Conditional Probability of Survival in Patients with Glioblastoma Multiforme in the Temozolomide Treatment Era

Annals of Oncology 23 (Supplement 9): ix144–ix151, 2012 doi:10.1093/annonc/mds394

CNS tumors 410O

CONDITIONAL PROBABILITY OF SURVIVAL IN PATIENTS WITH GLIOBLASTOMA MULTIFORME IN THE TEMOZOLOMIDE TREATMENT ERA

Introduction: Glioblastoma multiforme (GBM) is the most aggressive of gliomas. With standard treatment consisting of surgery followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ), median survival is approximately 14.6 mo. These estimates are not as informative to patients ( pts) who have survived for some time after diagnosis. Aim: To retrospectively review outcomes and report conditional probability estimates in the TMZ treatment era of pts who presented to a multidisciplinary team at the tertiary referral center PrincessMargaretHospital, Toronto, with a diagnosis of GBM. Methods: 892 pts were followed from 01/04 – 08/10. Complete demographics, performance status (PS), GBM localization, extent of surgery, percent receiving RT +/− TMZ, overall survival (OS) and conditional probability were analyzed. Results: The cohort includes 548 (61%) males with median age 62 (5-93). Baseline PS was 0-1 in 600 (67%), 2-3 in 251 (28%) pts. 205 (23%) had frontal lobe tumors. Extent of surgery; 26% biopsy, 68% partial/subtotal resection, 6% unknown. 516 (58%) received concurrent RT/TMZ +/− adjuvant TMZ. Survival was similar for those with frontal lobe tumors vs other locations (10.2 vs 9.7 mo, Logrank test p = 0.28). OS for biopsy pts was 4.5 mo (3.5 – 6.2), and partial/subtotal resection pts; 11.6 mo (10.3 – 12.5) ( p < 0.001). OS for pts receiving standard RT/TMZ +/− TMZ was 14.2 mo (13.3 – 15.1). Age and PS were significant prognostic factors for OS ( p < 0.001). The OS and conditional probability of survival for entire cohort of 892 pts is detailed in Table. 43 (5%) are still alive, 727 (81%) deceased, status unknown in 122 (14%).

Time

Overall Survival (%)

1 Year 2 Year 3 Year 4 Year 5 Year

43.1 17.9 10.3 8.3 7.1

95% CI 39.8 15.2 8.0 6.1 5.0

– 46.4 – 20.7 – 12.8 – 10.9 – 9.7

Conditional Probability of Survival (%) 41.4 57.4 80.6 85.6 81.5

95% CI 35.9 47.5 68.4 71.1 60.9

– 47.0 – 67.4 – 92.8 – 100 – 100

Conclusion: The conditional probability of surviving an additional yr after survival to 2 yrs post diagnosis exceeds the 1 yr survival rate, indicating that the future prognosis of a pt who has survived for 2 yrs may be as good as those recently diagnosed. Conditional probabilities of survival in this general disease population in the era of TMZ therapy may provide more accurate life expectancy predictions for survivors of GBM. Disclosure: All authors have declared no conflicts of interest.

411O

A PILOT STUDY CORRELATING IDH-1/2 GENE STATUS WITH 2-HYDROXYGLUTARATE (2HG) CONCENTRATION IN PLASMA AND URINE FROM PATIENTS (PTS) WITH GLIOMA

G. Lombardi1, G. Corona2, P. Farina1, F. Zustovich1, R. Bertorelle3, P. Fiduccia1, A. Della Puppa4, M.P. Gardiman5, A. Salvalaggio1, G. Toffoli2, V. Zagonel1 1 Medical Oncology 1, Venetian Oncology Institute – IRCCS, Padua, ITALY, 2 Molecular Oncology and Translational Medicine, Experimental and Clinical Pharmacology Unit, Aviano, ITALY, 3Molecular Immunology and Oncology, Venetian Oncology Institute – IRCCS, Padua, ITALY, 4Neurosurgery Department, Azienda Ospedaliera di Padova, Padua, ITALY, 5Pathology Department, Azienda Ospedaliera di Padova, Padua, ITALY Background: IDH-1/2 mutations are a prognostic markers in gliomas. These mutations results in the production of 2HG. We investigated whether 2HG produced

U_2HG* P_2HG (ng/mL) P_2HG/U_2HG*

IDH wt 7.49 ± 3.87 86.42 ± 38.74 13.96 ± 7.54

IDH mutated 5.00 ± 3.08 112.74 ± 73.19 23.83 ± 9.00

p 0.03 0.26 0.006

*Concentration of 2HG (µg/mL) normalized by creatinine concentration (mg/mL) Disclosure: All authors have declared no conflicts of interest.

412O

TYROSINE KINASE INHIBITORS WITHOUT RADIATION THERAPY FOR BRAIN METASTASES FROM EGFR-MUTANT ADENOCARCINOMA OF LUNG

T. Iuchi1, M. Shingyoji2, T. Sakaida1, S. Yokoi3, M. Itakura2, K. Kawasaki1, Y. Hasegawa1, H. Kageyama3, T. Iizasa2 1 Neurological Surgery, Chiba Cancer Center, Chiba, JAPAN, 2Thoracic Disease, Chiba Cancer Center, Chiba, JAPAN, 3Cancer Diagnosis, Chiba Cancer Center Research Institute, Chiba, JAPAN Backgrounds: Whole-brain radiation therapy (WBRT) and/or stereotactic radiosurgery (SRS) are standard treatments for brain metastases (BMs). However, patients ( pts) treated by radiation therapy (RT) have a risk of decline in learning and memory functions. The aim of this study is to clarify the efficacy and safety of chemotherapy without RT for BMs. Materials and methods: BMs from lung adenocarcinomas (Ads) with EGFR-mutation were enrolled. As tyrosine kinase inhibitors (TKIs), gefitinib was used at first, and erlotinib was administrated at tumor progression. Erlotinib was also selected for pts in whom intracranial lesions appeared after gefitinib. The response to TKIs was evaluated on MRI. WBRT or SRS was performed only at tumor progression after TKIs. The primary endpoint was overall survival, and the secondary endpoints were maximum response to TKIs, progression-free survival and time to RT after diagnosis of BMs. Results: In this study, 37 pts were enrolled. The types of EGFR-mutations were as follows: Ex19 deletion (Ex19del) in 20, Ex21L858R in 14, and other types of mutations in 3 cases. The maximum response was PD in one, SD in 3, PR in 22 and CR in 9 pts (response rate: 83.8%). The progression-free and overall survival times were 8.9 and 28.3 months. The median time to RT (WBRT in 14 and SRS in 3 cases) from diagnosis of BMs was 14.3 months. During the follow-up period, 9 deaths were observed but none of them were owing to the intracranial lesions. Among these 9 pts, no RT was required in 2. Pneumonitis was observed in one case after gefitinib, but no other severe adverse event was observed. When we divided the pts owing to the types of mutations (Ex19del vs. others), response to TKI was superior in Ex19 deleted cases ( p = 0.031), and the progression-free survival time was significantly longer in cases with Ex19del (14.5 months) in compared with those with other types of mutations (8.0 months, p = 0.002). In Ex19 deleted cases, TKIs could delay RT for 18.3 months.

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abstracts

M. McNamara1, Z. Lwin2, H. Jiang3, C. Chung4, B. Millar4, N. Laperriere4, W. Mason1 1 Medical Oncology, Princess Margaret Hospital, Toronto, CANADA, 2Medical Oncology, Mater Adult Hospital, Brisbane, QLD, AUSTRALIA, 3Biostatistics, Princess Margaret Hospital, Toronto, ON, CANADA, 4Radiation Oncology, Princess Margaret Hospital, Toronto, ON, CANADA

by IDH-1/2 mutant gliomas accumulates in patient’s plasma and urine and whether this accumulation can be used to assess IDH-1/2 mutation status. Methods: we prospectively studied PTS with intracranial gliomas and measurable disease on brain-MRI. All PTS had a partial surgical resection or a recurrent disease. The resected tissues were analyzed for IDH-1/2 mutational status; subsequently, in absence of chemotherapy and after 3 weeks from a prior surgery, a plasma and an overnight-urine samples collection were taken from consecutive PTS. 2HG concentrations were determinate by liquid chromatography tandem mass spectrometry. The statistical significance of the difference in the level of 2HG between the PTS with IDH-1/2 mutated and control group were evaluated by non parametric Mann- Whitney test. Results: we analyzed 13 PTS with IDH-1 mutated and 13 PTS with IDH-1/2 wild-type; 2 PTS with low-grade glioma and 24 PTS with high-grade glioma; 10 females and 16 males. In all PTS we analyzed the mean 2HG concentration in plasma (P_2HG) and urine samples normalized by creatinine concentration (U_2HG). The results are shown in Table 1. We found significant differences in mean U_2HG, and in mean P_2HG/U_2HG in patients with or without IDH mutated. No statistically significant associations of tumor volume and U_2HG, of tumor volume and P_2HG were found in all PTS and in PTS with IDH1 mutated. Conclusions: U_2HG and P_2HG/U_2HG might be used as markers to differentiate between gliomas with and without IDH mutated. No associations were found between tumor volume and U_2HG and P_2HG, indicating that 2HG might not be utilized as marker to monitor tumor growth. However, a larger number of samples need to be analyzed to draw final conclusions.

