The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study.

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.

Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma.Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

International survey on skin patch test procedures, attitudes and interpretation.

BACKGROUND Skin patch test is the gold standard method in diagnosing contact allergy. Although used for more than 100 years, the patch test procedure is performed with variability around the world. A number of factors can influence the test results, namely the quality of reagents used, the timing of the application, the patch test series (allergens/haptens) that have been used for testing, the appropriate interpretation of the skin reactions or the evaluation of the patient's benefit. METHODS We performed an Internet -based survey with 38 questions covering the educational background of respondents, patch test methods and interpretation. The questionnaire was distributed among all representatives of national member societies of the World Allergy Organization (WAO), and the WAO Junior Members Group. RESULTS One hundred sixty-nine completed surveys were received from 47 countries. The majority of participants had more than 5 years of clinical practice (61 %) and routinely carried out patch tests (70 %). Both allergists and dermatologists were responsible for carrying out the patch tests. We could observe the use of many different guidelines regardless the geographical distribution. The use of home-made preparations was indicated by 47 % of participants and 73 % of the respondents performed 2 or 3 readings. Most of the responders indicated having patients with adverse reactions, including erythroderma (12 %); however, only 30 % of members completed a consent form before conducting the patch test. DISCUSSION The heterogeneity of patch test practices may be influenced by the level of awareness of clinical guidelines, different training backgrounds, accessibility to various types of devices, the patch test series (allergens/haptens) used for testing, type of clinical practice (public or private practice, clinical or research-based institution), infrastructure availability, financial/commercial implications and regulations among others. CONCLUSION There is a lack of a worldwide homogeneity of patch test procedures, and this raises concerns about the need for standardization and harmonization of this important diagnostic procedure.

REST Regulates Oncogenic Properties of Glioblastoma Stem Cells.

Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. STEM CELLS 2012;30:405-414.

Optimal management of elderly patients with glioblastoma.

Median age at diagnosis in patients with glioblastoma (GB) is slowly increasing with an aging population in Western countries, and was 64years in 2006. The number of patients age 65 and older with GB will double in 2030 compared with 2000. Survival in this older cohort of patients is significantly less than seen in younger patients. This may in part be related to more aggressive biology of tumor, reduced use of standard management approaches, increased toxicity of available therapies, and increased presence of comorbidities in this older patient population. Limited data do support the use of more extensive resection in these patients. Randomized data support the use of post-operative radiotherapy (RT) versus supportive care, but do not demonstrate a benefit for the use of the standard 6weeks course of RT over hypofractionated RT given over 3weeks. Preliminary data of randomized studies raise the possibility of temozolomide alone as an option for these patients. The use of 6weeks of RT with concurrent and adjuvant temozolomide has been associated with reasonably good survival in several uncontrolled small series of selected older patients; however, this better outcome may be related to the selection of better prognosis patients rather than the specific therapy utilized. The current National Cancer Institute of Canada (NCIC) and European Organization for Research and Treatment of Cancer (EORTC) CE.6/26062/22061 randomized study of short course RT with or without concurrent and adjuvant temozolomide will help determine the optimal therapy for this older cohort with currently available therapies.

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy.

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6-7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.

RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422.

CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy.

Current concepts and management of glioblastoma.

Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice. Ann Neurol 2011;

Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.

Purpose: Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods: Patients (age >= 18 to >= 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results: Fifty-two patients ( median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% ( 95% CI, 21% to 46%). Median PFS was 8 months ( 95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival ( OS) rates were 68% ( 95% CI, 53% to 79%) and 35% ( 95% CI, 22% to 48%). Median OS was 16.1 months ( 95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion: Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation. J Clin Oncol 28:2712-2718. (C) 2010 by American Society of Clinical Oncology

Clinical utility of g-cimp and idh1 status as dual prognostic markers in glioblastoma

