Abstract
BackgroundTo assess the influence of molecular markers with potential prognostic value to groups of patients with newly diagnosed glioblastoma patients were examined: group A with 36 patients (surgical resection plus standard combined chemoradiotherapy) and group B with 36 patients (surgical resection, standard combined chemoradiotherapy plus carmustine wafer implantation).Our aim was to determine chromosomal alterations, methylation status of MGMT, p15, and p16 (CDKN2A) in order to analyse the influence on patient survival time as well as radio- and chemotherapy responses. Promoter hypermethylation of MGMT, p16, and p15 genes were determined by MS-PCR. Comparative genomic hybridisation (CGH) analyses were performed with isolated, labelled DNA of each tumor to detect genetic alterations.ResultsAge of onset of the disease showed a significant effect on overall survival (OS) (p < 0.0001). Additional treatment with carmustine wafer (group B) compared to the control group (group A) did not result in improved OS (p = 0.562). Patients with a methylated MGMT promotor showed a significant longer OS compared to those patients with unmethylated MGMT promotor (p = 0.041). Subgroup analyses revealed that patients with methylated p15 showed a significant shorter OS when administered to group B rather than in group A (p = 0.0332). In patients additionally treated with carmustine wafer an amplification of 4q12 showed a significant impact on a reduced OS (p = 0.00835). In group B, a loss of 13q was significantly associated with a longer OS (p = 0.0364). If a loss of chromosome 10 occurred, patients in group B showed a significantly longer OS (p = 0.0123).ConclusionA clinical benefit for the widespread use of additional carmustine wafer implantation could not be found. However, carmustine wafer implantation shows a significantly improved overall survival if parts of chromosome 10 or chromosome 13 are deleted. In cases of 4q12 amplification and in cases of a methylated p15 promotor, the use of carmustine wafers is especially not recommended.The MGMT promoter methylation is a strong prognostic Biomarker for benefit from temozolomide and BCNU chemotherapy.
Highlights
To assess the influence of molecular markers with potential prognostic value to groups of patients with newly diagnosed glioblastoma patients were examined: group A with 36 patients and group B with 36 patients
Univariate Cox models of clinical covariates revealed that age of onset of the disease had a statistically significant effect on overall survival (OS) (HR = 1.048, 95% CI = [1.024, 1.072], p < 0.0001)
Methylation analysis We found a methyl-guanine-methyl transferase (MGMT) methylation index (MI) of 58% (21/ 36) in group A and a methylation index of 42% (15/36) in group B
Summary
To assess the influence of molecular markers with potential prognostic value to groups of patients with newly diagnosed glioblastoma patients were examined: group A with 36 patients (surgical resection plus standard combined chemoradiotherapy) and group B with 36 patients (surgical resection, standard combined chemoradiotherapy plus carmustine wafer implantation). Our aim was to determine chromosomal alterations, methylation status of MGMT, p15, and p16 (CDKN2A) in order to analyse the influence on patient survival time as well as radio- and chemotherapy responses. MGMT [21]: (methylated, 122 bp, 54 °C) forward: 5′-GTTTTTAGAACGTT TTGCGTTTCGAC-3′ reverse: 5′-CACCGTCCCGAAA AAAAACTCCG-3′ (unmethylated, 129 bp, 56 °C) forward: 5′-TGTGTTTTTAGAATG TTTTGTGTTTTGAT-3′ reverse: 5′-CTACCACCATCCCA AAAAAAAACTCCA-3′ p16 [23]:. Some authors showed a benefit regarding overall survival (OS) when carmustin wafers were implanted postresectionally [7, 8]. Whether carmustine wafer implantation is recommendable or not could depend on patients’ individual (genetic) characteristics
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