M. Martinez-Garcia

Bevacizumab plus irinotecan in recurrent malignant glioma shows high overall survival in a multicenter retrospective pooled series of the Spanish Neuro-Oncology Research Group (GEINO).

There is no ‘standard of care’ for recurrent malignant glioma (MG). Our aim is to confirm the efficacy and safety of bevacizumab 10 mg/kg plus irinotecan 125 mg/m2 (or 340 mg/m2 if enzyme-inducing antiepileptic drugs) every 2 weeks for a maximum of 1 year in a retrospective pooled series of patients with recurrent MG. The inclusion criteria were as follows: age 18 years and above, histology of MG, progression after radiation and temozolomide, Karnofsky performance status (KPS) of at least 60, and signed informed consent for bevacizumab compassionate use. Response was assessed by MRI using the Macdonald criteria and evaluation of the FLAIR sequence every 8 weeks. A total of 130 patients were enrolled; 72% had glioblastoma (GBM). The median age of the patients was 53 years (20–78); the median KPS was 80%; the median number of prior chemotherapy lines was 2 (1–5); the median interval between the diagnosis of MG and inclusion was 14.6 months (2–166); and the median number of bevacizumab infusions was 8 (1–39). The median follow-up duration was 7.2 months (1–47). The median overall survival (OS) was 8.8 months for GBM and 11.2 months for anaplastic glioma (AG). The median progression-free survival was 5.1 months for GBM and 4.6 months for AG. The response rate was 56% for GBM and 68% for AG. Neurological and KPS improvements were observed in 49 and 45% of patients. Only KPS less than 80% was associated with a worse significant response rate (odds ratio, 0.57; 95% confidence interval, 0.22–0.96). The most frequent grades 3–4 toxicities were asthenia (7%), diarrhea (6%), and thromboembolic events (5%). There were five toxic deaths (4%). Bevacizumab plus irinotecan in recurrent MG improves responses, progression-free survival, and OS compared with historical data. KPS of at least 80% was a predictive factor for response and OS.

Role of flow cytometry immunophenotyping in the diagnosis of leptomeningeal carcinomatosis

PURPOSE To explore the contribution of flow cytometry immunophenotyping (FCI) in detecting leptomeningeal disease in patients with solid tumors. EXPERIMENTAL DESIGN Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n = 49), without LC (n = 26), and undetermined (n = 3). RESULTS FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp = 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P = .06). Receiver-operator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC. CONCLUSION FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.

Differences in cerebrospinal fluid inflammatory cell reaction of patients with leptomeningeal involvement by lymphoma and carcinoma

Dissemination of neoplastic cells into the cerebrospinal fluid (CSF) and leptomeninges is a devastating complication in patients with epithelial cell neoplasia (leptomeningeal carcinomatosis [LC]) and lymphomas (lymphomatous meningitis [LyM]). Information about the surrounding inflammatory cell populations is scarce. In this study, flow cytometry immunophenotyping was used to describe the distribution of the main leukocyte populations in the CSF of 83 patients diagnosed with neoplastic meningitis (LC, n = 65; LyM, n = 18). These data were compared with those obtained in the CSF from 55 patients diagnosed with the same groups of neoplasia without meningeal involvement (solid tumors, n = 36; high-grade lymphoma, n = 19). Median (interquartile) rates of lymphocytes, monocytes, and polymorphonuclear (PMN) cells were 59.7% (range, 35-76.6%), 24% (range, 16-53%), and 1.5% (range, 0-7.6%) in LC, respectively, and 98.5% (range, 70.8-100%), 1.5% (range, 0-29.3%), and 0% in LyM, respectively (P < 0.001). No difference was observed between patients with breast adenocarcinoma (n = 30) and lung adenocarcinoma (n = 21), nor with different rates of malignant CSF involvement. Patients with lymphoma (with or without LyM) had a similar CSF leukocyte distribution, but cancer patients with LC and without LC had a distinctive PMN cell rate (P = 0.002). These data show that CSF samples from patients with LC have a greater number of inflammatory cells and a different leukocyte distribution than seen in the CSF from patients with LyM. Description of PMN cells is a distinctive parameter of patients with LC, compared with the CSF from patients with LyM and patients with cancer but without LC.

P17.35GEINO-10: A PROSPECTIVE OBSERVATIONAL MULTICENTER STUDY OF THE CHARACTERISTICS OF PATIENTS WITH INTRA-AXIAL BRAIN TUMOURS AND THEIR THERAPEUTIC MANAGEMENT IN SPANISH HOSPITALS.

