Background MET signaling has a role in gliomagenesis and glioma stem cell maintenance and midkine (ALK ligand) promotes resistance of glioma cells to anticancer therapies. Crizotinib is an ALK and c-MET inhibitor with a preclinical rationale to be tested in newly diagnosed GB. Methods Elegible patients received crizotinib in addition to standard RT and TMZ and then adjuvant TMZ. Maintenance treatment with crizotinib beyond 6 TMZ cycles was allowed. The primary objective was safety evaluation. Secondary objectives included efficacy (progression free survival (PFS) and overall survival (OS)) and an exploratory biomarker analysis. PFS and OS were estimated with Kaplan–Meier method. The results of the dose-escalation cohort (DE) have been reported previously. 250 mg/d was the crizotinib dose selected for the expansion cohort (EC). We report here safety and efficacy for the whole cohort. Results 38 patients (pts) were enrolled, 37 evaluable for safety and 36 for efficacy (12 included in DE). Median age 52 years (33-76). 44%were male. Median KPS 90%, Barthel 100%. 44% were MGMT methylated and 3 pts had IDH1/2 mutation. Most common related adverse events (AE) (all grades) included: nausea (67.6%), asthenia (62.2%), transaminase elevation (40.5%), neutropenia (32.4%) thrombocytopenia (29.7%), diarrhea (29.7%), anorexia (29.7%), vomiting (27%) and constipation (24.3%). In the EC 8/25 pts (32%) presented grade ≥3 AEs (transaminase elevation, thrombocytopenia). 97.2% finished concomitant therapy. 94.4% initiated adjuvant treatment, 67.7% completed 6 TMZ cycles. 18 pts (50%) started maintenance therapy. 8 pts are still on treatment. At the time of this analysis 24 pts have progressed and 1 died without progression. Median follow up was 13.7 months (m), median PFS was 10.78m (95% CI, 7.61-13.94), with 6 month PFS and 12 month PFS of 71.6% and 40.2% respectively. Median OS was 31.4 m(95% CI, 12.64-50.10) with 12month OS of 78.9% and 24month OS of 56.6%. Conclusions In this phase Ib study addition of crizotinib to standard RT and TMZ was safe and resulted in highly promising efficacy for newly diagnosed GB, deserving further investigation. Clinical trial identification NCT02270034. Legal entity responsible for the study GEINO. Funding PFIZER. Disclosure M. Martinez Garcia: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: ROCHE; Travel / Accommodation / Expenses: PFIZER. E. Pineda: Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Amgen. All other authors have declared no conflicts of interest.

PurposeWe retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients.Patients and methodsWe compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy.ResultsOS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13weeks for the NA group and 4.2weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12weeks and the shortest by patients who started radiotherapy within 4weeks (12.3 vs 6.6months) (P=0.05). OS was 6.6months for patients who started radiotherapy before the optimal cutoff of 6.43weeks and 19.1months for those who started after this time (P=0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P=0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor.ConclusionIn our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

