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2047 Background: The treatment of recurrent glioblastoma (GBM) remains an open issue, and the role of bevacizumab (BEV) has been widely debated since a few studies compared this agent with the stan...

2058 Background: Following the EORTC/NCIC trial investigating temozolomide concurrent and adjuvant to radiotherapy, this regimen is considered standard treatment for newly diagnosed glioblastoma (G...

2003 Background: To assess the efficacy of treatment of medulloblastoma (MB) in adults (> 18 years). Methods: Ninety-five MB patients (pts) were enrolled a prospective phase II trial conducted betw...

2022 Background: In the last decade, progression-free survival (PFS) at 6 months (PFS-6) has been considered the best endpoint in phase II trials on recurrent glioblastoma (GBM). However, since a n...

2027 Background: MGMT promoter methylation status is known to be a potent prognostic factor in newly diagnosed glioblastoma (GBM) patients (pts). However, it is not yet clear whether and, if so, how MGMT methylation status may change; nor is it known whether the prognostic role of this epigenetic feature is retained during the disease course. Methods: A retrospective analysis was made using a database of 614 GBM pts treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18; PS 0–2; two distinct surgical procedures; histological diagnosis of GBM both at first and at second surgery for recurrence; postoperative treatment consisting of: a) radiotherapy (RT) followed by temozolomide (TMZ) until 2005, and b) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 month between first and second surgery. The study aim was to evaluate changes of MGMT status during the course of GBM. The log-rank test was employed to evaluate the significance of the prognostic variables. The percentages of MGMT methylated cases at first and second surgery were compared using the McNemar test. Results: MGMT status, evaluated at first and second surgery in all 44 pts (M:F 32:12, median age: 49 years, range: 27–67), was assessable in 38 (86.4%) cases: MGMT promoter was methylated in 13 (34.2%) pts at first surgery. MGMT methylation status, unchanged in 63.2% of second surgery samples, changed more frequently in methylated than in unmethylated pts (61.5% vs 24%, p = 0.03). The median survival was 24.3 months (95% CI: 20.8–27.7), being 35.2 months (95% CI: 10.1–60.2) and 21.9 months (95% CI: 17.3–26.5) for pts with methylated and unmethylated MGMT assessed at first surgery, respectively (p = 0.04). However, MGMT status at second surgery was no longer prognostic for survival (p = 0.1). Conclusions: Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. Moreover, while MGMT methylation status is prognostic at first surgery, it appears to be of no prognostic utility at the time of second surgery. No significant financial relationships to disclose.

e13003 Background: Chromosomes 1p/19q codeletion has been recognized as a prognostic and predictive factor in patients (pts) with grade 3 gliomas. Non-codeleted (intact) anaplastic oligodendroglioma showed a survival comparable to that usually observed in pts with anaplastic astrocytomas; MGMT methylation status, moreover, has been found to be a prognostic factor in glioblastoma and anaplastic gliomas (AG). Methods: A retrospective analysis was made using a database of 253 AG pts followed prospectively between January 1998 and August 2008. We evaluated only pts who met the following inclusion criteria: age ≥ 18 years; PS 0–2; histological diagnosis of AG with 1p/19q intact, as determined by FISH analysis; treatment with postoperative radiotherapy (RT) and chemotherapy (CT); MGMT status determined using methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in 1p/19q codeleted AG pts. The log-rank test was used to evaluate the significance of the prognostic variables. Results: 67 pts (m/f: 35/32, median age: 41.3 years, range: 18–70 years) were enrolled. Histology was anaplastic oligodendroglioma in 17 pts, anaplastic oligoastrocytoma in 20 pts, and anaplastic astrocytoma in 30 pts; all these pts were 1p19q intact and received surgery, RT, and CT. MGMT status, assessable in 58 pts (86.6%), was methylated in 33 pts (56.9%), and unmethylated in 25 pts (43.1%). Median progression-free survival (PFS) was 32.3 months (95%CI: 9.9–54.7). No enhancement at time of diagnosis (p = 0.003), gross total resection (p = 0.03), age (p = 0.001), and MGMT methylation (p = 0.05) were significantly correlated with better PFS. Median survival was 65.2 months (95% CI: 45–85.3). Only age (p = 0.001) and KPS (p = 0.02) correlated with a better survival. Conclusions: MGMT methylation status may provide adjunctive prognostic information in pts with 1p/19q intact AG, indicating a prolonged PFS in pts harboring MGMT promoter methylation. No significant financial relationships to disclose.