Annals of Oncology

Conclusions: TKIs showed favorable effect on control of EGFR-mutant BMs, and it delayed RT for more than one year. Ex19del was the significant predictor of response to TKIs in BMs. TKIs without RT was safe and acceptable treatment for BMs from EGFR-mutant lung Ads. Disclosure: All authors have declared no conflicts of interest.

413PD

HYPOFRACTIONATED RADIOTHERAPY FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A PROSPECTIVE CONTROLLED RANDOMIZED TRIAL

S.A. Ahmed1, E. Eldebaway2, N. Elkhateeb2, M.S. Zaghloul2 1 Radiotherapy Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT, 2 Radiotherapy Department, Children’s Cancer Hospital, Cairo, EGYPT

414PD

IS BRAIN-ONLY METASTATIC BREAST CANCER A DISTINCT ENTITY?

415PD

THE CAREGIVERS PERSPECTIVE ON THE END-OF-LIFE PHASE OF GLIOBLASTOMA PATIENTS

B. Flechl1, M. Ackerl1, C. Sax1, S. Oberndorfer2, B. Calabek3, E. Sizoo4, J. Reijneveld4, R. Crevenna5, M. Preusser1, C. Marosi1 1 Internal Medicine, Medical University of Vienna, Vienna, AUSTRIA, 2Neurology, Landesklinikum St. Pölten, St. Pölten, AUSTRIA, 3Neurology, Kaiser Franz Josef Hospital, Vienna, AUSTRIA, 4Neurology, VU University Medical Centre, Amsterdam, NETHERLANDS, 5Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, AUSTRIA Objective: Glioblastoma multiforme (GBM) still harbours an inevitably fatal prognosis. The specially course of this disease poses unique challenges in care provision to the relatives. We lack data about the caregiverś perspective on the end-of-life (EOL) phase of GBM patients to improve counseling and support. Methods: In this retrospective study we included 52 caregivers of deceased GBM patients treated in two hospitals in Vienna, Austria. We used a specially developed questionnaire by the Medical University of Amsterdam to explore and document the last three months of living of GBM patients. Results: Most of the included caregivers were the partners of the patients (88%) and two thirds were female. The most common symptom in GBM patients was fatigue (87%), followed by reduced consciousness (81%) and aphasia (77%). 22% of the patients were bedbound during their last three months increasing to 80% in the last week of life. 30% of the caregivers told that they felt incompletely informed for their task and about the illness of their loved one. They stated the quality of life (QOL) of the patients with 2.2 and their own with 2.8 on a scale of 1 to 7 whereas 7 displays the best possible answer. The majority of the patients (46%) died in hospitals and 38% at home, which was the most often expressed wish for place of death (45%) by patients. Regarding the caregiverś symptoms, sadness (90%), fear (69%), burnout (60%), less interest in others (54%) and irritation (42%) were the leading ones and did not differ significantly in-between the places of death. Conclusion: The caregivers reported that their quality of life (QOL) was only slightly better than the QOL they attributed to the patients. About two thirds of the caregivers felt overstrained and stress thereby the urgent need for support and dedicated educational programs. Disclosure: All authors have declared no conflicts of interest.

416PD

RE-SURGERY FOR RECURRENT GLIOBLASTOMA: OUTCOME ANALISYS AND CORRELTION WITH MGMT STATUS

A.S. Berghoff1, Z. Bago-Horvath2, G.G. Steger3, C. Zielinski3, R. Bartsch3, M. Preusser3 1 Institute of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 2Institute of Pathology, Medical University of Vienna, Vienna, AUSTRIA, 3Department of Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, Vienna, AUSTRIA

A. Brandes1, E. Franceschi1, R. Poggi1, R. Degli Esposti1, M. Di Battista1, L. Lombardo1, F. Girardi1, D. Palleschi1, S. Bartolini1, M. Ermani2 1 Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL, Bologna, ITALY, 2 Department of Neurosciences, Statistic and Informatic Unit, Azienda Ospedale-Università, Padova, ITALY

Background: Up to 40% of metastatic breast cancer patients ( pts) are diagnosed with brain metastases (BM) during their course of diseases. Some case reports and small patient series have indicated that breast cancer pts with the brain as only metastatic site (“brain-only”) may have a more favourable prognosis than BM pts with more widespread metastatic disease. Methods: We identified all breast cancer pts with BM treated at our institution between 1990 and 2011. For each patient, full information on follow up and administered therapies was mandatory for inclusion. Estrogen-receptor (ER), progesterone-receptor and HER2 status were determined according to standard protocols. We performed statistical analyses including computation of survival probabilities. Results: Overall, 223 female pts (26.0% luminal subtype; 47.5% HER2 subtype; 26.5% triple negative subtype) with BM of metastatic breast cancer were included in this study. In 60/223 pts (26.9%) the brain was the first metastatic site. Brain as first metastatic site was significantly less common in the HER2-positive subtype than in luminal and triple negative subtypes ( p = 0.005). 38/223 (17%) of BM pts did not develop extracranial metastases (ECM) during their disease course and were classified as “brain-only” cases. Brain-only metastatic behaviour was not associated with breast cancer subtype or number of BM. The median OS of the brain-only pts was 11 months (range 0-69) and was significantly longer than in pts with BM and ECM (5 months, range 0 to 104) ( p = 0.007). High KPS ( p = 0.02), single BM ( p < 0.001) and ER expression ( p = 0.014) were associated with favourable OS in the brain-only cohort. 7/38 (18.4%) brain-only pts had long-time survival of more than 3 years after diagnosis of BM.

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).

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Background: Pediatric Diffuse intrinsic pediatric glioma (DIPG) remained dismal regardless of the new therapeutic and technical attempts. Purpose: To investigate the efficacy and toxicity of hypofractionated radiotherapy in pediatric DIPG compared to conventional radiotherapy and to determine the prognostic factors for its overall (OS) and progression-free survival (PFS). Patients and methods: Sixty four children, below the age of 18 years, who presented to Children’s Cancer Hospital, Egypt (CCHE) during the period July 2007 and July 2011 were randomized into 2 groups. The hypofractionated group received 39 Gy in 13 fractions in 21/2 weeks and the conventional arm receiving 55.8 Gy in 31 fractions in 6 weeks using conformal radiotherapy technique. The two arms were not different in age, gender, performance status and tumor volume. Results: Thirty two children were randomized in each arm. The median OS for the whole group was 9.5 ± 1.0 months: 7.4 ± 1.0 months for the hypofractionated arm and 9.9 ± 1.0 months for the conventional arm. The whole group has median PFS of 7.3 ± 0.8 months; 7.0 ± 1.4 months for the hypofractionated and 7.7 ± 1.1 for the conventional arm. On the other hand, the 1-year and 2-year OS were 41.4 ± 9.2% and 28.4 ± 8,8% in the hypofractionated arm and 36.2 ± 8.7% and 32.3 ± 7.8% in the conventional arm. None of these differences was statistically significant. Furthermore, none of the tested factors (age, gender, performance status, tumor volume, radiation volume or tumor extension) proved to have statistically significant influence on OS or PFS. All patients showed marked degree of improvement in symptoms and signs with earlier response in the hypofractionated arm. The immediate and delayed side effects were not different between the 2 arms. Conclusions: Hypofractionated radiotherapy had similar overall, progression-free survival and delayed effect (in the long survivors) to conventional fractionation. It offers less burden on the patients, their families and the treating machines and departments. Disclosure: All authors have declared no conflicts of interest.

