Showing papers by "Roger Stupp published in 2019"

MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges.

Abstract: Glioblastoma (GBM) is the most common primary malignant brain tumor, with a universally poor prognosis. The emergence of molecular biomarkers has had a significant impact on histological typing and diagnosis, as well as predicting patient survival and response to treatment. The methylation status of the O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter is one such molecular biomarker. Despite the strong evidence supporting the role of MGMT methylation status in prognostication, its routine implementation in clinical practice has been challenging. The methods and optimal cutoff definitions for MGMT status determination remain controversial. Variation in detection methods between laboratories presents a major challenge for consensus. Moreover, consideration of other clinical and genetic/epigenetic factors must also be incorporated into treatment decision making. In this review, we distill the available evidence to summarize our position on the optimal use of available assays, and propose strategies for resolving cases with equivocal methylation status and a framework for incorporating this important assay into research and clinical practice.

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Abstract: Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, eg, cancer-associated fibroblasts and immune/inflammatory cells We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (eg, together with immuno-oncology agents) are needed

MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide. A Pooled Analysis of Four Clinical Trials.

Abstract: Purpose: The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma. A clinically optimized cutoff was sought allowing patient selection for therapy without temozolomide, while avoiding to withhold it from patients who may potentially benefit. Experimental Design: Quantitative MGMT methylation-specific PCR data were obtained for newly diagnosed glioblastoma patients screened or treated with standard radiotherapy and temozolomide in four randomized trials. The pooled dataset was randomly split into a training and test dataset. The unsupervised cutoff was obtained at a 50% probability to be (un)methylated. Receiver operating characteristics (ROC) analysis identified an optimal cutoff supervised by overall survival (OS). Results: For 4041 patients valid MGMT results were obtained, whereof 1725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log2[1000x(MGMT+1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was -0.28 (AUC=0.61), classifying "truly unmethylated" (≤-0.28) and "grey zone" patients (>-0.28, ≤1.27), the latter comprising ~10% of cases. In contrast, for MGMT methylated patients (>1.27) more methylation was not related to better outcome. Both methylated and grey zone patients performed significantly better for OS than truly unmethylated patients (HR=0.35, 95% CI: 0.27-0.45, p<0.0001; HR=0.58, 95% CI: 0.43-0.78, p<0.001), validated in the test dataset. The MGMT assay was highly reproducible upon retesting of 218 paired samples (R2=0.94). Conclusions: Low MGMT methylation (grey zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting unmethylated glioblastoma patients into trials omitting temozolomide.

Newly Diagnosed Glioblastoma: A Review on Clinical Management

Abstract: Glioblastoma is an aggressive primary tumor of the central nervous system. This review will focus on clinical developments and management of newly diagnosed disease, including a discussion about the incorporation of molecular features into the classification of glioblastoma. Such advances will continue to shape our thinking about the disease and how to best manage it. With regards to treatment, the role of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields will be presented. Pivotal studies defining our current standard of care will be highlighted, as will key ongoing trials that may influence our management of glioblastoma in the near future.

Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas.

Abstract: BACKGROUND Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying. METHODS The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide. RESULTS In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003). CONCLUSIONS With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.

Symptom clusters in newly diagnosed glioma patients : which symptom clusters are independently associated with functioning and global health status?

Abstract: Background. Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients’ functioning. Methods. Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQC30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders. Results. Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5–10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from −11.3 to −15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of −12.3, P < 0.001), independent of other factors. Conclusions. Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients’ functioning as measured with a self-report questionnaire.

A phase 0 first-in-human study using NU-0129: A gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients.

Abstract: 3012Background: Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. SNAs, i.e., gold nanoparticle cores covalently conjugated wit...

Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

Abstract: Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15–20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients. Pre-treatment and on-treatment α-[11C]-methyl-l-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ. Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment. Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.

Impact of Radiation Target Volume on Health-Related Quality of Life in Patients With Low-Grade Glioma in the 2-Year Period Post Treatment: A Secondary Analysis of the EORTC 22033-26033.

Abstract: Purpose It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL. Methods and Materials We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time. Results We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue. Conclusions The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.

Overcoming the Blood-Brain Barrier with an Implantable Ultrasound Device.

Abstract: Ultrasound-based blood-brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome.See related article by Idbaih et al., p. 3793.

Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).

Abstract: 2021Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for GBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with ant...

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Abstract: Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/614024v1_ufig1.gif" ALT="Figure 1">nView larger version (14K):norg.highwire.dtl.DTLVardef@310f7org.highwire.dtl.DTLVardef@14ed578org.highwire.dtl.DTLVardef@a0d9c0org.highwire.dtl.DTLVardef@37f59a_HPS_FORMAT_FIGEXP M_FIG C_FIG

Qolp-03. measuring change in health-related quality of life: the added value of analysis on the individual patient level in glioma patients in clinical decision making

Abstract: Health-related quality of life (HRQoL) is often used as an outcome in glioma research, reflecting the impact of disease and treatment on a patient’s functioning and wellbeing. Data on changes in HRQoL scores may provide important information for clinical decision-making, but different analytical methods may lead to different interpretations of the impact of treatment on HRQoL. This study aimed to examine three different methods to evaluate change in HRQoL, and to study whether these methods result in different interpretations. HRQoL and sociodemographical/clinical data from 15 randomized clinical trials were combined. Change in HRQoL scores was analyzed in three ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms over time, (2) at the patient level per scale/item by calculating the percentage of patients that deteriorated, improved or remained stable on a scale/item per scale/item, and (3) at the individual patient level combining all scales/items. Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level (method 1), only the item ‘hair loss’ showed a significant and clinically relevant change (i.e. ≥10 points) over time, whereas change scores on the other scales/items showed a statistically significant change only (all p<.001, range in change score: 0.1–6.2). Analyses on the patient level per scale (method 2) indicated that, while a large proportion of patients had stable HRQoL over time (range 27–84%), many patients deteriorated (range: 6–43%) or improved (range: 8–32%) on a specific scale/item. At the individual patient level (method 3), the majority of patients (86%) showed both deterioration and improvement, while only 1% of the patients remained stable on all scales. Clustering on clinical characteristics (WHO performance status, sex, tumor type, type of resection, newly diagnosed versus recurrent tumor and age) did not identify subgroups of patients with a specific pattern of change in their HRQoL score. Different analytical methods of changes in HRQoL result in distinct interpretations of treatment effects, all of which may be relevant for clinical decision-making. Additional information about the joint impact of treatment on all outcomes, showing that most patients experience both deterioration and improvement, may help patients and physicians to make the best treatment decision.