Showing papers by "Roger Stupp published in 2016"

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study

Abstract: Summary Background Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. Methods For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m 2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age ( vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. Findings Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups ( IDH mt, with or without 1p/19q co-deletion [ IDH mt/codel], or IDH wild type [ IDH wt]; p=0·013). Patients with IDH mt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21–2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDH mt/codel and IDH wt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one ( Interpretation Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. Funding Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Corticosteroids compromise survival in glioblastoma

Abstract: Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.

Abstract: PurposeSymptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma.Patients and MethodsTo confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter...

Tumor treating fields: a novel treatment modality and its use in brain tumors

Abstract: Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. This novel treatment modality has shown promise in a variety of tumor types. It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM. TTFields are continuously delivered by 4 transducer arrays consisting each of 9 insulated electrodes that are placed on the patient's shaved scalp and connected to a portable device. Here we summarize the preclinical data and mechanism of action, the available clinical data, and further outlook of this treatment modality in brain tumors and other cancer indications.

Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study

Abstract: Summary Background Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. Methods We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0–1 vs 2), age ( vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m 2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. Findings Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI −4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. Interpretation The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Funding Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082)

Abstract: Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed. Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus. Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR.

ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016

Abstract: The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Abstract: // Michael Weller 1 , Louis Burt Nabors 2 , Thierry Gorlia 3 , Henning Leske 4 , Elisabeth Rushing 4 , Pierre Bady 5, 6, 7 , Christine Hicking 8 , James Perry 9 , Yong-Kil Hong 10 , Patrick Roth 1 , Wolfgang Wick 11, 12 , Simon L. Goodman 8 , Monika E. Hegi 7 , Martin Picard 8 , Holger Moch 13 , Josef Straub 8 , Roger Stupp 14 1 Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland 2 University of Alabama at Birmingham, Birmingham, AL, USA 3 EORTC Data Centre, Brussels, Belgium 4 Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland 5 Department of Education and Research, University of Lausanne, Lausanne, Switzerland 6 SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland 7 Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland 8 Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany 9 Sunnybrook Health Sciences Centre, Toronto, ON, Canada 10 The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea 11 Neurology Clinic, University of Heidelberg, Heidelberg, Germany 12 Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 13 Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland 14 Department of Oncology, University Hospital Zurich, Zurich, Switzerland Correspondence to: Michael Weller, e-mail: michael.weller@usz.ch Keywords: glioblastoma, integrin, pSmad, TGF-β, biomarker Received: January 03, 2016 Accepted: January 29, 2016 Published: February 22, 2016 ABSTRACT Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O 6 -methylguanine DNA methyltransferase ( MGMT ) promoter methylation. These trials failed to meet their primary endpoints. Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224). αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide. Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation.

EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma.

Abstract: 2001Background: Phase II data from BELOB suggested the combination of bevacizumab and lomustine to produce an overall survival (OS) benefit for patients with progressive glioblastoma. EORTC 26101 aimed investigating whether the combination of bevacizumab and lomustine improves OS in patients with first progression of a glioblastoma compared to lomustine alone. Methods: Patients with progressive disease after standard chemoradiation at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m2 (cap. 160 mg with toxicity-driven escalation to cap. 200 mg from cycle 2 on) every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m2(cap. 200 mg) every six weeks followed by best investigators choice at further progression. Targeted hazard ratio (HR) was 0.72 for the comparison of OS as the primary endpoint. Progression-free survival (PFS) was an important secondary endpoint. Neuroimaging according to a standard protocol was assessed locally and centr...

Ltbk-01: prospective, multi-center phase iii trial of tumor treating fields together with temozolomide compared to temozolomide alone in patients with newly diagnosed glioblastoma

Abstract: BACKGROUND: Tumor Treating Fields (TTFields) is an established, frequency-tuned, anti-mitotic, physical treatment modality that acts in metaphase, anaphase and telophase. TTFields are delivered to the brain by a patient operated, portable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) was initiated in 2009 to test the efficacy and safety of combining TTFields with temozlomide (TMZ) compared to TMZ alone following radiation therapy with adjuvant TMZ in patients with newly diagnosed GBM. Results of a protocol pre-specified successful interim analysis on the first 315 patients randomized has been reported (Stupp et al. JAMA 2015). Here we report the main outcomes of all 695 patients enrolled with a mature minimum follow-up of 18 month (median follow-up 36 months) for all patients (Range 19–80 months).