Conclusions: Among breast cancer pts with BM, brain-only metastatic behaviour is not associated with breast cancer subtype, but with favourable survival prognosis. Exploitation of all multimodal treatment options is warranted in breast cancer pts with brain-only metastatic disease, as long-term survival is not uncommon in this patient population. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

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.

417PD

A PHASE 2 TRIAL OF THE MULTITARGETED KINASE INHIBITOR LENVATINIB (E7080) IN PATIENTS (PTS) WITH RECURRENT GLIOBLASTOMA (GBM) AND DISEASE PROGRESSION FOLLOWING PRIOR BEVACIZUMAB TREATMENT

D.A. Reardon1, E. Pan2, J. Fan3, J. Mink3, D.P. Barboriak4, J.J. Vredenburgh5, A. Desjardins5, K. Peters5, J.P. O’Brien3, P.Y. Wen1 1 Neuro-oncology Department, Dana-Farber Cancer Insitute, Boston, MA, UNITED STATES OF AMERICA, 2Neuro-oncology, Moffitt Cancer Center, Tampa, FL, UNITED STATES OF AMERICA, 3PCU, Eisai Inc., Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 4Radiology, Duke University Medical Center, Durham, NC, UNITED STATES OF AMERICA, 5Medicine, The Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, UNITED STATES OF AMERICA

418PD

ASSOCIATION BETWEEN CANCER STEM CELLS AND CD133+ BLOOD VESSELS IN GLIOBLASTOMA MULTIFORME

J. Jaal1, M. Kase2, A. Minajeva3, K. Niinepuu3, S. Kase4, M. Vardja1, T. Asser5 1 Dept of Radiotherapy and Oncological Therapy, Tartu University Hospital, Haematology and Oncology Clinic, Tartu, ESTONIA, 2Dept. of Radiotherapy, North Estonia Medical Centre, Oncology and Haematology Clinic, Tallinn, ESTONIA, 3Faculty of Medicine, University of Tartu, Tartu, ESTONIA, 4Nursing, Health Care College, Tartu, ESTONIA, 5Dept of Neurosurgery, Tartu University Hospital, Tartu, ESTONIA Background: Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor in adults. Histologically, GBMs are highly angiogenic. It has been suggested that GBM stem cells might support tumor vascularization. The aim of our study was

ix | Abstracts

419PD

STRONG ADDITIVE EFFECT OF EVEROLIMUS AND OCTREOTIDE OR PASIREOTIDE ON MENINGIOMA CELLS IN VITRO: A NEW THERAPEUTIC STRATEGY FOR THESE TUMORS

A. Barlier1, T. Graillon2, C. Defilles1, A. Mohamed1, A. Saveanu3, D. Figarella-Branger4, O. Chinot5, P. Roche6, A. Enjalbert1, H. Dufour2 1 CRN2M, UMR7286-CNRS, Aix-Marseille University, Marseille, FRANCE, 2 Neurosurgery Department, AP-HM Timone, Marseille, FRANCE, 3Molecular Biology Laboratory, AP-HM Conception, Marseille, FRANCE, 4Neuropathology Department, AP-HM Timone, Marseille, FRANCE, 5Neurooncology, AP-HM Timone, Marseille, FRANCE, 6Neurosurgery Department, AP-HM Nord, Marseille, FRANCE Meningiomas are the most frequent brain tumors after 35 years-old. When total surgical removal is not possible, radiotherapy and radiosurgery are able to control tumoral growth in some cases. But no chemotherapy has ever been demonstrated to be really efficient. Then, in cases of recurrence ( particularly in WHO grade 2 and 3 meningiomas), no therapeutic exist at present, leading to fatal issue. Pi3Kinase-Akt-mTor pathway is activated in meningiomas, due to Merlin protein (encoded by NF2 gene) inactivation. SST2 somatostatin receptors are strongly expressed in meningiomas. These receptors are targeted by somatostatin agonists (octreotide and a new “pan-sst” agonist, pasireotide) which antiproliferative effect is known in other types of tumors. The aim of our study is to test in vitro effects of m-Tor inhibitor (Everolimus) and/or somatostatin agonists Octreotide or pasireotide, on human meningiomas in primary culture. By real time PCR, we found that sst2 was expressed in all meningiomas. The expression level of Merlin was highly variable between tumors and was inversely correlated with mTor pathway activation ( p < 0.025). Everolimus decreased cell viability in a dose dependent manner, in the 10 analyzed meningiomas, including that of grade 2 and 3. However, an increase in AkT activation was observed. In neuroendocrine cell lines, octreotide is able to decrease AKT activation through a direct interaction between sst2 and the p85, the regulatory subunit of Pi3Kinase. In primary culture of meningiomas, we demonstrated that octreotide and pasireotide were able to decrease cell viability in a dose dependant manner by inducing inhibition of AKT activation. A clear additive effect between everolimus and octreotide or pasireotide was observed on cell viability on the 6 analysed tumors including grades 2 and 3: the percentage of cell viability inhibition, around -25% under one drug, decrease to -40% under mTor inhibitors plus somatostatin analogs. Moreover an additive effect of both drugs was clearly observed on the AKT and mTor pathway This study is the first proof of concept in vitro on the interest of everolimus with octreotide or pasireotide to control tumoral growth of human meningiomas. This study clearly set up the foundations of clinical trials. Disclosure: A. Barlier: the research prgramm was partially supported by Novartis. All other authors have declared no conflicts of interest.

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Background: There is no effective therapy for recurrent GBM pts following progression on the vascular endothelial growth factor (VEGF)-targeting agent bevacizumab (BV), with historical series reporting progression-free survival at 6 months (PFS-6) of only 2%. Several mechanisms of tumor adaptation following anti-VEGF therapy have been proposed, including upregulation of alternative angiogenic cytokines. We therefore performed a single-arm phase 2 study to evaluate lenvatinib (L), an oral tyrosine kinase inhibitor targeting FGFR1-4, PDGFRβ, VEGFR1-3, RET, and KIT, in pts with recurrent GBM progressing on BV. Methods: 32 pts with recurrent GBM (≤2 prior progressions) and progression on BV received L 24 mg once daily in 28-day cycles until PD or unacceptable toxicity. Dynamic contrast-enhanced MRI was performed before and after 1 day of L on a subset of pts (n = 16). Response was assessed using Response Assessment in Neuro-Oncology criteria. Primary endpoint was PFS-6. This cohort has completed enrollment; 1 pt is still ongoing. Results: Median age was 52 y, 56% were male, and 19% had a KPS <80; 16% required dose reduction for toxicity and 25% withdrew from therapy due to treatment-related toxicity. Most common AEs were hypertension 47% (Gr 3: 18.8%), fatigue 44% (Gr 3: 15.6%), headache 41%, proteinuria 31% (Gr 3: 6.3%), and diarrhea 31%; 2 pts (6.3%) experienced Gr 4 fatigue and hypertension, respectively. One patient died due to pulmonary embolism; 28% of pts achieved stable disease. No objective responses were observed. PFS-6 rate was 8.3%; median PFS was 1.9 months (95% CI: 0.95-2.73); 6-month overall survival (OS) rate was 28%; median OS was 4.11 months (95% CI: 3.02-5.88). A ≥33% reduction in mean Ktrans was observed in 10 pts (63%) and a significant decrease in lesion volume (mean reduction: 33%, P = 0.00287) was found 1 day after therapy, indicating L affected tumor vascularity and vascular permeability. Conclusions: Lenvatinib has modest activity and a similar toxicity profile when compared with other tyrosine kinase inhibitors. Further study of VEGF therapy failure mechanisms as well as biomarkers of outcome is needed. Disclosure: D.A. Reardon: D. Reardon discloses reimbursement for serving as an advisory board member for Genentech/Roche and Schering/Merck in the past year. E. Pan: E. Pan has been reimbursed as an advisory board member for Genentech in the past year. He has also been on the Speakers’ Bureau for Genentech, Merck, and Sigma Tau in the past year. J. Fan: J. Fan is an Eisai employee. J. Mink: J. Mink is an employee of Eisai. D.P. Barboriak: D. Barboriak discloses receiving imaging core lab support from Eisai Pharmaceuticals, ACRIN, NIBIB / RSNA QIBA Member of GE Medical Systems Neuro MRI advisory board Pulse sequence support from Siemens Healthcare. J.J. Vredenburgh: J.J. Vredenburgh received financial compensation from Genentech/Roche for Speakers Bureau participation and consultation. A. Desjardins: A. Desjardins received financial compensation from Genentech/Roche for Speakers Bureau participation. J.P. O’Brien: J. P. O’Brien is an employee of Eisai. P.Y. Wen: P. Wen discloses research support from Eisai. All other authors have declared no conflicts of interest.

