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The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide ± cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

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...

Summary The complementary role of sestamibi scintimammography (SSM) in patients with breast cancer (BC) is well established. The aim of this study was to establish whether a relationship exists between sestamibi uptake, evaluated as a tumour-to-background ratio (TBR), and the main prognostic factors of BC. SSM with the measurement of TBR was performed preoperatively in 102 women (median age 57 years, range 32–81 years) who underwent curative surgery for primary BC. Final pathology showed 4 (3.9%) with pT1a, 17 (16.7%) with pT1b, 44 (43.1%) with pT1c and 37 (36.3%) with pT2 breast carcinomas. The overall sensitivity of SSM was 80.4%. An ANOVA showed significant ( P 0.01 ) differences between the TBR of patients with G1 vs. G3 tumours, and between the TBR of those with G2 vs. G3 breast carcinomas. Moreover, there was a difference ( P = 0.021 ) between the TBR of patients ( n = 12 , 11.8%) with CEA serum levels >10 ng/ml (2.031±0.420), and those with normal ( n = 90 , 88.2%) CEA values (1.713±0.446), whilst no difference ( P =NS) was found between patients ( n = 27 , 26.5%) with CA 15-3 >30 U/ml (1.893±0.401) and those with normal ( n = 75 , 73.5%) CA 15-3 values (1.699±0.462). There was a mild inverse correlation between TBR and both the oestrogen ( R = 0.25 , P = 0.011 ) and the progesterone receptor ( R = 0.23 , P = 0.02 ) rate. The logistic regression analysis showed that only size and CA 15-3 serum levels represent true independent parameters, but the function was able to predict only 11 out of 21 (52.4%) patients with false-negative SSM. TBR is independent of age and mainly correlates with the size of the tumour. There are no reliable preoperative prognostic factors that are really useful for improving SSM sensitivity in patients with small breast carcinomas.

Background: The initial studies on nitrosoureas were performed >30 years ago. These drugs remain the standard chemotherapy for glioblastoma. However, because the criteria used to evaluate the activity of nitrosoureas in a neuro-oncologic setting have changed, new data on their activity are needed. Methods: The authors conducted a phase II study on 40 patients with recurrent glioblastoma following surgery and standard radiotherapy. They analyzed progression-free survival at 6 months (PFS-6), time to progression (TTP), response rate, and toxicity. Patients were treated with 80 mg/m 2 carmustine on days 1 to 3, every 8 weeks for a maximum of six cycles. Results: Median TTP was 13.3 weeks (95% CI, 10.26 to 16.86 weeks), and PFS-6 was 17.5% (95% CI, 8.9 to 34.3). Response to chemotherapy, age ≤40 years, and performance status ≥90 were significant prognostic factors for TTP; however, with multivariate analysis, only response to chemotherapy was significant. The major side effects were reversible hematologic and long-lasting hepatic and pulmonary toxicity. Conclusion: The activity of this BCNU regimen is comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity is high and recovery is slow, thus compromising the administration of further drugs in patients with progressive disease.

Breast cancer (BC) is the most common cancer among women. However, few studies consider the possible relationship between the main breast complaints referred to by non-screened patients and cancer onset. The objective of this study was to evaluate the relationship between the principal breast complaints (breast pain, breast lump and nipple discharge) and the risk of BC. A group of 347 symptomatic women (median age 59 years, range 35-83) with confirmed BC (cases) was age-matched with a population-based group of 351 symptomatic women (controls) who were followed-up for at least three years (median 78 months, range 36-146) to exclude the presence of a missed BC. Breast pain was the most common (p0.05) complaint in younger patients (50 years or less = 39.0%, 51-60 years = 51.2%), while breast lump was most common in patients aged60 years (65.4%). Since the odds ratio (OR) ranged from 0.80 to 1.20 at a 95% confidence interval (CI) of 0.54-1.80, there was no overall significant association between breast complaints and risk of BC. There was some evidence of increased risk among patients with breast lump (OR = 1.20, 95% CI 0.80-1.80), and no risk in those with breast pain (OR = 0.86, 95% CI 0.54-1.36) and nipple discharge (OR = 0.8, 95% CI 0.37-1.74). In conclusion, a relationship between breast complaints and the onset of BC does not seem to exist.

