Showing papers by "Roger Stupp published in 2012"

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial

Abstract: Summary Background Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. Methods Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m 2 on days 1–5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. Findings 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1–9·5; n=93] vs 6·0 months [95% CI 5·1–6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52–0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5–8·6; n=98], HR 0·85 [0·64–1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3–9·4; n=119] vs 7·4 months [6·4–8·4; n=123]; HR 0·82, 95% CI 0·63–1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21–0·56], p vs standard radiotherapy 0·59 [95% CI 0·37–0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0–11·4] vs 6·8 months [5·9–7·7]; HR 0·56 [95% CI 0·34–0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69–1·38]; p=0·81). As expected, the most common grade 3–4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3–5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. Interpretation Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. Funding Merck, Lion's Cancer Research Foundation, University of Umea, and the Swedish Cancer Society.

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status

Abstract: The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.

Phase II Study of Imatinib in Advanced Chordoma

Abstract: Purpose To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)–positive chordomas. Patients and Methods In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score. Results Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD...

Performance of 18F-Fluoro-Ethyl-Tyrosine (18F-FET) PET for the Differential Diagnosis of Primary Brain Tumor: A Systematic Review and Metaanalysis

Abstract: For the past decade, PET with 18F-fluoro-ethyl-tyrosine (18F-FET) has been used in the evaluation of patients with primary brain tumors (PBTs), but so far series have reported only a limited number of patients. The purpose of this systematic review and metaanalysis was to assess the diagnostic performance of 18F-FET PET in patients with suspicion of PBT. Methods: We examined studies published in the literature using MEDLINE and EMBASE databases. Inclusion criteria were use of 18F-FET PET for initial assessment of patients with a newly diagnosed brain lesion; patients who had no radiotherapy, surgery, or chemotherapy before 18F-FET PET; and use of histology as a gold standard. Metaanalysis was performed on a per-patient basis. We secondarily performed receiver-operating-characteristic analysis of pooled patients to determine tumor-to-background ratio (TBR) of 18F-FET uptake and best diagnostic value. Results: Thirteen studies totaling 462 patients were included. For the diagnosis of PBT, 18F-FET PET demonstrated a pooled sensitivity of 0.82 (95% confidence interval [CI], 0.74–0.88), specificity of 0.76 (95% CI, 0.44–0.92), area under the curve of 0.84 (95% CI, 0.80–0.87), positive likelihood ratio of 3.4 (95% CI, 1.2–9.5), and negative likelihood ratio of 0.24 (95% CI, 0.14–0.39). Receiver-operating-characteristic analysis indicated that a mean TBR threshold of at least 1.6 and a maximum TBR of at least 2.1 had the best diagnostic value for differentiating PBTs from nontumoral lesions. Conclusion:18F-FET PET demonstrated excellent performance for diagnosing PBTs. Strict standardization of PET acquisition protocols and prospective, multicenter studies investigating the added value over current MRI are now needed to establish 18F-FET PET as a highly relevant tool for patient management.

Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice

Abstract: Histological subtyping and grading by malignancy are the cornerstones of the World Health Organization (WHO) classification of tumors of the central nervous system. They shall provide clinicians with guidance as to the course of disease to be expected and the choices of treatment to be made. Nonetheless, patients with histologically identical tumors may have very different outcomes, notably in patients with astrocytic and oligodendroglial gliomas of WHO grades II and III. In gliomas of adulthood, 3 molecular markers have undergone extensive studies in recent years: 1p/19q chromosomal codeletion, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and mutations of isocitrate dehydrogenase (IDH) 1 and 2. However, the assessment of these molecular markers has so far not been implemented in clinical routine because of the lack of therapeutic implications. In fact, these markers were considered to be prognostic irrespective of whether patients were receiving radiotherapy (RT), chemotherapy, or both (1p/19q, IDH1/2), or of limited value because testing is too complex and no chemotherapy alternative to temozolomide was available (MGMT). In 2012, this situation has changed: long-term follow-up of the Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951 trials demonstrated an overall survival benefit from the addition to RT of chemotherapy with procarbazine/CCNU/vincristine confined to patients with anaplastic oligodendroglial tumors with (vs without) 1p/19q codeletion. Furthermore, in elderly glioblastoma patients, the NOA-08 and the Nordic trial of RT alone versus temozolomide alone demonstrated a profound impact of MGMT promoter methylation on outcome by therapy and thus established MGMT as a predictive biomarker in this patient population. These recent results call for the routine implementation of 1p/19q and MGMT testing at least in subpopulations of malignant glioma patients and represent an encouraging step toward the development of personalized therapeutic approaches in neuro-oncology.

Epilepsy meets cancer: when, why, and what to do about it?

Abstract: The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial

Abstract: Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

Individualized targeted therapy for glioblastoma: fact or fiction?