to evaluate the association between CD133-positive (CD133+) cancer stem cells and blood vessels in GBM tissue. Methods: Between Jan 2006 and Dec 2008, 42 patients (30-77 years) received postoperative radiotherapy and chemotherapy. Surgically excised GBM tissues were examined for CD133 expression prior anticancer therapy. After immunohistochemistry, the proportion of CD133+ stem cells (%), the number of CD133+ blood vessels ( per microscopic field), and the staining intensity of endothelial CD133 expression (arbitrary score 0-3) were evaluated. Results: The expression of CD133 was determined by 2 independent researchers whose results were in good accordance. The proportion of CD133+ GBM stem cells was 33% ± 24% (mean ± SD). GBM tissue consisted of both CD133+ and CD133blood vessels. However, endothelial staining of CD133 was found in all types of GBM blood vessels, including small capillaries and microvascular proliferations. The number of CD133+ blood vessels per microscopic field was 1.4 ± 1.3 (mean ± SD), and the endothelial CD133 staining intensity 1.0 ± 0.5 (mean ± SD). A significant association was found between the proportion of CD133+ stem cells and the number of CD133+ blood vessels ( p = 0.004). Also, a correlation between the number of CD133+ blood vessels and the endothelial CD133 staining intensity was detected ( p < 0.001). Median survival time of the study group was 10.0 months (95% CI 9.0-11.0). In multivariate analysis, next to well-known prognostic factor Karnofsky Performance Score, the proportion of CD133+ GBM stem cells emerged as a significant independent predictor for longer overall survival (HR 2.0, 95% CI 1.0-3.8, p= 0.04). Conclusion: In the present study, a significant association was found between CD133 + GBM stem cells and CD133+ blood vessels. Favourable CD133+ expression has to be taken into account in the strategies under preclinical or clinical development for GBM stem cell targeting. This work was supported by grant ETF8862 and Roche scientific grant. Disclosure: J. Jaal: This work was partly supported by Roche scientific grant. M. Kase: This work was partly supported by Roche scientific grant. A. Minajeva: This work was partly supported by Roche scientific grant. K. Niinepuu: This work was partly supported by Roche scientific grant. S. Kase: This work was partly supported by Roche scientific grant. M. Vardja: This work was partly supported by Roche scientific grant. T. Asser: This work was partly supported by Roche scientific grant.

Annals of Oncology 420PD

SYSTEMIC TEMSIROLIMUS ADMINISTRATION REDUCES TUMOR GROWTH IN AN ORTHOTOPIC MOUSE MENINGIOMA MODEL

C. Mawrin, D. Pachow, E. Kirches Neuropathology, University of Magdeburg, Magdeburg, GERMANY

421P

OUTCOME AND MOLECULAR CHARACTERISTICS OF YOUNG ADULT PATIENTS WITH NEWLY DIAGNOSED PRIMARY GLIOBLASTOMA: A STUDY OF THE SOCIETY OF AUSTRIAN NEUROONCOLOGY (SANO)

C. Marosi1, A. Leibetseder2, M. Ackerl3, B. Flechl3, C. Sax3, A. Wöhrer4, M. Preusser5, K. Dieckmann6, J. Pichler7, S. Spiegl Kreinecker7 1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA, 2 Oncology, Medizinische Universität Wien, Wien, AUSTRIA, 3Internal Medicine, Medical University of Vienna, Vienna, AUSTRIA, 4Institute for Neurology, Medical University of Vienna, Vienna, AUSTRIA, 5Department of Medicine I, Medical University of Vienna, Wien, AUSTRIA, 6Radiotherapy, Medical University Vienna, Vienna, AUSTRIA, 7Neurooncology, Wagner Jauregg Spital, Linz, AUSTRIA Background: Young age is well-known as favorable prognostic factor for patients with glioblastoma multiforme (GBM). We reviewed the outcome and molecular tumor characteristics of “young” adult patients with newly diagnosed GBM treated in two Austrian Neurooncology centers. Patients and methods: Data of patients with histologically proven GBM diagnosed between age 18 and 40 were retrospectively analysed. All cases presented as newly diagnosed GBM without previous history of neurological disease. All were treated with standard first line therapy. IDH1-R132H mutation status was analyzed by immunohistochemistry. Moreover, tumour samples were tested for MGMT promoter methylation using methylation-specific polymerase chain reaction (MS-PCR). The primary endpoint was overall survival (OS) and time to tumour progression (TTP). Results: We included 70 patients (36 men and 34 women; 47 from Vienna, 23 from Linz) with a median age of 33 (range 18 to 40 years) in our study. IDH1-R132H mutations were detected in 22/56 (39.3%) cases and MGMT promoter methylation in 33/54 (61.1%) cases with available tissue samples. IDH1 mutation was highly significantly associated with MGMT promoter methylation ( p < 0.0001, Chi-square test). In patients with wild type IDH median TTP was 12.6 months and median OS 43.0 months, versus 22.2 months (TTP) and 50.6 months (OS) observed in patients with mutated IDH. Neither IDH1 nor MGMT status showed a statistically significant association with TTP or OS in our cohort. Of note, the social and economical situation of the young GBM patients was alarming, as only a minority of patients (17%) succeeded in staying employed after receiving the diagnosis. Conclusions: We found a high frequency of IDH1 mutations and MGMT promoter methylation among young adult patients with primary GBM that may contribute to the generally favourable outcome associated with young age in glioblastoma patients. The social and economic coverage of glioma patients remains an unsolved socio-ethical problem. Disclosure: All authors have declared no conflicts of interest.

Volume 23 | Supplement 9 | September 2012

THE IMPACT OF VALPROIC ACID IN OVERALL SURVIVAL OF PATIENTS WITH GLIOBLASTOMA MULTIFORME

S.R. Meireles1, M.L. Salgado1, D. Almeida1, L. Castro2, P. Linhares3, L. Osório4, A.S.A. Costa1, C. Caeiro1, M. Damasceno1 1 Medical Oncology Department, Hospital São João, Porto, PORTUGAL, 2 Histopathology Department, Hospital São João, Porto, PORTUGAL, 3 Neurosurgery Department, Hospital São João, Porto, PORTUGAL, 4 Radiotherapy Department, Hospital São João, Porto, PORTUGAL Background: Seizures occur in up to 50% of patients with glioblastoma multiforme (GBM). Retrospective analysis of the pivotal European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada clinical trial showed that the use of the antiepileptic (AED) valproic acid (VPA) may improve survival among patients with newly diagnosed glioblastoma receiving temozolamide compared to other AED or no treatment. We aimed to analyse the impact of VPA in overall survival (OS) of GBM patients submitted to Stupp’s protocol. Material and methods: Retrospective study of GBM patients who completed concomitant phase of Stupp’s protocol from March 2004 until December 2011. Patients needing two AED to seizure control were excluded. Results: One hundred thirty two patients were included. Median age at diagnosis was 61 years-old [24;79] and 68,2% were male. Seizures were present at diagnosis in 16,7% of cases. 55,3% were AED-free, 35,6% received VPA and 9,1% took another AED. Median OS was 15 months (95%CI: 13,3-16,7) and 2-year OS was 31,8%. Patients submitted to VPA had better median OS versus other AED or no treatment at all, although the difference was not statistically meaningful (16 vs 15 vs 14 months, p = 0.74). In univariate and multivariate analysis, ECOG PS ≥ 1 (HR: 1.58, 95% CI 1.01-2.47, p = 0.04), corticosteroid use (HR: 1.83, 95% CI 1.05-3.18, p = 0.03) and < 6 cycles of temozolamide in maintenance phase (HR: 3.15, 95% CI 2.05-4.85, p < 0.001) were the only independent factors with negative impact on OS. VPA treatment was not significantly correlated with OS (HR: 0.96, 95% CI 0.47-1.96, p = 0.90). Conclusion: Opposite to the literature data, VPA didn’t show any survival advantage in GBM patients. ECOG PS ≥1, corticosteroid use and < 6 cycles of temozolamide in maintenance phase were correlated with worst prognosis. Future studies are needed to confirm and understand which mechanisms justify any potencial survival benefit of VPA. Disclosure: All authors have declared no conflicts of interest.