Background: There is no standard treatment in recurrent GB and overall survival (OS) ranges from 3 to 9 months (m). The aim of this study was to identify clinical or biological factors that guide the best therapeutic strategy. Methods: We identified 397 patients (Pts) from GLIOCAT database (432 patients uniformly treated with Stupp’s regimen) who had recurrent GB: 250 Pts received 1 or more active treatment (TT) and 147 Pts didn’t. We analysed clinical and molecular characteristics, treatments received, OS and progression-free survival (PFS). Results: The median TT lines after recurrence was 1 (0-5). At 1st recurrence surgery was performed in 51 (30 alone), RT in 8 and systemic therapy (ST) in 208 Pts (189 without any local TT): Bevazicumab (BV) ± Irinotecan (IR) 90; clinical trial (CT) 42; TMZ 27; Nitrosoureas (NU) 27]. Pts without any TT were older (p < 0.001), had worse KPS (p < 0.001), worse Mini-Mental (MM) (p = 0.003), more biopsies than resection (p < 0.001) and did not complete the 6 cycles of adjuvant TMZ (p < 0.001) analyzed by χ2. In the multivariate analysis the only two variables statistically significant for OS were receiving treatment at progression (OS 2.5m vs 10.6m p < 0.0001) and biopsy versus partial or complete resection at diagnosis (p = 0.005). Methylated MGMT tumours had a worse OS from the time of relapse, irrespective of the treatment administered (p = 0.014). Salvage surgery did not present better OS (p = 0.69). 230 Pts had a 2nd recurrence: 128 received a 2nd line TT (surgery 8; RT 5 and ST 114: BV ± IR 42; NU 31; TMZ 19; CT 11; other 11). 110 Pts had a 3th recurrence: 42 received a 3th line. Pts who received TT had better OS than those who did not receive TT in 2nd (p < 0.0001) and in 3th recurrence (p < 0.0001) evaluated by Log rank test (Kaplan-Meier). BV was the TT that obtained the highest median PFS in the 1st and 2nd relapse. There were no significant differences in OS between the different TT regimens (median OS from relapse 7.7 m). Conclusions: Pts who received TT at recurrence offered a better OS in multivariate analysis. Pts undergoing surgery did not present better OS than those who only received ST. MGMT methylation is not a predictor of better OS in recurrence. Pts treated with BV had longer PFS but not OS. Legal entity responsible for the study: GLIOCAT Funding: None Disclosure: M. Gil-Gil: Membership on a Roche advisory board. All other authors have declared no conflicts of interest.

INTRODUCTION:Skull base metastases (SBM) are an infrequent and late type of cancer progression that are associated to poor prognosis. Its clinical manifestations may be grouped in five clinical syndromes and radiotherapy is its more frequent treatment. Because of the improvement in imaging tests and the close follow up of cancer patients, SBM can be diagnosed incidentally. In this group the best option of treatment has not been established. AIM:To analyze the clinical features and outcomes of patients with SBM diagnosed incidentally. PATIENTS AND METHODS:Between January 2012 and December 2015, 31 patients with diagnoses of SBM from solid primary tumor were reviewed. RESULTS:SBM were diagnosed due to skull base syndromes (n = 24) or incidentally (n = 7). Symptomatic patients were treated with radiotherapy. Patients diagnosed incidentally remained without symptoms of craneal base involvement during the follow up, although they frequently had other types of intracranial progression. A statistically significant difference in survival was observed between symptomatic and asymptomatic patients (p = 0.001). CONCLUSIONS:The incidentally diagnosed SBM were frequently associated to other types of intracranial progression, limiting the options of treatment.

Prognosis of GBM is especially poor for unresected patients even when treated with the standard EORTC regimen. We analyzed clinical characteristics, median progression free survival (PFS) and median overall survival (OS) of unresected patients from the database of the GLIOCAT study (432 patients uniformly treated with the EORTC regimen). Sixty-five patients began concurrent therapy. OS for all patients who started treatment was 7.2 months (95% CI:4.3-10.2). Fourteen patients could not even complete the concomitant phase (TMZ + RxT) (21.5%). Fifty-one patients (78.5%) completed concomitant treatment and are described here. Median age: 61 years old (29 males and 22 females). Multifocal tumor in 12 patients. Median lapsed time to start RT: 4 weeks. PFS was 6 months (95% CI: 3.9-8.03) and OS was 9 months (95% CI:6.4-11.5). MGMT status was available for 31 patients. OS and PFS were 12 months (95% CI: 5.1-18.7) and 8 months (95% CI: 6.5-9.4) for mMGMT vs 7 months (95% CI: 1.1-12.8) and 5 months (95% CI: 3.2-6.7) for mMGMT (NS). Only age (older than ≥50) emerged as a poor prognostic factor: OS 8 (95% CI: 5.7-10.2) vs. 19 (95% CI: 9.4-28.5); P = 0.05. Treatment at recurrence was administered to 20 patients (30.7%). OS and PFS for those patients was 18 months (95% CI: 15.3-20.6) and 7 months (95% CI: 5.9-8.0), respectively, compared with 6 months (95% CI: 5.0-6.9) and 4 months (95% CI: 1.6-6.3) for patients without a second line treatment. Median OS for unresected patients treated with the standard treatment is similar to that reported in the pivotal trial. However, 21.5% could not even complete concurrent therapy, and only 30.7% could receive a second line therapy.