2052 Background: MGMT methylation status has been found to be an important prognostic factor in glioblastoma patients (pts). However, further data on the epigenetic feature are needed before its role in rare diseases such as anaplastic astrocytomas (AA) can be established. Methods: A retrospective analysis was made on a database of 139 AA pts followed prospectively from January 1995 and August 2008. We evaluated only pts who met the following inclusion criteria: age >18 years; PS 0–2; histological diagnosis of AA; postoperative radiotherapy (RT) and chemotherapy (CT). MGMT status was determined with methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in AA. The log-rank test was employed to evaluate the significance of the prognostic variables. Results: 80 pts (m/f: 46/34, median age: 41 years, range: 18–71 years) were enrolled. MGMT was assessable in 71 of 80 pts (88.8%), being methylated in 30 (42.9%), and unmethylated in 41 (57.7%) pts. Median PFS was 48.6 months (95% CI: 33.7 - 63.5), being 96 months (95% CI: 29–163) and 38 months (95%CI: 18.9–57.2) in MGMT methylated and unmethylated pts, respectively (p = 0.09). At univariate analysis, complete resection (p = 0.02), age (p = 0.002), and KPS (p = 0.003) were significantly correlated with PFS. At multivariate analysis only age remains correlated with PFS (p = 0.01). Median survival (OS) was 93.7 months (95% CI: 63.5–123.8), being not reached and 77 months (95% CI: 20–134.2), in MGMT methylated and unmethylated pts, respectively (p = 0.03). MGMT methylation (p = 0.03), age (p = 0.0003), and KPS (p = 0.03) were significantly correlated with OS at univariate analysis. At multivariate analysis, age (p = 0.0002) and MGMT methylation (p = 0.01) were correlated with a better OS. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. This datum should provide the background to improve the therapeutic index with temozolomide concurrent with and adjuvant to RT in AA. No significant financial relationships to disclose.

2027 Background: Temozolomide (TMZ), concomitant with and adjuvant to radiotherapy (RT), has become the standard treatment for newly diagnosed glioblastoma (GBM). The aim of the present analysis wa...

2018 Background: Due to the rarity of medulloblastoma (MB) in adults, the few studies available on this condition are retrospective, and the follow-up tends to be short. Furthermore, the different therapeutic strategies used in these patients makes it difficult to assess survival rates and prognostic factors. Methods: Between January 1989 and February 2001, a prospective phase II trial was performed to evaluate the efficacy of treatment for adults with medulloblastoma. Patients were completely staged with a neuroradiological examination of the brain and neuraxis and by CSF cytology, according to Chang’s staging system. Low risk patients received radiotherapy alone, while high risk patients were given 2 cycles of upfront chemotherapy followed by radiotherapy and adjuvant chemotherapy. The results of the preliminary analysis of this study at a median follow-up of 3.7 years are reported elsewhere. The present papers reports on the long- term results of the same trial. Results: After a median follow up of 7.6 years, among a total of 36 enrolled adults with medulloblastoma, overall progression free survival (PFS) and overall survival (OS) at 5 years were 72% (range 59% to 84%) and 75% (62% to 91%), respectively. No difference was found between low and high risk patients in terms of PFS and OS at 5 years: in low-risk patients the 5-year PFS was 80% (range, 59–100%) and the 5-year OS, 80% (range, 58 - 100%); in high-risk patients the 5-year PFS was 69% (range, 54 -89%) and the 5-year OS, 73% (range, 58 - 92%). Conclusions: A long-term follow-up is essential to evaluate the real impact of treatments in adult patients with MB. Since there is no significant difference between low-risk and high-risk patients for PFS and OS, the use of chemotherapy is also questionable in low-risk patients. No significant financial relationships to disclose.

