O10.06 * A PHASE II STUDY OF AINO (ITALIAN ASSOCIATION OF NEURO-ONCOLOGY) ON BEVACIZUMAB AND FOTEMUSTINE FOR RECURRENT GLIOBLASTOMA: OUTCOME, PATTERNS OF RELAPSE AND SALVAGE TREATMENTS

Abstract

BACKGROUND: Information on outcome after the combination of bevacizumab and nitrosoureas in recurrent glioblastomas are lacking. PATIENTS AND METHODS: We have performed a phase 2 trial of combined bevacizumab (BEV) and fotemustine (FTM)(a higly lipophilic nitrosourea) for patients with GBM at first relapse after radiotherapy and concomitant and adjuvant temozolomide. Treatment consisted of BEV at 10 mg/kg on day 1, 15 and FTM at 75 mg/m2/die on day 1, 8 and, after 3 weeks interval, followed by BEV at 10 mg/kg and FTM at 75mg/m2 every 3 weeks as a maintenance treatment, until tumor progression or unacceptable toxicity. MRI was performed at baseline, after 6 weeks from the start of therapy, and thereafter every 2 months. Response on MRI was evaluated according to RANO. RESULTS: Between May 2007 and December 2010, 54 patients were enrolled. The median age was 57 years. Forty-six patients had unifocal tumors, while 8 multifocal tumors. At study entry 41/54 of patients were on steroids, with a median dosage of 4mg. Twenty patients had MGMT unmethylated tumors while 18 had MGMT methylated tumors (in 16 patients data were not available). Median PFS was 5.2 months, and PFS-6 rate was 42.6%. Median OS was 9.1 months and OS-6 and OS-12 were 75.9% and 29.7% respectively. The overall RR was 52% (4% CR, 48% PR) with 37% of SD and 11% of PD. The median time to maximum response was 4 weeks (range 4-12 weeks). Among the 41 patients who were on steroids at study initiation, 32 were able to taper, including 17 who completely stopped. MGMT methylation was not associated with response, PFS or OS. Patterns of tumor failure on MRI after study treatment were available in 50/54 patients. All 8 tumors, that were multifocal before treatment, had a multifocal progression. Forty-two patients had unifocal tumors before treatment, and patterns of progression were as follows: local (enhancing) in 76%, distant (enhancing) in 7%, multifocal (local + distant enhancing) in 4.5%, diffuse (nonenhancing) in 9.5% and isolated leptomeningeal spread in 2%. The pattern of tumor failure was not associated with previous response to treatment. Overall survival after failure was not significantly different according to patterns of tumor progression. Following progression on BEV + FTM, 21/50 patients received salvage chemotherapy and in 1 of these patients BEV was maintained beyond progression in association with chemotherapy. Twenty-nine out of 50 patients received supportive care alone. Patients who received salvage chemotherapy had a median survival of 4.53 months, while patients who received supportive care alone had a median survival of 2.2 months. CONCLUSIONS: This study failed to demonstrate a superiority of the combination of BEV and FTM over either BEV or FTM alone as historical controls. Patterns of tumor progression after treatment did not influence the outcome while the prognosis was poor regardless of salvage chemotherapy or palliative care.