Temozolomide and radiotherapy in newly diagnosed glioblastoma patients: O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status and Ki-67 as biomarkers for survival and response to treatment

Abstract

This phase II study aimed at investigating the correlation between O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and protein expression, together with Ki-67 labeling index (LI), to response, time to progression (TTP), and overall survival (OS) in newly diagnosed glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ) concomitant with and adjuvant to radiotherapy (RT). From June 2005 to August 2008, 34 adult patients (18–65 years), PS ≥70, with newly diagnosed GBM received TMZ 75 mg/m2 plus RT up to 60 Gy, followed by TMZ 175 mg/m2 5 days every 4 weeks for 12 doses. MGMT Methylation-specific PCR assay, MGMT protein expression, and Ki-67 expression using immunohistochemistry (IHC) were performed on the tissue blocks. The patients were followed by MRI while MR spectroscopy (MRS) was performed for the stable cases or to confirm progression and accordingly Bevacizumab 10 mg/kg every 2 weeks was added to 7 patients till further progression was proved. 31 cases were evaluable, 12 (38.7%) had unmethylated MGMT, while 19 (61.3%) were methylated. Seventeen cases (55%) were MGMT immunonegative while 14 cases (45%) were immunopositive. The cut off value of Ki-67 LI in relation to survival was 17%, where 15 were < 17% (48.4%), and 16 were ≥ 17% (51.6%). Response evaluation started after the second dose of the adjuvant TMZ and was repeated every 2 months. The overall disease control rate (ODC) was 74.2%, where 2 patients had complete response (CR), 14 had partial response (PR), and 7 had stable disease (SD), while 8 (25.8%) had progressive disease (PD). The ODC was significantly higher among methylated patients and in those with Ki-67 < 17% (P = 0.0003). The median overall TTP was 12 months and the median OS was 20 months for all the patients including those who received Bevacizumab for some stable cases or as a salvage treatment in patients with good PS, the MGMT-methylated patients had a higher median TTP of 13 months (range 8 to 18 months, 95% CI of 9.36 to 12.9), and OS of 24 months (range 12 to 31 months, 95% CI of 16.1 to 21.32), while the unmethylated patients had a median TTP of 6.5 months and a median OS of 12 months, such correlations were highly significant (P = 0.0001). MGMT immunoexpression failed to show significant correlation with MGMT promotor methylation or the outcome of the patients. Patients with Ki-67 < 17% had a median TTP of 16 months and median OS of 24 months compared to 7 and 12.5 months respectively for the patients with Ki-67 ≥17%. Significant correlation was found between the ODC, TTP, and OS with age < 52, near total excision, and TMZ doses received ≥ 10. The commonest grade 3 and 4 toxicities was neutropenia recorded in 3 patients (9.67%), thrombocytopenia in 4 patients (12.9%), and one patient with G3 nausea, vomiting, and constipations (3%), all were medically manageable. MGMT promotor methylation status and Ki-67 LI (but not the MGMT protein expression), could serve as prognostic markers for survival, also MGMT could identify the newly diagnosed GBM patients who will have better response to TMZ.