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CAN TIME FROM LAST CHEMOTHERAPY TO RECURRENCE BE A PREDICTOR OF CHEMOSENSITIVITY IN RCURRENT GLOBLASTOMA?

E. Franceschi1, R. Agati2, R. Poggi3, P. Dall’Occa1, M. Bartolotti1, M. Di Battista1, G. Marucci4, F. Girardi3, M. Ermani5, A. Brandes3 1 Department of Medical Oncology, Bellaria and Maggiore Hospitals, Azienda USL Bologna, Bologna, ITALY, 2Neuroradiology Department, Bellaria-Maggiore Hospital, Azienda USL, Bologna, ITALY, 3Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL, Bologna, ITALY, 4Section of Pathology M. Malpighi, Department of Haematology and Oncological Sciences L. and A. Seragnoli, Bellaria Hospital, University of Bologna, Bologna, ITALY, 5Department of Neurosciences, Statistic and Informatic Unit, Azienda Ospedale-Università, Padova, ITALY 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 < 0.00001). Univariate analysis showed that longer TTR ( p = 0.007) and type of chemotherapy (TMZ vs nitrosoureas p = 0.033) were both significantly correlated with PFS. Only TTR showed an effect on PFS ( p = 0.07) in multivariate analysis. Median OS from recurrence was 8.6 months (95%CI:7.4-9.8), and 11.3 months (95% CI:9.5-13), 7.4 months (95%CI:6.3-8.5), and 7.1 months (95%CI:4.6-9.8), with TMZ, nitrosoureas, or other treatments, respectively. TTR and type of chemotherapy at recurrence were significantly correlated with OS ( p = 0.026 and p = 0.016) in univariate but not in multivariate analysis.

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Meningiomas represent the most frequent intracranial tumors. While most cases correspond to WHO grade I, about 5% belong to the aggressive atypical subtype, and 1% are anaplastic meningiomas with poor clinical outcome. However, even the treatment of benign subtypes might be challenging in recurrent tumors and if complete resection is impossible. So far, no chemotherapy regime has been proven to be effective; radiotherapy is used to treat aggressive meningiomas. We have previously established that human meningiomas have activated mTORC-1 signalling, and that meningioma cells are responsive to mTORC-1 inhibitors. In the present study, we used an orthotopic mouse meningioma model established in our lab to monitore the effect of systemic temsirolimus treatment on meningioma cells grown in the subarachnoidal space. Following orthotopic injection of malignant IOMM-Lee meningioma cells, mice (n = 8) were treated daily with 20mg/kg temsirolimus intraperitoneally for nine days, beginning at day 3. Control animals (n = 8) were treated with diluent only. Tumor growth was monitored by magnetic resonance imaging (MRI). We observed that at day 9, mice treated with temsirolimus had a significantly ( p < 0.01) reduced tumor volume in MRI measurements compared to controls. Western blot analysis of tumor tissue removed from the skull showed reduced phosphorylation of mTOR and p70S6K in treated mice, indicating successful orthotopic inihibition of mTORC-1 activity by intraperitoneal treatment. Thus, our study demonstrates the successful systemic inhibition of malignant meningioma cell growth by targeting the mTORC-1 pathway. These data might serve as a basis for starting a clinical trial using temsirolimus in patients with recurrent or aggressive meningiomas. Disclosure: C. Mawrin: Work was supported in part by Pfizer Inc. and the Deutsche Krebshilfe. D. Pachow: work was supported in part by Pfizer Inc. and the Deutsche Krebshilfe. E. Kirches: work was supported in part by Pfizer Inc. and the Deutsche Krebshilfe

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Annals of Oncology

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.

425P

CLINICAL IMPACT OF [11C]-METHIONINE POSITRON EMISSION TOMOGRAPHY ON THE TREATMENT OF PRIMARY AND RECURRENT GLIOMAS

Santoni1,

Berardi2,

Bittoni2,

Paccapelo3,

Nanni4,

Fanti4,

M. R. A. A. C. S. L. Burattini2, S. Cascinu2 1 Clinica Di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche, Ancona, ITALY, 2Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3Medical Oncology, Ospedali Riuniti Torrette, Ancona, ITALY, 4Department of Nuclear Medicine, University of Bologna, Bologna, ITALY

426P

COMPARISON OF MICRORNA EXPRESSION LEVELS BETWEEN INITIAL AND RECURRENT GLIOBLASTOMA SPECIMENS

A. Ilhan-Mutlu1, A. Wöhrer2, A.S. Berghoff3, G. Widhalm4, C. Marosi1, L. Wagner5, M. Preusser1 1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA, 2 Institute for Neurology, Medical University of Vienna, Vienna, AUSTRIA, 3Institute of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 4Department of Neurosurgery, Medical University of Vienna, Vienna, AUSTRIA, 5Department of Nephrology, Medical University of Vienna, Vienna, AUSTRIA Background: Glioblastoma is the most frequent primary brain tumour in adults. Recent therapeutic advances increased patient’s survival rates, but tumour recurrence inevitably occurs and is associated with dismal prognosis. The pathobiological mechanisms involved in glioblastoma recurrence are still mostly unclear. MicroRNAs are a recently identified class of small non protein encoding RNAs and tumour‐ specific microRNA signatures have been proposed as novel indicators for tumour proliferation, aggressiveness, differentiation and metastases development for many cancer types. However, there are only few data on the involvement of microRNAs in therapy resistance and recurrence of glioblastoma. Methods: We selected the following 7 microRNAs with potential relevance for glioblastoma pathobiology by means of a comprehensive literature search: microRNA196b, microRNA21, microRNA10b, microRNA181b, microRNA181c, microRNA221, microRNA222 and microRNA195. We further selected 17 primary glioblastoma patients, of whom formalin fixed and paraffin embedded tissue (FFPE) tumor tissue samples of the initial operation and a re-operation for tumor recurrence were available. Patients had received first line treatment consisting of postoperative combined radiochemotherapy with temozolomide (n = 15) or fotemustine and dacarbazine (n = 2). We analysed the expression of the 7 microRNAs in all 34 tumor tissue samples by RT-qPCR. Expression levels were correlated with each other and with clinical parameters. Results: All microRNAs except microRNA196b showed detectable levels of expressions. Comparison of microRNA levels between first and second resections revealed no significant change. Cox regression analyses showed no significant association of microRNA expression levels in the tumor tissue with progression free survival times. Conclusion: Expression levels of microRNA21, microRNA10b, microRNA181b, microRNA181c, microRNA221, microRNA222 and microRNA195 do not to differ significantly between initial and recurrent tumors and seem not to influence time to recurrence in primary glioblastoma. Disclosure: All authors have declared no conflicts of interest.

ix | Abstracts

ABLATIVE RADIOTHERAPY OF BRAIN METASTASES AND POSTOPERATIVE RADIOTHERAPY WITH OR WITHOUT “PROPHYLACTIC” CRANIAL IRRADIATION USING RAPIDARC AND SIMULTANEOUS INTEGRATED BOOST (SIB)

P.A. Gut1, K.F. Kothbauer2, R. Seiler1, R. Greiner1 1 Radioonkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND, 2 Neurochirurgie, Luzerner Kantonsspital, Luzern, SWITZERLAND Objective: Patients with solitary or few brain metastases and good performance status should be treated with a local radical intention. It remains unclear, whether additional whole brain radiotherapy WBRT is necessary. We report about our alternative radiotherapy procedure with fractionated radical dose to metastases and "mild" dose to the remaining brain. Materials and methods: From 1/2010 until 12/2011 we treated 84 metastases in 46 patients with radical intent. 25 patients had a solitary lesion and 12 were irradiated after resection. Using RapidArc technique with simultaneous integrated boost (SIB) most metastases were treated to 15 × 4 Gy = 60 Gy (PTV1) and the whole brain received - if indicated- a "prophylactic" dose of 15 × 1.8 Gy = 27 Gy (PTV2) . 13 Patients received local treatment for their metastases without WBRT. Following resection of the metastasis the tumour bed was irradiated to 15 x 3.2 Gy = 48 Gy, residual/unresected macroscopic tumour to 15 x 4 Gy = 60 Gy. A 3-5 mm margin was used from GTV to PTV, with no additional margin for CTV. The minimum dose of PTV1 was 95% of the prescribed dose, wheras the median dose for PTV2 was 27 Gy. Results: This treatment regime was tolerated very well without major toxicity and in general better than conventional WBRT (10 × 3 Gy). Median follow-up time after treatment was 7 months. 18 (39%) patients died and the median survival time is 12 months. Local tumour control after treatment with15x4 Gy has been 100%, whereas one metastasis relapsed after resection and postoperative RT (15 × 3.2 Gy). 10 patients (21%) were presented with new distant brain metastases. Conclusions: Ablative treatment of brain metastases can be performed efficiently with RapidArc and combined with prophylactic cranial irradiation using SIB. Local tumor control is nearly 100% and the toxicity is very low. Disclosure: All authors have declared no conflicts of interest.