Introduction treatment options for glioblastoma at recurrence are various despite the limited efficacy. Surgical resection have been used both for confirmation of recurrent disease as well as for debulking in order to provide relief of symptoms. Therefore, the role surgical resection for recurrent glioblastoma, has not been completely clarified. Methods A retrospective analysis was made for glioblastoma patients followed between 01/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; PS:0-2; chemotherapy at disease progression after RT/TMZ, availability of data regarding second progression. Results 232 patients with recurrent glioblastoma (mean age: 52 years, range: 18-77 years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were evaluated. At progression after RT/TMZ, 102 patients (44%) were treated with re-surgery followed by chemotherapy, and 130 patients (56%) with chemotherapy alone. Overall survival from first surgery was 22.4 moths (95% CI: 20–24.7), being 25.8 months (95%CI:20.6–31) in patients who received second surgery at recurrence, and 18.6 months (95%CI:17–20.1–p = 0.003) in patients treated without surgery. However, in multivariate analysis no significant effect of re-surgery was found (p = 0.11) being age (p = 0.001), MGMT methylation (p = 0.002) and PFS6 (p = 0.0001) the only significant prognostic factors. Moreover, median time between first and second surgery was 13.1 months, being significantly longer in patients with MGMT methylated than in patients MGMT unmethylated (19.3 vs 13 months, p = 0.001). Median survival time calculated from first recurrence was 8.6 months (95%CI:7.4–9.8), and 9.6 months (95%CI:7.5–11.6) and 7.5 months (95%CI:5.7–9.3) in patients that received second surgery or not, respectively (p = 0.3). Conclusions Our data suggested that second surgery may have a limited impact in the clinical course of recurrent glioblastoma patients. MGMT methylation status, as well other clinical factors (i.e. age) remain the major prognostic determinants of the outcome. Disclosure All authors have declared no conflicts of interest.

Purpose Since temozolomide in combination with radiotherapy (RT/TMZ) became a new standard for newly diagnosed glioblastoma, the scenario at recurrence became less defined. Moreover, the role of prognostic and predictive factors for the second treatment has not been clarified. Methods A retrospective analysis was made for glioblastoma patients followed between 01/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; PS:0-2; chemotherapy at disease progression after RT/TMZ, availability of data regarding second progression. Results 232 patients with recurrent glioblastoma (mean age: 52 years, range: 18-77years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were evaluated. At progression after RT/TMZ, 102 patients (44%) were treated with surgery followed by chemotherapy, and 130 patients (56%) with chemotherapy alone. Chemotherapy consisted in TMZ rechallenge 5/28 in 80 patients (34%), nitrosoureas in 120 patients (52%), experimental treatments in 32 patients (14%). PFS-6 calculated from 1st to 2nd PD was 22% (95%CI:16.3-26.9%). Time from the last adjuvant TMZ treatment to recurrence (TTR) was shorter in patients treated with nitrosoureas (2.6 months) than in patients treated with TMZ (9.8 months, p Conclusions As in other cancer types (i.e. ovarian cancer), TTR seems to be promising as a predictive factor for PFS obtained with treatments for recurrence and could be useful in patients' stratification. TMZ rechallenge seems more useful than nitrosoureas if TTR is longer. Disclosure All authors have declared no conflicts of interest.

Several risk factors for breast cancer (BC) have been investigated in different reports, but none has been really useful in preventing BC development. The aim of this study was to evaluate the risk of BC in self-selected symptomatic women in comparison with the healthy population residing in an urban area of Italy. A group of 404 women (median age 59 years, range 26-89 years) with confirmed BC (cases) were age-matched with 389 healthy women (Group A), and 391 (Group B) symptomatic non-screened patients without BC, who were referred to our Breast unit. The results of univariate analysis showed a significant (P0.01) difference between cases and controls in (1) age at menarche, (2) number of birth and age at first births, (3) lactation and months of lactation, and (4) estrogen replacement therapy (ERT) and duration of ERT. Multivariate analysis using a logistic regression model adjusted for age showed that five independent parameters (no pregnancy, age at first birth30 years, no lactation, use of ERT, ERT40 months) significantly (P0.01) correlated with BC onset. The relative odds ratios (ORs) at 95% confidence interval (95% CI) were 5.25, 2.47, 2.82, 2.80, and 5.56, respectively. The cumulative OR (95% CI) calculated from the observed vs. predicted values was 7.15. No differences (P = NS) were found between groups A and B. In conclusion, in our study population, the prolonged use (40 months) of ETR in menopausal women resulted in an increased risk of BC, and represented the only risk factor that could be removed.