LR/PsP is more frequent in Met patients than in UnMet ones and it is considered an expression of therapeutic efficacy due to the combination with temozolomide and radiotherapy (TMZ&RT) of the Stupp's scheme. Our aim was to figure out if an ER at first evaluation (no PsP) was better or worse than a LR/PsP. From the GLIOCAT study data base (432p) we identified those patients who had the first disease assessment within 60 days after the last day of concurrent TMZ&RT having further evaluations at 3/6 months or until progression while continuing on adjuvant TMZ treatment (256p). We defined ER as those patients without progression at first evaluation, and LR/ PsP as those that progressed at first evaluation but improved or maintained stable disease at subsequent evaluations. At first evaluation 128/256 (50%) p had an ER and 128/256 (50%) were at suspected progression (P); 56 of them improved at second and 4 at third evaluation (so 60 patients (23.5%) were considered as LR/PsP and 68 p (26.5%) were real P. PsP/LR was seen for any kind of initial surgery (0.12) and was more frequently seen in Met p (66%) than in unMet ones (34%). Conversely Met p had less real progressions (37.7%) than unMet p (62.3%) p = 0.01. All IDH1 mutated p (9) had ER (7) or PsP/LR (2) to treatment. Median Overall Survival (OS) was not different for patients with LR/PsP (17.9m) than those with ER (19.7); P = 0.48. (OS was only 12.3m for P patients). Nevertheless, Met p lived longer if they had ER (N = 45: 30.9m) than if they had LR/PsP (N = 33: 17.9m); P = 0.59. This held not true for unMet p: ER (N = 53: 18.0m) vs LR/PsP (N = 17: 17.9m); P = 0.44. Although differences were not significant, our results suggest that LR/PsP does not increase survival and that it is a deleterious effect especially for Met p where it is more frequently observed. This should be explored in a larger series.

GB incidence is growing in elderly patients (pts), and approximately 50% of GB pts are over 65 years old. There is no standard treatment for newly diagnosed GB elderly patients. Elderly population is lacking of known molecular prognostic factors. We report a multicenter study of newly diagnosed GB treated with Ch-RT(Stupp regimen). In this substudy we analysed outcome and prognostic factors in > 65y. Baseline characteristics and preliminary survival results will be presented at 2016 ASCO meeting, abstract 2045. We report the final survival and new data regarding pseudoprogression and molecular analysis. Between 2005 to 2014, 148 pts over 65y were enrolled. There were 117 (79%) >65-75y and 31 (21%) >75y with a median age of 72y. 19 pts (14.7%)presented pseudoprogression(psPD) in >65y, comparing to 42 (17.6%) in younger population (p = 0.47). MGMT methylation status was studied in 116 pts of which 65 (56%) were methylated vs 87 (40.3%) in ≤65y (p = 0.006). IDH1 status was studied in 82 pts >65y, none of them presented mutated IDH1vs 10 (5.6%) in younger pts(p = 0.029). Median follow up was 13.5 months (mo). In the global population median progression-free survival (mPFS) and overall survival (mOS) were 8 mo(95% CI, 7.49-8.5) and 14 mo (95% CI, 12.74-15.25) respectively, compared to 7 mo(95% CI, 6.09-7.9) and 10 mo (95% CI, 7.97-12.02) in >65y (p = 0.020 and p< 0.000). mOS in elderly pts presenting pseudoprogression was 16mo (95% CI, 13.23-18.76) vs 9 mo (95% CI 7.29-10.7) without it (p = 0.022). Pts with methylated MGMT had a higher incidende of psPD (p = 0.05). For elderly pts on multivariate analysis, gross total resection and pseudprogression but not KPS or MGMT were independent predictors of OS and PFS. We confirmed that PFS and OS were poorer in >65y. There were no differences in the rates of pseudoprogression and MGMT methylation in the elderly population comparing to younger pts. Pseudoprogression had significant impact in OS. None of the elderly pts studied presented IDH1 mutation. For elderly patients, type of resection and pseudoprogression were the more relevant prognostic factors in newly diagnosed GB treated with the Stupp regimen.