The glioma CpG island methylator phenotype (G-CIMP) has been shown to be highly correlated with prognosis andwas noted to be highly concordant with IDH1mutation in malignant glioma in the limited number of samples analyzed. To better understand the relationship of G-CIMP with IDH1 mutation status and patient outcome, we examined G-CIMP status in detail in a larger retrospective series of glioblastomas as well as tumor samples from the RTOG 0525 clinical trial. Sampleswere tested for 6 CIMPmarkers andwere correlated with patient outcomes. In the retrospective tumor set (n ¼ 301),we found 3 distinct survival groups based on the number of CIMP markers: 0-1 (CIMP-negative), 2-4 (CIMP-intermediate), and 5 or greater (CIMP-positive) with median survivals 13.8, 20.1, and 90.6 months, respectively. This finding was validated in the RTOG 0525 samples (median survivals 15.0, 20.3, and 37.0 months). Among 787 cases with both IDH and CIMP data, 617 were CIMP-negative, 136 were CIMP-intermediate, and 34 were CIMP-positive. Seven hundred forty-four were wild type for IDH1 mutation, and 43 were mutant. CIMP and IDH status were positively correlated but outliers were found. Among the 610 CIMP-negative tumors, there were 7 IDH-mutant tumors, which showed no difference in outcome. Similarly, among the 34 CIMP-positive tumors, there were 21 IDH-mutant cases, which also showed no difference in outcome. However, among the CIMP-intermediate cases, there were 15 IDH-mutant cases with significantly (p ¼ 0.0003) improved outcome (medians not reached vs. 18.5 months, 2 year survival 87% vs. 32%). Multivariate analysis showed that both IDH1 mutation status and CIMP status were independent predictors of outcome. These findings suggest the clinical utility of refining the CIMP status into negative, intermediate, and positive groups and the finding that both IDH1 and CIMPstatus are important molecular markers in GBM.

Updated survival data of the phase iii clinical trial of novottf-100a versus best standard chemotherapy for recurrent glioblastoma

NovoTTF-100A (TTF) is a portable device delivering low-intensity, intermediate-frequency, alternating electric fields using noninvasive, disposable scalp electrodes. TTF interferes with tumor cell division, and it has been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent glioblastoma (rGBM) based on data from a phase III trial. This presentation describes the updated survival data 2 years after completing recruitment. Adults with rGBM (KPS ≥ 70) were randomized (stratified by surgery and center) to either continuous TTF (20-24 h/day, 7 days/week) or efficacious chemotherapy based on best physician choice (BPC). The primary endpoint was overall survival (OS), and secondary endpoints were PFS6, 1-year survival, and QOL. Patients were randomized (28 US and European centers) to either TTF alone (n ¼ 120) or BPC (n ¼ 117). Patient characteristics were balanced, median age was 54 years (range, 23-80 years), and median KPS was 80 (range, 50-100). One quarter of the patients had debulking surgery, and over half of the patients were at their second or later recurrence. OS in the intent-to-treat (ITT) population was equivalent in TTF versus BPC patients (median OS, 6.6vs. 6.0 months; n ¼ 237; p ¼ 0.26; HR ¼ 0.86). With a median follow-up of 33.6 months, long-term survival in the TTF group was higher than that in the BPC group at 2, 3, and 4 years of follow-up (9.3% vs. 6.6%; 8.4% vs. 1.4%; 8.4% vs. 0.0%, respectively). Analysis of patients who received at least one treatment course demonstrated a survival benefit for TTF patients compared to BPC patients (median OS, 7.8 vs. 6.0 months; n ¼ 93 vs. n ¼ 117; p ¼ 0.012; HR ¼ 0.69). In this group, 1-year survival was 28% vs. 20%, and PFS6 was 26.2% vs. 15.2% (p ¼ 0.034). TTF, a noninvasive, novel cancer treatment modality shows significant therapeutic efficacy with promising long-term survival results. The impact of TTF was more pronounced when comparing only patients who received the minimal treatment course. A large-scale phase III trial in newly diagnosed GBM is ongoing.

Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study.

BACKGROUND: The study aimed to compare the cost-effectiveness of concomitant and adjuvant temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma multiforme versus initial radiotherapy alone from a public health care perspective. METHODS: The economic evaluation was performed alongside a randomized, multicenter, phase 3 trial. The primary endpoint of the trial was overall survival. Costs included all direct medical costs. Economic data were collected prospectively for a subgroup of 219 patients (38%). Unit costs for drugs, procedures, laboratory and imaging, radiotherapy, and hospital costs per day were collected from the official national reimbursement lists based on 2004. For the cost-effectiveness analysis, survival was expressed as 2.5 years restricted mean estimates. The incremental cost-effectiveness ratio (ICER) was constructed. Confidence intervals for the ICER were calculated using the Fieller method and bootstrapping. RESULTS: The difference in 2.5 years restricted mean survival between the treatment arms was 0.25 life-years and the ICER was euro37,361 per life-year gained with a 95% confidence interval (CI) ranging from euro19,544 to euro123,616. The area between the survival curves of the treatment arms suggests an increase of the overall survival gain for a longer follow-up. An extrapolation of the overall survival per treatment arm and imputation of costs for the extrapolated survival showed a substantial reduction in ICER. CONCLUSIONS: The ICER of euro37,361 per life-year gained is a conservative estimate. We concluded that despite the high TMZ acquisition costs, the costs per life-year gained are comparable to accepted first-line treatment with chemotherapy in patients with cancer.