery, gliadel wafers and limited field radiation plus concomitant temozolomide followed by adjuvant temozolomide , 2008 .

[20]  Manfred Westphal,et al.  A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. , 2003, Neuro-oncology.

[21]  M R Grever,et al.  Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. , 1994, Cancer research.

[22]  E. Bruera,et al.  Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  L. Stribinskiene,et al.  A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients (pts) with newly diagnosed supratentorial high grade malignant glioma (MG) who have undergone surgery with carmustine (BCNU) wafer insertion , 2005 .

[24]  B. Spiegel,et al.  Clinical Impact of Adjuvant Chemotherapy in Glioblastoma Multiforme , 2007, CNS drugs.

[25]  R. Tamargo,et al.  Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain. , 1993, Cancer research.

[26]  Z. Ram,et al.  Gliadel® wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial , 2006, Acta Neurochirurgica.

[27]  S. Markowitz,et al.  Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. , 1996, Cancer research.

[28]  R. Mirimanoff,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. , 2009, The Lancet. Oncology.

[29]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[30]  H Kalimo,et al.  Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. , 1997, Neurosurgery.

[31]  G. Reifenberger,et al.  NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Klaus Sartor,et al.  Early Postoperative Magnetic Resonance Imaging after Resection of Malignant Glioma: Objective Evaluation of Residual Tumor and Its Influence on Regrowth and Prognosis , 1995 .

[33]  E. Newlands,et al.  3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. , 1996, British Journal of Cancer.