Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

BACKGROUND: Standardized salvage treatment has not yet proved effective in glioblastoma multiforme (GBM) patients who receive prior standard radiotherapy plus concomitant and adjuvant temozolomide. METHODS: Patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg m(2)) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m(2)) every 3 weeks for < or =1 year. RESULTS: Forty-three patients (29 M, 14 F; median age 51 years, range 34-68; median KPS 90) were enrolled. Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: 9-33%); three patients (7.1%) had partial response (PR); 15 (34.9%), disease stabilization (SD). The median survival was 6 months (95% CI: 5-7). MGMT promoter status was methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease control was 75% versus 34.6% in methylated and unmethylated MGMT patients (P = 0.044); no significant difference was found between groups for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 20.9 and 16.3% of patients, during the induction phase, and in 0 and 9.5% patients during the maintenance phase, respectively. CONCLUSIONS: The findings of the present trial, that evaluate fotemustine in a homogeneous population, may represent a new benchmark for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing GBM previously treated with radiotherapy and temozolomide.

Temozolomide three weeks on and one week off as first line therapy for patients with recurrent or progressive low grade gliomas.

BACKGROUND: Patients with recurrent or progressive low grade gliomas survive for a decade or more following diagnosis, and may be at a higher risk for treatment-related complications, such as cognitive impairment from radiotherapy. PURPOSE: The aim of the present study was to determine in patients with progressive or recurrent low grade gliomas, the response rate and toxicity incurred by a continued schedule of temozolomide chemotherapy administered before radiation therapy, and to explore correlations between response and survival with 1p/19q deletions and MGMT promoter methylation status. METHODS: Progressive radio and chemotherapy naïve low grade glioma patients with O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) promoter status evaluation were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days for 12 cycles. RESULTS: A total of 30 patients (median age 45 [range: 24.2-68.6] years) with a median KPS of 90 (range 60-90) were accrued. The overall response rate was 30% (9 partial responses); 17 patients (56.7%) had disease stabilization. CONCLUSION: The prolonged temozolomide schedule considered in the present study is followed by a high response rate; toxicity is acceptable. Further randomized trials should therefore be conducted to confirm the efficacy of this regimen as first-line therapy in patients with progressive low grade glioma.

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO).

The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

Is protracted low-dose temozolomide feasible in glioma patients?

The authors investigated the safety of 75 mg/m2 temozolomide for 21 days every 28 days in glioma patients. This schedule could lead to DNA repair enzyme O6-alkylguanine-DNA alkyltransferase depletion, contributing to overcoming drug resistance. Although Phase III studies are forthcoming, no data are available on the long-term toxicity of temozolomide, which, in this series, incurred prolonged, cumulative lymphopenia, which leads to a high incidence of infections.