Abstract: Purpose This review will address the current state of individualized cancer therapy for glioblastoma. Glioblastomas are highly malignant primary brain tumors presumably originating from neuroglial progenitor cells. Median survival is less than 1 year. Design Recent developments in the morphologic, clinical, and molecular classification of glioblastoma were reviewed, and their impact on clinical decision making was analyzed. Results Glioblastomas can be classified by morphology, clinical characteristics, complex molecular signatures, single biomarkers, or imaging parameters. Some of these characteristics, including age and Karnofsky Performance Scale score, provide important prognostic information. In contrast, few markers help to choose between various treatment options. Promoter methylation of the O-methylguanine methyltransferase gene seems to predict benefit from alkylating agent chemotherapy. Hence, it is used as an entry criterion for alkylator-free experimental combination therapy with radiotherapy. Screening for a specific type of epidermal growth factor receptor mutation is currently being explored as a biomarker for selecting patients for vaccination. Positron emission tomography for the detection of ανβ3/5 integrins could be used to select patients for treatment with anti-integrin antiangiogenic approaches. Discussion Despite extensive efforts at defining biological markers as a basis for selecting therapies, most treatment decisions for glioblastoma patients are still based on age and performance status. However, several ongoing clinical trials may enrich the repertoire of criteria for clinical decision making in the very near future. The concept of individualized or personalized targeted cancer therapy has gained significant attention throughout oncology. Yet, data in support of such an approach to glioblastoma, the most malignant subtype of glioma, are limited, and personalized medicine plays a minor role in current clinical neuro-oncology practice. In essence, this concept proposes that tumors that are currently lumped together based on common morphologic features can be subclassified in a way that the resulting subentities are more homogeneous, for example, in molecular signatures and will therefore be amenable to selective therapeutic interventions. At present, the major "biomarkers" used to allocate treatment in glioblastoma are age and Karnofsky Performance Scale score, and these markers have so far survived all efforts at more sophisticated approaches to the management of this disease. Treatment allocation basically means intensity of treatment, especially the use of the standard-of-care or radiotherapy alone beyond age 65 to 70 years or below a Karnofsky Performance Scale score of 60.

EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma

Abstract: The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.

Clinical Implications of Molecular Neuropathology and Biomarkers for Malignant Glioma

Abstract: Malignant gliomas are currently diagnosed based on morphological criteria and graded according to the World Health Organization classification of primary brain tumors. This algorithm of diagnosis and classification provides clinicians with an estimated prognosis of the natural course of the disease. It does not reflect the expected response to specific treatments beyond surgery (eg, radiotherapy or alkylating chemotherapy). Clinical experience has revealed that gliomas sharing similar histomorphological criteria might indeed have different clinical courses and exhibit highly heterogenous responses to treatments. This was very impressively demonstrated first for oligodendrogliomas. The presence or lack of combined deletions of the chromosomal segments 1p/19q was associated with different benefit from radiotherapy and chemotherapy. We review current molecular markers for malignant gliomas and discuss their current and future impact on clinical neuro-oncology.

Brain metastasis: opportunity for drug development?

Abstract: Purpose of review Brain metastases are a common clinical problem, and only limited treatment options exist. We review recent advances in medical brain metastasis research with a focus on the most common tumor types associated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculate on opportunities for drug development in patients with brain metastases, both as a treatment of established disease and as an adjuvant and prophylactic strategy. Recent findings BRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breast cancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermal growth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potential role of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factor receptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lung cancer. Summary Novel drugs are beginning to enter clinical practice for selected patients with brain metastases. The promising findings from recent studies may fuel more research on brain metastases and their optimal drug treatment.

APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.

Abstract: 2034 Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblas...

18F-fluorodeoxyglucose PET/CT findings in pleural effusions of patients with known cancer: A cytopathological correlation

Abstract: AIM Pleural effusion is common in cancer patients and to determine its malignant origin is of huge clinical significance. PET/CT with ¹⁸F-FDG is of diagnostic value in staging and follow-up, but its ability to differentiate between malignant and benign effusions is not precisely known. PATIENTS, METHODS We examined 50 PET/CT from 47 patients (29 men, 18 women, 60 ± 16 years) with pleural effusion and known cancer (24 NSCLC, 7 lymphomas, 5 breasts, 4 GIST, 3 mesotheliomas, 2 head and neck, 2 malignant teratoma, 1 colorectal, 1 oesophageal, 1 melanoma) for FDG uptake in the effusions using SUV(max). This was correlated to cytopathology performed after a median of 21 days (interquartile range -3 to 23), which included pH, relative distribution (macrophages, neutrophils, eosinophils, basophils, lymphocytes, plasmocytes), and absolute cell count. RESULTS Malignant cells were found in 17 effusions (34%) (6 NSCLC, 5 lymphomas, 2 breasts, 2 mesotheliomas, 2 malignant teratomas). SUV in malignant effusions were higher than in benign ones [3.7 (95%CI 1.8-5.6) vs. 1.7 g/ml (1.5-1.9), p = 0.001], with a correlation between malignant effusion and SUV (Spearman coefficient r = 0.50, p = 0.001), but not with other cytopathological or radiological parameters (ROC area 0.83 ± 0.06). Using a 2.2-mg/l SUV threshold, 12 PET/CT studies were positive and 38 negative with sensitivity, specificity, positive and negative predictive values of 53%, 91%, 75% and 79%, respectively. For NSCLC only (n = 24), ROC area was 0.95 ± 0.04, 7 studies were positive and 17 negative with a sensitivity, specificity, positive and negative predictive values of 83%, 89%, 71 and 94%, respectively. CONCLUSION PET/CT may help to differentiate the malignant or benign origin of a pleural effusion with a high specificity in patients with known cancer, in particular NSCLC.