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PHASE 1 STUDY OF VELIPARIB WITH CONCURRENT WHOLE BRAIN RADIATION THERAPY (WBRT) IN PATIENTS (PTS) WITH BRAIN METASTASES (METS)

M.P. Mehta1, W.J. Curran2, D. Wang3, F. Wang4, L. Kleinberg5, A. Brade6, J. Qian7, T. Leahy,8, B. Desai9, V.L. Giranda9 1 Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, UNITED STATES OF AMERICA, 2Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, UNITED STATES OF AMERICA, 3Department of Oncology/hematology, Henry Ford Hospital, Detroit, MI, UNITED STATES OF AMERICA, 4Dept. of Radiation Oncology, Kansas University Medical Center, Kansas City, KS, UNITED STATES OF AMERICA, 5Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, UNITED STATES OF AMERICA, 6Dept. of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, ON, CANADA, 7Global Statistics and Data Management, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA, 8Clinical Program Management-oncology, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA, 9 Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA Background: Veliparib, an oral PARP-1 and -2 inhibitor, potentiates the antitumor activity of DNA damaging agents including radiation therapy in vivo, and is shown to cross the blood-brain barrier. Updated data on safety and antitumor activity from an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts with brain mets are presented here. Methods: Pts with brain mets (including leptomeningeal) from primary non-CNS metastatic solid tumors (except germ cell cancer), adequate organ function, and Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10– 300 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety and exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1 dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates were calculated for all pts who had at least 1 measureable lesion at baseline. Median survival time was estimated using Kaplan-Meier methodology for all dosed pts. Results: To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal (n = 3), renal (n = 1), and others (n = 8); 74.2% pts had multiple lesions, and 16.7% had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities were grade 3 hypokalemia and hyponatremia in 1 pt each at the 150 mg dose. Grade 3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration (6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and

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Purpose: To assess whether 11C-methionine positron emission tomography (11C-MET PET) has a clinical significance in the management of glioma patients. Patients and methods: Fifty-three patients with histologically proven primary gliomas (16 grade II, 15 grade III, and 22 grade IV) were investigated repeatedly with 11C-MET PET. A total of 249 PET scans were performed, with a median of 4 scans for each patient. Functional imaging with PET was compared with concurrent MRI or CT. Results: We registered high sensibility and specificity in the management of glioma patients. The mean 11C-MET uptake index results significantly correlated with histological grade. The overall survival (OS) of GBM patients who underwent 11C-MET PET serial controls and parallel CT or MRI scans resulted to be 29.24 months, significantly higher compared to OS of GBM who underwent CT or MRI alone during follow up. Conclusion: 11C-MET PET allowed the detection of malignant progression in low grade glioma patients and the assessment of post-surgery status in both low and anaplastic gliomas with high sensibility and specificity. Thus, 11C-MET PET expresses its maximum potential in earlier disclosing recurrence during the long-term follow-up of GBM patients, with a relevant impact on therapeutic course and survival of these patients. Disclosure: All authors have declared no conflicts of interest.

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Annals of Oncology

hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8% and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer. Conclusion: Addition of veliparib up to 200 mg BID was well tolerated with concurrent standard WBRT and dose escalation is ongoing. These encouraging safety and preliminary efficacy data suggest that veliparib requires further evaluation as a radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial. Disclosure: M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure, Tomotherapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix; Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr. Curran had served on the advisory board of Lilly, BMS, and Plexxikon. There are no conflicts. D. Wang: As a clinical investigator, and the principle investigator at Henry Ford Health System, I have conducted this clinical trial that is financially supported by Abbott Oncology. I have no other conflict of interest to be disclosed, otherwise. L. Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B. Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott employee and stockholder. All other authors have declared no conflicts of interest.

429P

NEUROLOGICAL (NEU) AND CYTOLOGICAL (CYT) RESPONSE (R) AS EARLY PREDICTORS OF TIME-TO-PROGRESSION (TTP) AND OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH LEPTOMENINGEAL CARCINOMATOSIS (LMC) TREATED WITH INTRATHECAL (I.T) LIPOSOMAL CYTARABINE (LYC)

Background: The palliative treatment of LMC involves i.t chemotherapy or supportive care. Lcy is a slow-releasing cytarabine formulation approved for leptomeningeal involvement of hematological malignancies. In pts with LMC from solid tumors interesting Neu and Cyt R rates after i.t Lcy have been observed. However, the potential use of those responses as early predictors of TTP and OS has never been explored. Here we show how both Neu and Cyt R can precociously predict a longer TTP and OS. Patients and methods: Twenty-seven pts with LMC consecutively treated at our institution with i.t Lcy under compassionate use (17/27 female), were studied. All pts received i.t Lcy (50 mg) every 2 weeks (w) during induction and every 4 w during maintenance. Neu and Cyt responses were assessed before every Lcy cycle. Results: The predominant primary tumor origin was breast (15/27), followed by gastrointestinal (3), lung (3), brain (2), and 4 other organs. A complete Neu R (resolution of all Neu symptoms) was seen in 3/27 pts; partial R (improvement of >50% of Neu symptoms for >2 w) in 6/27 pts; stable disease (no change in Neu symptoms) in 8/27 pts and progressive disease ( progression or appearance of new Neu symptoms) in 10/27 pts. The Cyt assessment was available in 9/27 pts with a Cyt complete R confirmed in 7/9 pts. The median time to Neu and Cyt R was 15 days (d) and 14 d, respectively. The overall median TTP was 22 d and the median OS was 41 d. In a subgroup analysis regarding the type of R achieved with the treatment, the median TTP and OS for pts showing a combined Neu and Cyt R were significantly longer compared to those in pts showing both, Neu and Cyt progression as shown in table 1. The most frequently reported adverse event was grade 2 headache with no grade 4 toxicities. Conclusions: For the first time, Neu and Cyt R are shown to be early predictors of TTP and OS in pts receiving i.t Lcy for LMC. This result could help to early select patients most likely to benefit from i.t Lcy and to consider discontinuation when very poor prognosis is estimated.

Neu R Yes Yes No No

Cyt R Yes No Yes No

TTP (d) 122 14 42 3

OS (d) 141 32 72 3

p 0.001 0.001 0.001 0.001

Disclosure: All authors have declared no conflicts of interest.

430P

DEMOGRAPHIC DATA AND TREATMENT OUTCOME IN RETINOBLASTOMA: RETROSPECTIVE REVIEW FROM TERTIARY CENTRE IN INDIA

F.A. Ansari1, P. Shukla2, V. Roshan1, B. Mohanti1 1 Radiotherapy, aiims, Delhi, INDIA, 2Radiation Oncology, All India Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi, INDIA Purpose: To characterize the patient population and analyse treatment outcome in patients with retinoblastoma. Method and material: A retrospective study of 180 patients with retinoblastoma affecting a total of 297 eyes. Demographic data, tumor features and outcome were assessed.