Development of OXY111A, a novel hypoxia-modifier as a potential antitumor agent in patients with hepato-pancreato-biliary neoplasms - Protocol of a first Ib/IIa clinical trial

Abstract: Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome. The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed. In this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included. The novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors. Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11th, 2014.

Phase II part of EORTC study 26101: The sequence of bevacizumab and lomustine in patients with first recurrence of a glioblastoma.

Abstract: 2019Background: Both lomustine (LOM) and bevacizumab (BEV) are approved agents for recurrent or progressive glioblastoma. We aimed at evaluating the optimal treatment sequence (single agent vs sequential vscombination) of these agents in a randomized phase II design. Methods: Progressive patients after initial radiotherapy and temozolomide were randomized 2:2:2:1 between Arm 1: LOM 90 mg/m2 (max. 160 mg) every 6 weeks plus BEV (10 mg/kg) every 2 weeks until progression, subsequent salvage treatment at the investigators best choice (MD choice); Arm 2: LOM 110 mg/m2 (max. 200 mg) every 6 weeks, at progression switch to BEV every two weeks; Arm 3: BEV every 2 weeks, at progression add LOM 90 mg/m2 (max. 160 mg) every 6 weeks and continue BEV; and Arm 4: LOM single agent 110 mg/m2 (max. 200 mg) every 6 weeks, at progression MD choice (arm 4). Eligibility criteria included performance status 0-2, adequate hematological, liver and renal function, and an interval since the end of radiotherapy of ≥ 3 months to ru...

PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status

Abstract: PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

Treatment for Patients With Newly Diagnosed Glioblastoma--Reply.

Abstract: the cumulative risk for a suicide attempt or completion over the next year 10-fold and 100-fold, respectively.2 Self-report is more sensitive for detecting suicidal ideation than clinician interviews.3 Depressed residents, evaluated by the HANDS inventory (Harvard Department of Psychiatry/ National Depression Screening Day Scale), make 6.2 times as many medication errors per month.4 Underscoring the significance of depression data from surveys, clinical guidelines explicitly support their use in assessing and treating depression.5 In the article, we provided a table of the sensitivities and specificities of inventories included in the meta-analysis to allow readers to judge the degree to which these estimates reflected true MDD prevalence. We invite Levis and colleagues to apply these parameters to the instrument-specific prevalence estimates in Figure 3 in the article, as doing so demonstrates that MDD among residents is several-fold higher than in the general population. The methods used by some primary studies in our metaanalysis have limitations. Future studies should incorporate well-validated assessment tools, longitudinal follow-up, and large sample sizes. This discussion, however, should not distract from the conclusion that resident depression and depressive symptoms are alarmingly high. The relevant question is not whether they are high but rather why they are high. The response to this question will have an important effect on residents and their patients.