13589 Background: While age-associated comorbidities are not usually an obstacle to the administration of chemotherapy regimens for CRC, they could instead limit the access to an anti-angiogenic therapy. Hypertension, proteinuria, arterial thrombosis, bleeding and gastrointestinal perforation are the principal bevacizumab (Avastin®)-related events. The aim of this analysis was to estimate the percentage of patients ≥ 70 years potentially amenable with bevacizumab, taking into account age-associated cardiovascular, gastrointestinal (GI) or kidney diseases possibly interfering with its administration. Methods: From January 2004 to December 2005, 91 consecutive patients older than 70, with histologically proven CRC adenocarcinoma for whom chemotherapy had been planned (44 as an adjuvant treatment, 30 as a palliative therapy, 17 for a neoadjuvant program) and entered in our Geriatric Oncology Program, were analysed. Principal variables considered were age and the afore mentioned comorbidities. Results: Median age was 76 years (range, 70–84) and the male:female ratio, 62:28. Sixty-five patients (71.4%) had associated comorbidities. Of these, 39 had cardiovascular-, 17 had cardiovascular and GI-, 5 GI-, 2 kidney and cardiovascular-, and 2 kidney, cardiovascular and GI-associated diseases. Twenty nine out 91 (31.9%) cases presented a grade ≥ 2 either cardiovascular or GI or kidney comorbidities according to the Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, 36 (39.5%) a grade 1 and 26 (28.6%) no comorbidities. Conclusions: In view of the most common bevacizumab-related adverse events, almost one third of our CRC patients with cardiovascular, GI- or kidney- associated diseases of CIRS grade ≥ 2 could have been considered at high risk for its administration. Also in about 40% of patients with CIRS grade 1 still the use of bevacizumab could have been questionable. Then less than in one third of our patients older than 70 years bevacizumab could have been safely administered. No significant financial relationships to disclose.

1514 Background: Encouraging results have been obtained inlow grade glioma (LGG) patients (pts) following TMZ therapy at the standard schedule of 200 mg/m2 for five-days every 28 days. A continuous dose TMZ schedule leads to DNA repair enzyme AGAT level depletion in tumor cells. By removing TMZ-produced methyl adducts, AGAT contributes to the development of resistance to alkylating agents. Methods: Pts with a diagnosis of LGG received TMZ 75 mg/m2/d for 21 days every 28 days at clinical or radiological progression. MiniMax Simon’s design with P0=0.2, P1=0.4, α=0.1, β=0.1 was used and a sample size of 36 pts was planned. The primary end-point was to assess the response rate (RR=CR+PR), and the secondary end-point to investigate the correlations between 1p/19q deletions by FISH and MGMT promoter methylation by methylation specific PCR (MSP). Results: 22 oligodendroglioma (O), 4 oligoastrocytoma (OA) and 10 astrocytoma pts (A) were enrolled (median age of pts 47 years, range 24–69 years; median KPS 90, range 50–100). Eleven pts were pre-treated with radiotherapy; 5 (13.5%) had enhancing lesion at MRI scan. RR was 30.5% (11 PR), all RR being obtained in pts with non-enhancing lesions; 20 pts (55.5%) had disease stabilization; 8/11 responders were assessable for 1p/19 q deletions and, of these, 6 pts (75%) had combined 1p/19q deletion. Median PFS was 17.4 months (interquartile ranges, 9.3–25). PFS at 1 year was 73% (SE 8%). Preliminary data on molecular assessment are: 29 pts were assessable for 1p and 19q deletions, both being present in 19 pts (65.5%). 1p/19 q loss was significantly greater in pts with O/OA than A (p=0.01). Of 11 assessable pts, 7 (63.6%) presented MGMT promoter gene methylation and all 7 pts presented 1p and 19q deletions (p=0.03). Grade 3 lymphopenia was observed in 4 pts (11.1%) and 1 patient had G2 reversible renal toxicity. Conclusion: TMZ for 21 days every 28 is an active and well tolerated regimen in pts with LGG. The analysis to verify any correlation between molecular markers and clinical outcome is ongoing. [Table: see text]

1564 Background: HGG comprehend a heterogeneous group of brain tumors with different histologies and prognosis. However, at second relapse, the response rate and PFS-6 are always discouraging for a...

1541 Background: The activity of TMZ, at a standard schedule of 200 mg/m2 for five-days every 28, appears encouraging in patients with relapsed and newly diagnosed malignant gliomas. A continuous dose schedule of TMZ leads to DNA repair enzyme AGAT level depletion in tumor cells. AGAT, by removing TMZ-produced methyl adducts, contributes to the development of resistance to alkylating agents. The aim of the present study was therefore to determine the safety of continuous low-dose TMZ administration. Methods: From November 2003 to October 2004, 55 patients (34 male; mean age 52, range 28–71 years) with progressive brain tumors had oral TMZ 75 mg/m2 for 21 consecutive days, every 28. Forty-six pts (83.6%) had prior RT; 46 were chemo-naive. Results: A total of 237 (median 4; range, 1–13) cycles were delivered. G2 and G3 toxicity were: lymphopenia, 27.5 and 17.6%; neutropenia, 1.9 and 3.9%; thrombocytopenia, 5.9% and 0; nausea, 3.6 and 3.6%; hepatic 3.6 and 1.8%, respectively. Two patients (3.6%) had reversib...