Volume 23 | Supplement 9 | September 2012

431

BLOOD VESSELS WITH DIFFERENT CHARACTERISTICS HAVE DISTINCT IMPACT ON SURVIVAL OF GLIOBLASTOMA MULTIFORME PATIENTS

M. Kase1, A. Minajeva2, K. Niinepuu2, S. Kase3, A. Adamson2, M. Saretok2, M. Vardja4, T. Asser5, J. Jaal6 1 Dept. of Radiotherapy, North Estonia Medical Centre, Oncology and Haematology Clinic, Tallinn, ESTONIA, 2Faculty of Medicine, University of Tartu, Tartu, ESTONIA, 3Nursing, Health Care College, Tartu, ESTONIA, 4Dept of Radiotherapy and Oncological Therapy, Tartu University Hospital, Haematology and Oncology Clinic, Tartu, ESTONIA, 5Dept of Neurosurgery, Tartu University Hospital, Tartu, ESTONIA, 6Dept of Radiotherapy and Oncological Therapy, Tartu University Hospital, Tartu, ESTONIA Background: Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor in adults. GBMs are highly angiogenic: next to capillaries and bigger blood vessels, microvascular proliferations (MP) forming glomeruloid structures can be found. The aim of our study was to evaluate the prognostic significance of different blood vessel types in GBM. Methods: Between Jan 2006 and Dec 2008, 42 patients (30–77 years) received postoperative radiotherapy and chemotherapy. Surgically excised GBM tissues were histologically examined for overall proportion of MP (low, medium, high) and the total number of blood vessels ( per microscopic field). Also, immunohistochemical staining intensity of CD133 and ICAM-1 were determined in endothelial cells (arbitrary score 0–3). Finally, blood vessel parameters were correlated with patients overall survival. Results: The overall proportion of MP was low-medium in 39% and high in 61% of GBM patients. The number of blood vessels per microscopic field was 2.5 ± 1.4 (mean ± SD). A positive association was found between the number of blood vessels and endothelial CD133 staining intensity ( p = 0.03). However, between the number of blood vessels and endothelial ICAM-1 staining intensity, a negative correlation was detected ( p = 0.04). Median survival time of the study group was 10.0 months (95% CI 9.0–11.0). The proportion of MP did not significantly affect survival (log rank test, p = 0.07). However, the survival time clearly depended on the number of blood vessels in GBM tissue (log rank test, p = 0.03). Median survival times for patients with low (
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J.P. Fusco, E. Castanon Alvarez, L. Zubiri, P. Martín, O.E. Carranza Rua, J. Espinos Jimenez, J. Rodriguez, M. Santisteban, J.M. Aramendia, I. Gil-BazoDepartment of Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN

Results: The mean age of diagnosis was 32 months (range 2-204 months) for unilateral eyes and 26 months ( range 2-132months) for bilateral eyes. The male to female ratio was 1.4:1. The most common symptoms was leukokoria (74%), followed by proptosis of eye (11.5%), strabismus (8%) and poor vision (6.5%). Out of 297 eyes 39 were Group I-II, 17 were Group III, 198 were group IV-V and 43 had missing information. The mean basal diameter was 14mm (range 2–37mm). The mean interval between initial diagnosis and treatment was 7months ( range 1-36 months). Familial history was seen in eight patients (4.4%). Out of 180 patients 64 patients received radiation. 144 patients underwent enucleation. No children underwent bilateral enucleation. All patients were treated with 6–12 cycles of chemotherapy vincristine, etoposide and carboplatin. Chemotherapy offer satisfactory local control for Group I-III, with treatment failure necessitating additional radiation and or enucleation in only 14% of patients. The radiation doses were either 39Gy in 13 fraction, three fraction per week or 40Gy in 20 fraction, five fraction per week. The mean duration of follow up was 28 months (0-64months). The overall local control or freedom from relapse was 55%. Local control in patients receiving radiation after enucleation was 84%. Distant metastases were seen in 13 patients ( preauricular node (5), vertebrae (3), humerus (1), suprasellar (1), scalp (1), CSF(1), and meningeal dissemination (1)). No case of second malignant neoplasm has been reported. Conclusion: Lack of awareness leads to delay in diagnosis and treatment. Multimodality treatment is required for management of retinoblastoma. Chemoreduction offer satisfactory control retinoblastoma in group I-III, with preservation of vision. There is significant improvement in local control with radiation therapy in locally advance cases. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

432

GAMMA KNIFE RADIOSURGERY AS A MAIN MODALITY IN TREATING INTRACRANIAL LESIONS OF NF II PATIENTS

K. Abdel Karim, 1, N.M. Elmashad2, W. Reda1, A. El Shehaby1 1 Gamma Knife Center, Nasser Institute, Cairo, EGYPT, 2Clinical Oncology Department, Tanta University, Tanta, EGYPT

433

PEMETREXED AND WHOLE-BRAIN RADIATION THERAPY FOR TREATMENT OF BRAIN METASTASES FROM NON SMALL-CELL LUNG ADENOCARCINOMA: A SINGLE INSTITUTON ANALYSIS

Chargari1,

Moussaid2,

Helissey1,

Jacob1,

Bauduceau1,

C. Y. C. J. O. B. Ceccaldi1, L. Védrine1, S. Le Moulec1 1 Oncology and Radiation Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce, Paris, FRANCE, 2Rabat, Hopital d’Instruction des Armées Mohamed V, Rabat, MOROCCO Background: Folate antimetabolite pemetrexed was approved for treatment of patients with metastatic non small-cell lung carcinoma (NSCLC). Its activity on brain metastases makes it attractive in combination with whole brain radiation therapy (WBRT), but this regimen could also potentially increase toxicity. Patients and treatment: We retrospectively assessed the use of pemetrexed concurrently with WBRT in 12 consecutive patients with brain metastases from NSCLC. Patients received pemetrexed 500 mg/m2, either alone (n = 4) or combined with cisplatin 75mg/m2 (n = 6) or carboplatin AUC5 (n = 2). Median total number of pemetrexed-based chemotherapy cycles was 3.5 (range: 1–8). In the course of chemotherapy, patients received WBRT delivering 30 Gy in 10 fractions (n = 8) or 20 Gy in 5 fractions (n = 4). Results: Six patients improved neurologically with treatment (five complete and one partial responses). Four patients had their neurological symptoms stable. Best radiological response was complete response lasting until last follow-up in one patient. Five patients experienced partial response. One patient had stable disease. Progressions were identified in four patients, within a median time interval of 17 weeks (range: 6–58 weeks). Three patients were not analyzable for tumor response because of rapid systemic progression leading to death. Two of them had improved neurologically. No high-grade WBRT-toxicity was reported but one patient developed symptoms suggestive of a limbic encephalopathy five weeks after WBRT completion. Conclusion: The combination of pemetrexed with WBRT was associated with a substantial improvement of neurological deficits and tumor responses in most patients. However, survival remained disappointing and there were concerns about toxicity in one patient. A clinical trial is required for better analyzing the potential synergistic effects of drug with radiation and evaluating neurological toxicity. Disclosure: All authors have declared no conflicts of interest.

ix | Abstracts

LIMITED PREDICTIVE VALUE OF SCORING SYSTEMS FOR METASTATIC SPINAL CORD COMPRESSION (MSCC): RESTROSPECTIVE MONOCENTRIC STUDY

E. Tabouret1, C. Cauvin2, S. Fuentes3, B. Esterni4, T. Adetchessi3, N. Salem5, A. Madroszyk2, A. Gonçalves1, P. Viens6, G. Gravis-Mescam1 1 Medical Oncology, Paoli Calmettes, Marseille, FRANCE, 2Medical Oncology, Institut Paoli Calmettes, Marseille, FRANCE, 3Neuro-surgery, AP HM, Marseille, FRANCE, 4Biostatistic, Paoli Calmette, Marseille, FRANCE, 5Radiotherapy, Paoli Calmettes, Marseille, FRANCE, 6Cancer Center, Institute Paoli Calmettes, Marseille Cedex, FRANCE Background: Incidence of MSCC is increasing, paralleling increasing life expectancy of patients ( pts). We analyzed pts referred for surgery for MSCC to evaluate scoring system relevance, prognosis factors, efficiency and safety. Methods: From 2004 to 2010 148 pts (77 men) with oncologic (84%) and hematological (16 %) diseases had surgery for MSCC. Patients and tumoral characteristics were recorded. Prognostic value of Tomita, Tokuhashi scores, ASA score, Frankel score (FS) and pain was investigated. Results: Median age was 60 y (22–87). Lung (17%) and breast cancer (18%), were mainly represented. Multiple extra-bone metastases were observed in 39% of pts. Pain was present in 96% of pts and 66% were hyperalgic ( pain score > 6). FS was decreased for 49% of pts and median Karnofsky Performance Scale (KPS) was 70%. Majority had laminectomy with spinal fixation: 73 %. Radiotherapy was done for 68%. Median overall survival (OS) was 8.9 months (IC95: 4.4–13). Tokuhashi but not Tomita score was relevant. Survival predictive accuracy of TS was only 51%. By univariate analyses, moderate pain ( p = 0.001), primary breast ( p = 0.02) or hematological ( p < 0.001) diseases are associated with higher OS than lung cancer ( p = 0.004). Absence of extra-bone metastase ( p < 0.001), KPS > 70 ( p < 0.001), ASA score ( p < 0.001), FS ( p = 0.01), type of surgery ( p = 0.03), post surgery chemotherapy ( p < 0.001) presented prognostic value. By multivariate analysis extra-bone metastases ( p = 0.004), KPS ( p = 0.001) and ASA score ( p = 0.007) remained significant. Pain decrease was observed for 75% of pts. After surgery, 92% of pts were ambulatory and FS was improved for 31%. Surgery complications occurred in 16.8% and only 7% of pts died within 30 days. Conclusion: Surgery for MSCC is associated with limited morbidity, improvement of patients’ autonomy and remission of pain. In our study, usual scores seem not relevant, whereas ASA score, KPS and extra-bone metastases are significant survival prognostic factors. Disclosure: All authors have declared no conflicts of interest.