INTRODUCTION: Primitive brain tumours (BT) represent 2% of adult malignancies. BT patients are treated by different clinical specialists in Spanish hospitals. This means that we did not know with certainty how these patients are treated in Spain. To improve this knowledge the Neuro-Oncology Investigation Spanish Group (GEINO) designed this prospective observational multicenter study. OBJECTIVE: Describe the clinical and pathological characteristics and therapeutic management of intra-axial BT patients diagnosed after January 2010 in Spain. PATIENTS AND METHODS: Patients >18 years old, diagnosed after January 2010 of a intra-axial BT, treated or not, and gave written informed consent. RESULTS: 397 patients from 22 hospitals were enrolled between 08/01/2012 and 12/03/2013. The median age was 56.9 (18-83) years. 58% were male and 42% female. 87% had ECOG ≤2. 48.5% had comorbidity. 9% had previous history of cancer (2% BT). Symptoms at diagnoses: seizures 30%, epilepsy 25%, cognitive impairment 23.5%, ataxia 7.5%. BT was located in frontal lobe in 33.5%, temporal 29%, parietal 13%, posterior fosse or brainstem 5%. By histology Glioblastoma (GBM) were 67%, anaplastic astrocytoma (AA) 12%, oligodendroglioma or oligoastrocytoma grade 2-3 were 11%, low-grade astrocytoma 6%, medulloblastoma 2% and ependymoma 1%. Of the 313 patients with GBM or AA 98% underwent surgery (SR): 40% complete resection, 41% partial, 11% stereotactic biopsy and 7% open biopsy. 8% of patients received neoadjuvant temozolomide (TMZ) + /- bevacizumab (BV) into a clinical trial. 94% of patients received radiotherapy (RT): 72% focal, 21% whole-brain and 6% hemi-brain. 83% of patients received adjuvant chemotherapy (QT): 99% TMZ with a median of 5 cycles (1-18) and 1% PCV (all were AA). Median Progression Free survival was 10.4 months (95%CI: 9-11.8) for GBM and 31.1 months (95%CI: 12.2-49.9) for AA. 130/167 (78%) of GBM or AA patients received treatment at 1st relapse: 14% SR, 8% RT and 96% QT (CPT11 + BV 31.5%, TMZ 20%, BV 15.5%, fotemustine 12%, dacomitinib 4%, lomustine 3% other 10%). Radiological response (RR) was documented in 26% of cases. 52 (32.5%) patients received treatment at 2nd relapse: SR 4%, RT 2% and QT 100% (Fotemustine 59%, CPT11 + BV 29%, BV alone 28.5%, other 8%). RR was documented in 9% of cases. Only 15 (9%) patients received treatment at 3th relapse. Median overall survival (OS) for GBM was 23.6 months (95%CI: 16-31.2. Median OS for AA was not reached. CONCLUSION: This study reflects the clinical and pathological characteristics and the treatment administered to patients with intra-axial brain tumors treated at Cancer Services in Spain. First treatment was the standard in almost all patients. The exceptionally good OS in GBM patients probably reflects a selection of patients with good ECOG. This information can be useful to homogenize and to optimize treatment and for future clinical trials in BT patients.

417OMGMT METHYLATION IN TISSUE AND SERUM FROM UNRESECTABLE GLIOBLASTOMA (GBM) PATIENTS (P) INCLUDED IN THE GENOM 009 STUDY, A MULTICENTER RANDOMIZED STUDY BY THE GEINO GROUP COMPARING TEMOZOLOMIDE (TMZ) VERSUS TMZ-PLUS-BEVACIZUMAB (BEV). (CLINICALTRIALS.GOV NCT01102595)

ABSTRACT Aim: We compared treatment with TMZ versus TMZ + BEV prior to and concomitant with radiotherapy in unresectable GBM p. The potential prognostic role of MGMT methylation was examined in p with available tissue and/or serum samples. Methods: Patients were randomly assigned to receive either TMZ (200 mg/m2, days 1–5, for two 28-day cycles), followed by TMZ with concomitant radiotherapy (60Gy) (TMZ Arm) or the same regimen with the addition of BEV (10mg/kg /15 days) (BEV Arm). Both arms then received adjuvant TMZ for 6 cycles. The primary endpoint was overall response rate (ORR) according to RANO criteria after the two pre-radiotherapy cycles. Secondary endpoints included the analysis of MGMT methylation in serum and/or tissue as a potential prognostic marker. MGMT methylation was analyzed in a blinded fashion in two separate molecular biology laboratories using identical techniques. Results: 93 p were randomized – 45 to the TMZ Arm and 48 to the BEV Arm. ORR was higher in the BEV Arm (P = 0.001). Progression-free survival (PFS), overall survival (OS) and 1-year survival were longer in the BEV Arm but differences did not reach statistical significance. MGMT methylation was analyzed in tissue samples from 60 p, 55 of whom were evaluable for response and survival; MGMT was methylated in 28 and unmethylated in 29 (3 no evaluable). MGMT methylation was analyzed in serum samples from 77 p, 72 of whom were evaluable for response and survival; MGMT was methylated in 11 and unmethylated in 61 p. In 40 p with MGMT methylation results in both tissue and serum, no significant concordance between tissue and serum methylation was observed. Tissue MGMT methylation was associated with longer PFS (P = 0.01), OS (P = 0.001) and 1-year survival (P = 0.004), but no association between serum MGMT methylation and outcome was observed: PFS (P = 0.72). OS (P = 0.84) or 1-year survival (P = 0.98). Conclusions: MGMT methylation in serum is not useful to predict outcome in GBM p. The low proportion of p with serum MGMT methylation suggests a possible contamination of DNA with lymphocytes. Disclosure: C. Balana: Carmen Balana is a membership of advisory boards of Roche and has a grant from Roche and MSD to perform this study. All other authors have declared no conflicts of interest.