Reply to F. Felix et al and M.F. Fay et al

Abstract: In our recent article in Journal of Clinical Oncology titled, “Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma,” we reported that drug repurposing has attracted a lot of interest, specifically in glioblastoma, given the disappointing results obtained with initially promising, but ultimately inactive novel treatments and the availability of large databases suitable for exploratory analyses. In that regard, the potential impact on survival of the anticonvulsant drug, valproic acid, has been in focus for more than a decade. Yet, the pooled analysis of several contemporary clinical trials that enrolled almost 2,000 patients, which set out to strengthen the rationale for testing valproic acid in a randomized definitive phase III trial in newly diagnosed glioblastoma, failed to provide an adequate signal to support such a hypothesis in an otherwise molecularly unselected group of adult glioblastoma. Felix and Fontenele rightly raise the issue that patients in these trials were not enriched for any biomarker that predicted potential benefit from valproic acid and propose that valproic acid be tested specifically in pediatric patients with H3F3A mutation, mostly pontine gliomas. There is a possible biologic and molecular rationale to explore valproic acid in this subgroup of patients on the basis of the predicted epigenetic effects of valproic acid; however, three issues arise. First, such patients are relatively rare among those with glioblastoma and are underrepresented in the patient cohorts studied in the trials compiled for our analysis despite that our study included almost 2,000 patients (which underscores the rarity of this target). Second, the concentrations of valproic acid required to inhibit histone deacetylases may not be reached in human patients in vivo. Third, is valproic acid truly the best histone deacetylase inhibitor to study in this context? Fay et al raise some methodological issues about our analysis. They express concerns that confounders were not sufficiently analyzed, but the analysis we presented was adjusted for known important confounding factors, including O-methylguanine DNA methyltransferase promoter methylation status, and probably represents one of the best efforts that could be done in the context of clinical trial database analysis. The issue that sicker patients with larger tumors were more likely to have received valproic acid due to associated seizures was not substantiated by our database; there were no particular clinical characteristics of valproic acid–treated patients that differed from those not receiving it. That physicians would be less inclined to give valproic acid to patients with larger tumors with a higher bleeding propensity would argue against the authors’ hypothesis that we overlooked an effect of valproic acid because this would provide an even stronger bias in favor of superior survival in the valproic acid groups. As discussed in the present publication as well as in the initial report, the major weakness we acknowledge is the lack of solid data on the dose and duration of valproic acid exposure. Yet, the analysis was repeated at clinically relevant time points (at baseline and after concomitant temozolomide/radiotherapy) with the same conclusions. It is conceivable that for a beneficial effect in glioblastoma, early and high-dose treatment with valproic acid would be required, although no categorical data truly support this contention. Thus, we contend that analyses such as those reported here are not suitable to completely rule out an effect of valproic acid on outcome, especially on minuscule subsets with unique biologic characteristics. However, our data are robust enough to exclude any major effect of valproic acid, especially in significant proportions of patients with glioblastoma. Furthermore, any beneficial effect would have to be weighed against the major toxicity associated with prolonged high-dose valproic acid treatment (eg, hematologic abnormalities, hair loss, weight gain) in a patient population already significantly affected by other treatments such as corticosteroids, irradiation, and alkylating agent chemotherapy. We appreciate the interest of our colleagues in further studying this topic, and we agree that further retrospective studies are unlikely to resolve the issue unless we arrive at the conclusion that we have definitively ruled out a major benefit of valproic acid in molecularly unselected newly diagnosed glioblastoma. In fact, the European Organisation for Research and Treatment of Cancer Brain Tumor Group has arrived at the latter conclusion and will not further pursue the idea of a randomized phase III trial of valproic acid in newly diagnosed glioblastoma.

Gliome - was ich wissen muss in zehn Fragen Gliomas - What I Have to Know in ten Questions

Abstract: Zusammenfassung: Gliome sind die haufi gsten hirneigenen Tumoren und konnen sich mit einer Reihe von unspezifi schen neurologischen und Allgemeinsymptomen manifestieren. Der Goldstandard in der Diagnostik ist die zerebrale Magnetresonanztomografi e, welche durch eine histologische Diagnosesicherung erganzt werden muss. Zur symptomatischen Therapie kommen bei neurologischen Ausfallen und/oder Hirndrucksymptomatik Steroide, insbesondere Dexamethason und bei epileptischen Anfallen Antiepileptika zum Einsatz. Die Steroide sollten ausgeschlichen werden, sobald es klinisch vertretbar ist. Bei den Antiepileptika sind nicht-enzyminduzierende Medikamente zu bevorzugen. Bei Gliomen besteht ein hohes thrombembolisches Risiko. Nach einer Thrombose ist eine therapeutische Antikoagulation indiziert. Als tumorspezifi sche Therapie kommen die chirurgische Therapie, die Strahlentherapie und die systemische Therapie zum Einsatz. Bezuglich der Prognose und Therapieauswahl spielen molekulare Marker eine immer wichtigere Rolle in der onkologischen Praxis. Schlusselworter: Glioblastom – Oligodendrogliom – Antiepileptika – Thrombose – Steroide