BackgroundAt recurrence the use of nitrosoureas is widely-used as a therapeutic option for glioblastoma (GBM) patients. The efficacy of fotemustine (FTM) has been demonstrated in phase II clinical trials; however, these papers report a wide range of progression-free-survival (PFS-6 m) rates, ranging from 21% to 52%. We investigated whether FTM could have a different response pattern in respect to time to adjuvant temozolomide failure, or whether specific independent risk factors could be responsible for the wide range of response rates observed.MethodsRecurrent GBM patients have been treated with fotemustine 75-100 mg/sqm at day 1, 8, 15 and after 4/5 weeks of rest with 100 mg/sqm every 21 days. Patients were stratified in 4 groups according to time to temozolomide failure: before starting (B0), during the first 6 months (B1), after more than 6 months of therapy (B2), and after a treatment-free interval (B3). Primary endpoint was PFS-6 m. A multivariable analysis was performed to identify whether gender, time after radiotherapy, second surgery and number of TMZ cycles could be independent predictors of the clinical benefit to FTM treatment.Results163 recurrent GBM patients were included in the analysis. PFS-6 m rates for the B0, B1, B2 and B3 groups were 25%, 28%, 31.1% and 43.8%, respectively. The probability of disease control was higher in patients with a longer time after radiotherapy (p = 0.0161) and in those who had undergone a second surgery (p = 0.0306).ConclusionsFTM is confirmed as a valuable therapeutic option for patients with recurrent GBM and was active in all study patient groups. Time after the completion of radiotherapy and second surgery are independent treatment-related risk factors that were predictive of clinical benefit.

We investigated the sensitivity and specificity of [11C]-methionine positron emission tomography ([11C]-MET PET) in the management of glioma patients. We retrospectively analysed data from 53 patients with primary gliomas (16 low grade astrocytomas, 15 anaplastic astrocytomas and 22 glioblastomas) and Karnofsky Performance Status (KPS) > 70. Patients underwent [11C]-MET PET scans (N = 249) and parallel contrast-enhanced MRI (N = 193) and/or CT (N = 113) controls. In low grade glioma patients, MRI or CT findings associated with [11C]-MET PET additional data allowed discrimination residual disease from postsurgical changes in 96.22% of these cases. [11C]-MET PET early allowed detection of malignant progression from low grade to anaplastic astrocytoma with high sensitivity (91.56%) and specificity (95.18%). In anaplastic astrocytomas, we registered high sensitivity (93.97%) and specificity (95.18%) in the postoperative imaging and during the followup of these patients. In GBM patients, CT and/or MRI scans with additional [11C]-MET PET data registered a sensitivity of 96.92% in the postsurgical evaluation and in the tumour assessment during temozolomide therapy. A significant correlation was found between [11C]-MET mean uptake index and histologic grading (P < 0.001). These findings support the notion that complementary information derived from [11C]-MET PET may be helpful in postoperative and successive tumor assessment of glioma patients.

Abstract. O6 -alkylguanine-DNA alkyltransferase (AGAT), involved in temozolomide-induced DNA damage repair, plays a key role in the efficacy of temozolomide. AGAT activity may be reduced by protracted temozolomide doses. On the basis of the preclinical findings, we treated patients with a histologically-proven diagnosis of glioblastoma (GBM) following adjuvant temozolomide failure with a low protracted dose of temozolomide (130 mg/m 2 /day, days 1-7 and 15-21, every 4 weeks). The primary endpoint of the study was 6-month progression-free survival (PFS-6 m). The secondary endpoints were overall survival (OS) from the start of temozolomide alternative schedule and toxicity. Enrolment was ceased at 27 patients due to the lack of effectiveness of this regimen. Results indicate that our schedule is well-tolerated, but ineffective in patients with GBM and further strategies are required to improve the outcome of these patients. IntroductionAlthough temozolomide is considered to be the backbone in the treatment of brain tumors, the results are not particularly favorable. Its efficacy is limited by the presence of intrinsic or acquired resistance mechanisms (1). Temozolomide exerts its activity by DNA methylation at the N 7 and O 6 positions of guanine and at the O 3 position of adenine (2). The O6-methylguanine-DNA methyltransferase (MGMT) gene is located on chromosome 10q26 and encodes a DNA repair enzyme, O 6 -alkylguanine-DNA-alkyltransferase (AGAT), that counteracts the effects of alkylating cytotoxic drugs by removing methyl adducts from the O 6 position of guanine.In malignant gliomas, the MGMT gene is often inactivated due to aberrant methylation of its promoter region (3). Thus, MGMT promoter methylation status has become clinically relevant as a molecular marker associated with response to alkylating chemotherapy and survival of glioblastoma (GBM) patients (4). Protracted exposure to an alkylating agent may inactivate enzyme activity by saturating the AGAT available copies and newly synthesized molecules, overcoming the inherent resistance of glioma cells (5). A phase I study demonstrated that a protracted low-dose temozolomide schedule (75 mg/m 2 /day, for 21 days, every 28 days) was well-tolerated with a dose-limiting toxicity by thrombocytopenia. The maximum tolerated dose was 100 mg/m 2 (6). Based on the data, we assessed the effects of a prolonged temozolomide schedule (130 mg/m 2 /day on days 1-7 and 15-21) in GBM patients following adjuvant temozolomide failure. Materials and methodsPatients. The study was originally designed for 50 patients, however, only 27 patients were enrolled. We treated consecutive recurrent GBM patients following chemoradiation treatment with temozolomide and a sequentially failing adjuvant temozolomide schedule (200 mg/m 2 /day, days 1-5, every 4 weeks) (7). All patients had undergone previous surgery followed by standard radiotherapy (60 Gy/30 fractions). Patient characteristics are summarized in Table I. This study was approved by the ethics committee of the Polytechnic Unive...

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