Chiasmatic Infiltration Secondary to Late Malignant Transformation of Retinoma

Abstract: Purpose: To report the lethal course of malignant transformation of retinoma in an adult. Methods: Case report. A 40-year-old patient presented with retinoma in his right eye and retinoblastoma in his left eye. Enucleation was recommended but refused and the patient received whole eye radiotherapy elsewhere. Five years later he presented again, with temporal hemianopsia of the left eye secondary to chiasmatic invasion. Results: Diagnosis of retinoblastoma infiltration was confirmed by stereotactic biopsy of the chiasmatic lesion. Treatment with intravenous and intrathecal chemotherapy led to partial remission, and was followed by stereotactic irradiation of the chiasmatic mass and right optic nerve. The left eye was enucleated. Death occurred one year later due to cerebrospinal fluid metastases. Conclusion: Extraocular extension of retinoblastoma diagnosed in adulthood has never, to our knowledge, been reported. This case stresses the importance of lifelong retinoma monitoring and the necessity for radical treatment in the event of malignant transformation.

Identifikation maligner Pleura-Ergüsse mittels 18F-Fluordeoxyglukose-PET/CT – Eine Korrelation mit zytopathologischen Befunden

Abstract: Aim: Pleural effusion is common in cancer patients and to determine its malignant origin is of huge clinical significance. PET/CT with 18F-FDG is of diagnostic value in staging and follow-up, but its ability to differentiate between malignant and benign effusions is not precisely known. Patients, methods: We examined 50 PET/CT from 47 patients (29 men, 18 women, 60±16 years) with pleural effusion and known cancer (24 NSCLC, 7 lymphomas, 5 breasts, 4 GIST, 3 mesotheliomas, 2 head and neck, 2 malignant teratoma, 1 colorectal, 1 oesophageal, 1 melanoma) for FDG uptake in the effusions using SUVmax. This was correlated to cytopathology performed after a median of 21 days (interquartile range –3 to 23), which included pH, relative distribution (macrophages, neutrophils, eosinophils, basophils, lymphocytes, plasmocytes), and absolute cell count. Results: Malignant cells were found in 17 effusions (34%) (6 NSCLC, 5 lymphomas, 2 breasts, 2 mesotheliomas, 2 malignant teratomas). SUV in malignant effusions were higher than in benign ones [3.7 (95%CI 1.8–5.6) vs. 1.7 g/ml (1.5–1.9), p = 0.001], with a correlation between malignant effusion and SUV (Spearman coefficient r = 0.50, p = 0.001), but not with other cytopathological or radiological parameters (ROC area 0.83±0.06). Using a 2.2-mg/l SUV threshold, 12 PET/CT studies were positive and 38 negative with sensitivity, specificity, positive and negative predictive values of 53%, 91%, 75% and 79%, respectively. For NSCLC only (n = 24), ROC area was 0.95±0.04, 7 studies were positive and 17 negative with a sensitivity, specificity, positive and negative predictive values of 83%, 89%, 71 and 94%, respectively. Conclusion: PET/CT may help to differentiate the malignant or benign origin of a pleural effusion with a high specificity in patients with known cancer, in particular NSCLC.

