O. Gallego

Efficacy of Sequential High-Dose Doxorubicin and Ifosfamide Compared With Standard-Dose Doxorubicin in Patients With Advanced Soft Tissue Sarcoma: An Open-Label Randomized Phase II Study of the Spanish Group for Research on Sarcomas

PURPOSE To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma. PATIENTS AND METHODS Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m(2) per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m(2) delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B). RESULTS Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14). CONCLUSION Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.

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.

A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma.

To determine the maximum tolerated dose of irinotecan administered every 2 weeks, in combination with a fixed and continuous administration of temozolomide, in patients with glioblastoma at first relapse. Patients received oral temozolomide at a fixed and continuous dose of 50 mg/m2 divided into three daily doses, except for a single 100 mg/m2 dose, administered before every irinotecan infusion. Irinotecan was given intravenously on days 8 and 22 of 28-day cycles. The starting dose of irinotecan was 100 mg/m2, and this was escalated by increments of 15 mg/m2 in cohorts of 3–6 evaluable patients. Determination of the dose-limiting toxicity was based on toxicities recorded from day 1 of the first cycleto day 8 of the third cycle. Enzyme-inducing antiepileptic drugs were not allowed. Tumor response was assessed by MRI every 8 weeks. Twelve patients were enrolled in this phase I study. The three patients enrolled at dose level 1 and six of nine patients enrolled at dose level 2 were evaluable for toxicity. The maximum tolerated dose of irinotecan was 100 mg/m2. The dose-limiting toxicities were hematologic and gastrointestinal. Nine patients were evaluable for response: one patient achieved a partial response, four patients remained stable, and four patients had disease progression. The combination of metronomic temozolomide and irinotecan every 2 weeks can be safely administered at the recommended doses; a phase II study with this combination was started and has completed accrual.

Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification

Background We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Pseudoprogression as an adverse event of glioblastoma therapy

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression‐free survival (PFS), post‐progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5‐fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606–7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter–though not significantly so—for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma.

SEOM guideline for the treatment of malignant glioma

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients’ treatment, with the best results obtained when the three of them can be used.

Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma.

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m2/day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5–15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2–35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

Valor de la PET/TC cerebral con 18F-fluorocolina en la detección de recurrencias de neoplasias primarias del sistema nervioso central

AIM To study the usefulness of 18F-fluorocholine (FCH) in detecting the recurrence of primary brain tumours. MATERIAL AND METHODS A prospective study was conducted on brain PET/CT with FCH for compassionate use in 21 patients with suspected recurrence of a primary brain tumour. The distribution by pathology was: three grade ii astrocytomas, three grade iii astrocytomas, one grade ii oligodendroglioma, three grade iii oligodendrogliomas, one grade iii oligoastrocytoma, four glioblastoma multiform, one gliomatosis cerebri, and five meningiomas. Studies in which there was a visually significant uptake in the brain parenchyma were classified as positive. RESULTS A total of 17 patients were classified as positive, with the results being confirmed by histology (10 cases) or clinical follow-up and imaging, with no false positives or negatives. The mean SUVmax for positive patients was 8.02 and 0.94 for the negative ones, which was significantly different (P=.003) CONCLUSION: PET/CT with FCH shows encouraging results in the evaluation of patients with suspected recurrence of primary brain neoplasms.

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.

424PPATIENT PROFILE AND THERAPEUTIC MANAGEMENT IN GLIOBLASTOMA (GBM): A SUBGROUP ANALYSIS OF A LARGE PROSPECTIVE OBSERVATIONAL STUDY OF THE NEURO-ONCOLOGY INVESTIGATION SPANISH GROUP (GEINO)

ABSTRACT Aim: To date, sociodemographic data and therapeutic management have not been well explored in GBM patients (p) at Spanish level. The GEINO-10 study was designed to evaluate the clinical profile and therapeutic behaviors in p with intra-axial brain tumours (BT). GBM, the most common malignant adult tumour, is the most frequent in our database. Methods: Data on p with intra-axial BT were collected over years (2010-2013). Out of 397 p included, 67% had GBM. We aim to undertake an exploratory subanalysis of this poor prognostic group to describe the clinical and pathological characteristics as well as the therapeutic management of GBM in 28 Spanish institutions. Results: 265 p with GBM were enrolled. Median age: 61 years (19-83); male/female (%): 63/37; ECOG 0/1 (%): 23/48. 55% had comorbidity. 10% had history of previous cancer . Symptoms at diagnosis: 35% focal neurological deficit; 28% cognitive impairment; 19% epileptic seizures and 7% ataxia. Location (lobe): 32.5% frontal, 32% temporal, 15% parietal and 6% occipital. Treatment (Tx) received: 42% complete resection, 42% partial, 10% stereotactic biopsy and 6% open biopsy. 3% of p received neoadjuvant temozolomide (TMZ) ± bevacizumab (BV) into a clinical trial. 94% of p received radiotherapy (RT) (72% focal, 21% whole-brain and 6% hemi-brain) concomitant with TMZ. After the concomitant phase, 82% of p received active chemotherapy (CT) with a median of 5 cycles (1-14) and 97% of them with TMZ. Out of 188 p evaluable, a disease control rate was achieved in 70% and the median Progression Free Survival was 10.4 months (95%CI: 9-11.8). At progression, 41% of total p received Tx: 13% surgery, 8% RT and 95% CT (52% BV ± CPT11, 15.5% TMZ, 12% nitrosoureas, 4.5% dacomitinib and 9% other). Overall Survival achieved was 23.6 months (95%CI: 16-31.2). Conclusions: At diagnosis, almost all patients received RT + TMZ after surgery or biopsy. 41% were treated at progression, half of them with a BV regimen. The exceptionally good survival could reflect a selection of p with good PS. This information can be useful to homogenize and to optimize Tx and for future clinical trials in GBM. Disclosure: All authors have declared no conflicts of interest.