BACKGROUND: Glioblastoma (GBM) is the most life-threatening primary brain tumor, especially in elderly. Despite aggressive treatment, median survival among all GBM patients is only 12-15 months and is worse in elderly (6-9 months). The standard of care for elderly remains controversial. The purpose of this study is to assess the benefit of conventional treatment (Stupp regimen) in elderly patients. METHOD: We retrospectively reviewed a prospective database of 209 patients who were diagnosed with GBM at a single center from January 2005 to March 2013. All patients were divided into younger and elderly groups based on the cut-off age of 65 years. RESULTS: Of 209 patients diagnosed with GBM, 122 (58%) patients were younger than 65 years, and 87 (42%) patients were 65 years old or older. No differences were found in basal patient characteristics and neither in grade of resection between age subgroups. However elderly received less active treatment, radio-chemotherapy was less frequent in elderly (51% vs 73%) but radiotherapy alone (18% vs 8%) and non-oncological treatment after surgery was more frequent in elderly (31% vs 18%) (p = 0.002). No differences in median survival were found in elderly patients who received the same approach treatment than young patients. Median OS was 10.8 months in all GBM patients, 8.7 months in older and 13.6 months in younger patients (p = 0.019). Of all, 106 (51%) patients received Stupp regimen, 41 (47%) elderly and 65 (53%) young. Median OS in patients treated with conventional treatment was 18 months, without differences by age, 15.3 months in older and 18 months in younger (p = 0.228), neither differences were found in PFS (global of 8.2 months, 9.7 and 8.2 months, p = 0.307). MGMT status information was available only for 45.5% of patients that received Stupp regimen, 23 MGMT methylated, 25 MGMT unmethylated and 58 patients with MGMT not evaluable or not done. Surprisingly, no differences in OS were found between groups by MGMT status (19.2, 18.1 and 15.7 months respectively, p = 0.405). Significant differences in OS and post-progression survival (PPS) were found if patients received or not treatment at relapse (7.7 versus 20 months, p < 0.0001 and 1.7 versus 8.9 months, p < 0.0001). No differences between age subgroups in receiving it or not. Bevacizumab (BVZ) was the recurrence treatment in 60% of patients treated (31/52). PPS was better in patients treated with BVZ than in those treated with chemotherapy or surgery (12.4, 5.1 and 8.9 months, p < 0.0001). CONCLUSION: Elderly population newly diagnosed with GBM benefit from conventional treatment. Probably, undertreatment is the most important factor associated with poor survival in elderly newly diagnosed with GBM. Therefore, elderly patients should be encouraged to receive conventional active treatment. Recurrence treatment with bevacizumab might be an important factor in improving survival in the last few years.

BACKGROUNDConcurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT.PATIENTS AND METHODSPatients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF).RESULTSIn the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable.CONCLUSIONOverall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

Poster: ECR 2012 / C-1628 / Analysis of perfusion MR changes in radiated white matter by: Oleaga Zufiria, I. Valduvieco, M. T. Pujol Farre, E. Verger, F. Graus, T. Ribalta, L. Caral; Barcelona/ES

5594 Background: An association between folliculitis by cetuximab and improved survival has been previously reported. It is know that the addition of cetuximab increases epithelitis by RT. We analy...