Aim: The treatment of recurrent glioblastoma (GBM) remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. Methods: A multicenter, open label, randomized (2:1), non-comparative phase II study (EudraCT 2011-001363-46; AVAREG - ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks was conducted. Primary endpoint was overall survival at 6 months (OS6). Stratification factors were age ( 55 yrs) and resection for recurrent disease (yes vs no). Results: 91 patients (pts) with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 yrs (range: 28-78), ECOG PS was 0/1/2 in 42/35/14 pts. All pts received RT/TMZ accordingly with EORTC 26981-22981/NCIC CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At the time of recurrence, 21 pts (23.1%) underwent re-resection before the inclusion into the study (13/8 pts in BEV/FTM arms, respectively). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI: 48.4 - 74.5) and 73.3% (95%CI: 54.1 - 87.7), OS9 was 37.9% (95%CI: 25.5–51.6) and 46.7% (95%CI 28.3–65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI: 5.8 - 9.2) in the BEV arm and 8.7 months (95%CI: 6.3-15.4) in the FTM arm. In the BEV arm, OS6 and OS9 were 77.8% (95%CI: 57.7–91.4) and 59.3% (95%CI: 38.8 - 77.6) in pts ≤55 yrs, and were 48.4% (95%CI: 30.1 - 66.9) and 19.3% (95%CI: 7.4 - 37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts ≤55 yrs was 2.0 (95%CI: 1.0-4.1, p = 0.05). G 3-4- toxicity BEV FTM Neutropenia 1 (1.7%) 4 (12.5%) Thrombocytopenia 0 7 (21.9%) Intestinal perforation 2 (3.4%) 0 Cerebral ischaemia/haemorrage 2 (3.4%) 0 Pulmonary embolism 1 (1.7%) 0 Acute myocardial infarction 1 (1.7%) 0 Conclusions: BEV in recurrent GBM showed survival rates superimposable with FTM. Disclosure: V. Zagonel: Roche – Speaker; M. Reni: Genentech - Advisory board; G. Rosti: Roche - Speaker A. Galli: Roche – employee; S. Doria: Roche – employee; All other authors have declared no conflicts of interest.

The prognosis of patients with malignant glioma is generally poor in spite of the progress that has been made in neurosurgery and radiotherapy of these tumors.

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...

The aim of this study was to evaluate CEA and CA 15-3 changes in patients surgically treated for breast cancer. One hundred and three women (median age 59 years, range 31-83 years) with pT1-2, pN0-1, M0 breast cancer were followed up for at least 5 years. CEA and CA 15-3 serum levels were measured before operation and every 6 months during follow-up. The diagnostic sensitivity of CEA and CA 15-3 was 22.3% and 33.3% respectively. There was a significant difference (p0.01) between pre- and post-operative (6 months and 5 years after surgery) mean CEA serum levels independent of TNM staging. During follow-up, 21 (20.4%) patients showed recurrence of cancer and overall CEA and CA 15-3 sensitivity was 38.1% and 61.1%, with 98.8% and 91.2% specificity, respectively. Tumor marker measurement may be useful in post-surgical follow-up, but at present they are neither sensitive nor specific enough for early diagnosis of malignancy.

The aim of this study was to compare the sensitivity of different pre-operative parameters in patients with breast cancer (BC) recurrence using univariate and multivariate analysis.We retrospectively analyzed a series of 387 women (median age 60 years, range 35-83 years) who underwent curative surgery for pT1-2 BC. The patients were divided into two groups: Group 1: 325 (84.0%) patients with no evidence of disease during a median follow-up of 53 months (range 25-149 months) and Group 2: 62 (16.0%) patients who developed local or distant recurrences.Univariate analysis showed significant (p0.01) differences between the two Groups in age, size and grading of the tumor and hormone receptor rate. MIB1 proliferation rate, serum markers CEA and CA 15-3, and lymph node status were not useful in predicting relapse. Multivariate analysis using a logistic regression model showed that only age, size of the tumor and hormone receptor rate independently correlate with the onset of recurrences.There is no clear correlation between BC recurrence and the majority of the prognostic factors available. Multivariate analysis of several pre-operative parameters may help to correctly select the high risk population.

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.