Mona Matta

Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial

PURPOSE The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.

Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma

BACKGROUND A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab. METHODS Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS). RESULTS In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome. CONCLUSION In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.

CN-18RELATIONSHIPS BETWEEN DOSE INTENSITY, TOXICITY, AND OUTCOME IN OLIGODENDROGLIAL TUMORS (OG) TREATED WITH PCV REGIMEN.

BACKGROUND: In grade II and codeleted grade III gliomas, the procarbazine-CCNU-vincristine (PCV) combination increase survival when added to radiotherapy as first line treatment, despite the important toxicity of this treatment schedule. Our objective was to analyze the tolerance, feasibility and impact of dose intensity of the PCV regimen on outcome for patients with OG. METHODS: We retrospectively reviewed all grade III OG patients receiving PCV (CCNU:110mg/m2) who were referred to our two institutions. The total dose and dose adaptation, cycle delay, dose intensity, toxicity and premature discontinuation of CCNU were analyzed. Impact of these factors on patient outcome was evaluated. RESULTS: Between 2007 and 2011, 89 patients received PCV. Only 37% completed 6 cycles, whereas 13.4% prematurely discontinued PCV because of toxicity. Cycle delay and dose reduction were observed for 62% and 70% patients, respectively. Grade 3 and 4 toxicities were observed in 38% and 8% patients, respectively. Among patients who did not progress under PCV regimen, by multivariate analysis, premature discontinuation for toxicity was significantly correlated with poor PFS (p = 0.023, Hazard ratio (HR):2.354) and OS (p = 0.021, HR:5.093). By univariate analyses, absence of CCNU dose adaptation was correlated to poor PFS (p = 0.032). For OS, pejorative factors were high total CCNU dose (p = 0.029), absence of cycle delay (p = 0.009), absence of CCNU dose adaptation (p = 0.020) and grade 3/4 toxicities (p = 0.013). High CCNU dose-intensity tended to poorly impact PFS (p = 0.053) and OS (p = 0.112). By multivariate analysis, absence of CCNU dose adaptation remained significant for PFS (p = 0.001), while OS was negatively impacted by the absence of cycle delay (p = 0.049) and grade 3/4 toxicities (p = 0.045). CONCLUSION: Despite the efficacy of the PCV regimen, significant toxicity is associated with this schedule, which appears to impact its feasibility and efficacy. The optimal PCV schedule should be redefined taking into account this finding.