e17058 Background: With the new indications of chemotherapy or cetuximab in HNSC, the rate of pts receiving these therapies nowadays is unclear. Methods: This retrospective study identified all consecutive pts with HNSC from January 1, 2006, to December 31, 2007, presented in a multidisciplinary team to decide further treatment in a single institution. ASCO guidelines for larynx preservation were followed to select surgery or chemoradiotherapy (ChRt). We classified the intention-to-treat as palliative, adjuvant or induction therapy. In the last case, always with concomitant radiotherapy (Rt) or prior to concomitant ChRt. Cetuximab was indicated with Rt as induction therapy for pts with problems to receive platin-based chemotherapy. Results: : A total of 350 pts were identified, 320 were male (91%), and 30 female (9%), with mean age 60.4 (range 41–90). Primary tumor was located in glottis (41%), supraglottis (19%), hypopharynx (11%), oropharynx (20%), or mouth (9%). Staging was I (27%), II (22%), III (16%), or IV (35%). Surgery alone was performed in 136 pts (39%) and chemotherapy or cetuximab in 214 other pts (61%). The intention-to-treat was palliative in 69 (32%), adjuvant in 51 (24%), or induction 94(44%) of the pts respectively. Rt plus cetuximab was administered to 31/97 (33%) and Rt plus chemotherapy in 63/97 (67%) pts as induction therapy. During this 2-year period, some pts received both induction/adjuvant and palliative chemotherapy. Conclusions: Chemotherapy or cetuximab is indicated as part of treatment in more than a half of pts with HNSC. Induction therapy is the most frequent indication. No significant financial relationships to disclose.

13021 Background: Current standard treatment of newly diagnosed GBM is radiotherapy (RT) with concurrent Temozolomide (TMZ), followed by TMZ according to the EORTC/NCIC trial. MGMT promoter methylation status has been correlated with prolonged overall survival (OS) and survival benefit from treatment with TMZ and RT. The aim of our study is to assess the efficacy of this schedule in a cohort of patients (pts) out of a trial, and the prognostic implication of the MGMT methylation status in the same unselected population. Methods: From March 2002 to December 2005 89 pts were reviewed from 8 centers. A Kaplan Meier method and a multivariate analysis (MA) using the Cox model were performed to study the time to progression (TTP) and OS. DNA was available from paraffin in 71 samples. DNA was modified with bisulfit, and methylation specific PCR (MSP) was performed. MGMT promoter methylation status was assessed in 62 (69%) pts. Results: Median age 57 years(y) (18–80). 61,8% males. Complete resection (CR) in 33,7%, partial resection (PR) 48,3% and biopsy (B) 18%. Median Karfnosky (IK)90% (40–100). 58% needed dexamethasone (DXM) during RT. 92,1% completed RT-TMZ. 80,9% started adjuvant TMZ. 40,4% completed 6 cycles. Median number of cycles: 4. Median follow up 23 months(m). TTP: 6,9m (CI: 5,4–8,5). In the MA extend of surgery (RR CR vs PR: 1,43 (CI:0,83–2,43) and RR CR vs B: 2,22 (CI: 1,14–4,3)) and age >60y(RR 1.88 CI:1.17–3.04) were significant for recurrence. Median OS: 13,6m (CI 12.1–15.2). DXM treatment RR=1.96 (IC: 1.1–3.4) and >60y RR=1.94 (IC: 1.15–3.28) were significant in the MA for survival. No statistical difference was seen for gender, IK. MGMT methylation: 45,2%. Median survival for patients with methylated MGMT: not reached. Median survival for unmethylated: 12,5m. (p 0,029). No statistical difference was found in TTP according to methylation of MGMT (p 0,6). Conclusions: OS and TTP of this pts were similar to the EORTC/NCIC trial. Determination of methylation of MGMT is feasible and reproducible in the clinical practice. The % of methylation that we found is similar to previously reported. Methylated MGMT is a favourable prognostic factor for OS. Age> 60y and extend of surgery are prognostic factors for PFS, while DXM and age are for OS. No significant financial relationships to disclose.