18F-fluorodeoxyglucose PET/CT findings in pleural effusions of patients with known cancer

Abstract: Aim: Pleural effusion is common in cancer patients and to determine its malignant origin is of huge clinical significance. PET/CT with 18F-FDG is of diagnostic value in staging and follow-up, but its ability to differentiate between malignant and benign effusions is not precisely known. Patients, methods: We examined 50 PET/CT from 47 patients (29 men, 18 women, 60±16 years) with pleural effusion and known cancer (24 NSCLC, 7 lymphomas, 5 breasts, 4 GIST, 3 mesotheliomas, 2 head and neck, 2 malignant teratoma, 1 colorectal, 1 oesophageal, 1 melanoma) for FDG uptake in the effusions using SUVmax. This was correlated to cytopathology performed after a median of 21 days (interquartile range –3 to 23), which included pH, relative distribution (macrophages, neutrophils, eosinophils, basophils, lymphocytes, plasmocytes), and absolute cell count. Results: Malignant cells were found in 17 effusions (34%) (6 NSCLC, 5 lymphomas, 2 breasts, 2 mesotheliomas, 2 malignant teratomas). SUV in malignant effusions were higher than in benign ones [3.7 (95%CI 1.8–5.6) vs. 1.7 g/ml (1.5–1.9), p = 0.001], with a correlation between malignant effusion and SUV (Spearman coefficient r = 0.50, p = 0.001), but not with other cytopathological or radiological parameters (ROC area 0.83±0.06). Using a 2.2-mg/l SUV threshold, 12 PET/CT studies were positive and 38 negative with sensitivity, specificity, positive and negative predictive values of 53%, 91%, 75% and 79%, respectively. For NSCLC only (n = 24), ROC area was 0.95±0.04, 7 studies were positive and 17 negative with a sensitivity, specificity, positive and negative predictive values of 83%, 89%, 71 and 94%, respectively. Conclusion: PET/CT may help to differentiate the malignant or benign origin of a pleural effusion with a high specificity in patients with known cancer, in particular NSCLC.

EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology

Abstract: Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated. Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences.

Abstract 4031:MGMTmethylation based outcome prediction is associated with two CpG regions separated by a prediction minimum centred at the initiation start site

Abstract: Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Promoter methylation of the repair gene MGMT is a predictive factor for benefit from alkylating agent therapy in glioblastoma patients. High through-put platforms for genome wide DNA methylation analysis have allowed establishing the methylome of large series of patient samples that has identified a glioma CpG methylator phenotype (G-CIMP). However, classification of samples as being methylated or unmethylated for a given gene is not obvious, since the relationship between CpG-methylation at a given site and the extent of the overall CpG island methylation, and the effect on gene silencing is strongly dependent on the location. For the MGMT gene 176 CpGs are interrogated on the 450K chip of which 18 are located in the CpG island associated with the promoter region. Correlation of MGMT methylation at these 18 CpG sites in 63 glioblastoma and 5 non tumoral brain tissues and methylation prediction established previously by methylation specific PCR (MSP) indicated 2 regions with highest association. The two areas were separated by a prediction minimum centered at the initiation start site. The correlation of MGMT expression with the methylation status of CpGs followed the same pattern with the strongest negative correlation reaching –0.5 at the 2 peaks. Subsequently we tested the predictive value of the 18 CpGs for outcome in these patients treated within clinical trials with temozolomide containing chemo-radiotherapy. Most intriguingly, correlation with gene expression, survival analyses and association with MSP displayed almost superposable images of CpGs, at the previously identified CpG regions! A model for MGMT methylation classification based on stepwise logistic regression was constructed with a kappa value close to 0.85. The model was validated in a published external data set of homogeneously treated patient cohort with anaplastic glioma for which methylation data and survival information was available, and for which MGMT methylation was reported as prognostic factor. The model was subsequently applied to the methylation data available from the The Cancer Genome Atlas (TCGA) glioblastoma data-set comprising 241 samples. Classification of the samples for their MGMT methylation status based on the predictor revealed that MGMT is frequently methylated in glioblastoma with G-CIMP (simulated p=0.001 chi-square, Monte-Carlo method), but is not a G-CIMP gene. Taken together, the location of methylated CpGs within the promoter is crucial for prediction of MGMT silencing and subsequent impact on outcome. Hence, for efficient mining of large scale methylation data we need models to identify regions of CpGs with a high impact on gene silencing or other features relevant for the understanding of tumor biology and effect on response to therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4031. doi:1538-7445.AM2012-4031

A revised RTOG recursive partitioning analysis (RPA) model for glioblastoma based upon multiplatform biomarker profiles.

Abstract: 2001 Background: The Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) model, which relies on clinical variables, has been used worldwide to establish distinct prognosti...

C URRENT OPINION Brain metastasis: opportunity for drug development?

Abstract: Purpose of reviewBrain metastases are a common clinical problem, and only limited treatment options exist. We reviewrecent advances in medical brain metastasis research with a focus on the most common tumor typesassociated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculateon opportunities for drug development in patients with brain metastases, both as a treatment ofestablished disease and as an adjuvant and prophylactic strategy.Recent findingsBRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibodyipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breastcancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermalgrowth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potentialrole of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factorreceptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lungcancer.SummaryNovel drugs are beginning to enter clinical practice for selected patients with brain metastases. Thepromising findings from recent studies may fuel more research on brain metastases and their optimal drugtreatment.Keywordsbrain metastases, drug, prophylaxis, treatment