435TiP

A DUAL PHASE I/II STUDY OF TH-302 AND BEVACIZUMAB IN RESECTABLE RECURRENT GLIOBLASTOMA FOLLOWING BEVACIZUMAB FAILURE

R.M. Zuniga1, J. Sun2, J.R. Floyd1, S.R. Yerragudi1, C. Hart2, C. Eng2, A.J. Brenner1 1 Cancer Therapy and Research Center, University of Texas Health Sceince Center at San Antonio, San Antonio, TX, UNITED STATES OF AMERICA, 2 Clinical Operations, Threshold Pharmaceuticals, South San Francisco, CA, UNITED STATES OF AMERICA Introduction: Bevacizumab, a recombinant human monoclonal anti-VEGF antibody, exhibits anti-tumor activity in recurrent glioblastoma; however, the median progression free survival (PFS) of patients who progress on bevacizumab and are subsequently started on a non-bevacizumab containing regimen is only 1.6 months. Pre-clinical studies have shown that anti-angiogenic treatment leads to an increase in hypoxia in the tumor microenvironment leading to increased invasiveness. Hypoxia upregulates survival mechanisms, inhibits apoptosis, and stimulates invasiveness. TH-302 is a hypoxia-activated prodrug that once activated releases the alkylating agent Br-IPM. This drug has shown to potentiate, in vivo, the anti-tumor efficacy of other anti-angiogenic agents. This dual phase I/II study enrolled subjects with recurrent glioblastoma following bevacizumab failure that were planned for repeat craniotomy. Methods: Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered pre-operatively, followed by postoperative combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 dose escalated 240–480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Resected tumor tissue was evaluated for hypoxia induced pimonidazole adducts, endogenous CAIX staining, double-strand DNA damage by gamma-H2AX and MGMT expression. Results: Five patients underwent craniotomy and initiated TH-302 plus bevacizumab. No dose limiting toxicity was reported. There were no grade 3 or 4 adverse events (AEs) observed at 240mg/m2, and one grade 3 (skin ulceration) and no grade 4 AEs observed thus far in the second cohort at 340mg/m2. Of the initial 5 patients treated, one patient had a partial response (PR) and 3 patients had stable disease (SD) per RANO criteria. Histological assessment of resected tumors demonstrated extensive areas of hypoxia as measured by pimonidazole and a heterogeneous distribution of gamma-H2AX staining.

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Objective: Gamma knife radiosurgery GKS was used for the treatment of the patients with Neurofibromatosis type II (NFII) for years to achieve better tumor control and to avoid the post operative neurological deficits. This study aimed at exploring the effect of GKS on the tumor control rate, the avoidance of new neurological deficits, and the associated morbidity. Methods: We revised the data of 50 intracranial NFII patients (either vestibular schwannomas or meningiomas) who were treated consequently between July 2001 and October 2009 in our center, the data of 43 patients were evaluable. The mean follow up period was 43.7 months (range 6 to 96). We treated 22 females (51.2%) and 21 males (48.8%) with a mean age of 27.6 years (range 9–53 years). Eight patients (18.6%) had a family history of NFII, 29 patients (67.4%) had previous surgeries. A hundred and seventy NFII lesions were treated in 169 treatment procedures, 83/170 were vestibular schwannomas and 87 were meningiomas. The mean number of treated lesions per patient was 3.97 (range 1–14). The mean marginal dose was 11.9 Gy (range 8 to 13 Gy), with a mean isodose of 52.5%, mean percent coverage was 95.7% (ranged 71-100%). The mean target volume was 11.1 cc (range 0.1 to 26.11 cc). Results: Regarding the overall radiological response, 16 lesions (9.4%) had regressed, 146 (85.9%) remained stable, and 8 (4.7%) had progressed. For 83 schwannomas, 7 lesions (8.4%) had regression, 72 (86.7%) remained stable, and 4 (4.8%) developed progression. For the 87 meningiomas, 9 (10.3%) had regressed, 74 (85.1%) were stable, and 4 (4.6%) had progressed. The Overall survival rate (OS) for all patients was 95.3% (only 2 died), the mean tumor control rate of 95.1%. The overall Freedom from neurological deficits was 97.7%. Only one patient complained of Grade III facial palsy which was temporary and resolved after medical treatment. Using a median dose of 12 Gy maintained serviceable hearing in 56.6% of ears. Conclusion: Gamma knife radiosurgery for NFII patients can achieve good tumor control and preserved function with low risk of morbidity. Disclosure: All authors have declared no conflicts of interest.

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Annals of Oncology

Conclusions: TH-302 demonstrates good tolerability when combined with bevacizumab. The MTD has not been reached and only one grade 3/4 toxicity was observed. Dose escalation is ongoing, with planned expansion at the MTD. Disclosure: J. Sun: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. C. Hart: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. C. Eng: The author is an employee of pharmaceutical industry with a financial interest in the drug which is the subject of this abstract. All other authors have declared no conflicts of interest.

437TiP

A RANDOMISED PHASE II STUDY OF CARBOPLATIN AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA MULTIFORME (CABARET STUDY). COOPERATIVE TRIALS GROUP FOR NEURO-ONCOLOGY (COGNO)

K. Field1, M.A. Rosenthal1, H. Wheeler2, L. Cher3, E. Hovey4, A.K. Nowak5, C. Brown6, A. Livingstone6, K. Sawkins6, R.J. Simes6 1 Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, AUSTRALIA, 2Medical Oncology, Royal North Shore Hospital, Sydney, NSW, AUSTRALIA, 3Neuro-Oncology, Austin Hospital, Melbourne, VIC, AUSTRALIA, 4 Medical Oncology, Prince of Wales Hospital, Sydney, NSW, AUSTRALIA, 5 Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA, AUSTRALIA, 6 Clinical Trials, NH&MRC Clinical Trials Centre, University of Sydney, Sydney, NSW, AUSTRALIA

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doi:10.1093/annonc/mds394 | ix

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Background: Glioblastoma (GBM) is the most aggressive malignant glial tumor. There is no accepted standard management after disease progression. Much remains unknown about the optimal use of bevacizumab (bev), including the role of continuing beyond progression, and patterns of radiological progression during and

after use. In addition, the new Response Assessment in Neuro-Oncology (RANO) criteria have yet to be validated prospectively. Methods: This study is a multi-centre, stratified randomised phase II trial. Patients have recurrent GBM after radiotherapy and temozolomide, have had no other chemotherapy for GBM, and have ECOG performance status 0–2. At least three months have elapsed since radiotherapy. In Part 1, patients are randomised 1:1 to intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev monotherapy. On progression, eligible patients are randomised to continue or cease bev (Part 2). The primary objective is to determine the effect of bev plus carboplatin versus bev alone on progression-free survival according to modified RANO criteria. Secondary endpoints are response rates, cognitive function, quality of life, steroid dose, toxicity, and overall survival. CogState, a validated neurocognitive testing system, is being used prospectively for the first time in this population and compared with mini-mental state examination. Exploratory endpoints include biomarker analyses, comparison of modified RANO and modified MacDonald criteria, predictive value of early MRI after 2 doses of bev, steroid dosing, and location and type of radiological progression during and after therapy. Results: Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar 2012 with 122 patients randomised from 17 Australian sites. Randomisation to Part 2 continues. Feasibility and safety data will be presented; efficacy outcome results are not expected until 2013. Conclusions: The study results will significantly improve knowledge regarding the use of bevacizumab in the setting of recurrent GBM, as well as providing for the first time a prospective analysis of CogState neurocognitive testing for patients with brain tumours. Disclosure: M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak: Roche Advisory Board member and has received research funding through Roche Australia. R.J. Simes: Roche Advisory Board Member. All other authors have declared no conflicts of interest.