Showing papers by "Roger Stupp published in 2018"

cIMPACT-NOW Update 3: Recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

Abstract: Working Committee 1 concluded that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that contain high-level EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutations, correspond to WHO grade IV and should be referred to as diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV. Assessment of classification by DNA methylation profiling and additional +7/−10 signatures appear to be promising as well and could be considered in the future following additional experience and validation. We also concluded that specific molecular signatures in subsets of IDH-wildtype diffuse astrocytic gliomas are associated with better clinical outcomes and should not lead to a high-grade designation, including, but not limited to, those gliomas with MYB/MYBL or BRAF alterations as individual drivers.

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas

Abstract: According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.

Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer.

Abstract: Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.

IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma

Abstract: Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559-73. ©2018 AACR.

Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial.

Abstract: Importance Tumor-treating fields (TTFields) therapy improves both progression-free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients’ health-related quality of life (HRQoL). Objective To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma. Design, Setting, and Participants This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016. Interventions Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device. Main Outcomes and Measures Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items. Results Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months;P Conclusions and Relevance The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays. Trial Registration clinicaltrials.gov Identifier:NCT00916409

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033

Abstract: The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.

Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice.

Abstract: Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.

Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

Abstract: Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Progression-free survival (PFS) and overall survival (OS) were analysed for each medication in the pooled patient group. No association was found for co-medication with either drug for PFS or OS. Median OS was 22.1 (statins) versus 22.2 (control) months (HR 1.06, 95% CI 0.81-1.39, p = 0.69), 20.4 (ACEI) versus 22.6 (control) months (HR 1.25, 95% CI 0.96-1.62, p = 0.10), and 21.7 (sartans) versus 22.3 (control) months (HR 0.86, 95% CI 0.61-1.21, p = 0.38). None of the comparisons showed a signal for different PFS or OS when analyses were controlled for MGMT promoter methylation or treatment group (TMZ/RT → TMZ vs. RT + CIL + TMZ → TMZ + CIL). This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma. These data challenge the rationale for prospective studies on the possible role of these non-tumor-specific drugs within the concept of drug repurposing.

Primary Central Nervous System Lymphoma—PART 1: Epidemiology, Diagnosis, Staging, and Prognosis

Abstract: Primary central nervous system (CNS) lymphoma is a rare CNS neoplasm. Its highest incidence is in the elderly and the immunocompromised. The initial steps in establishing a diagnosis involve CNS imaging. Familiarity with the clinical presentation is important in order to limit the risk of a nondiagnostic biopsy. In addition to confirming the diagnosis, it is wise to evaluate for extra-CNS disease. There are important differences in the presentation and evaluation of immunocompetent patients and those of immunocompromised patients; we will delineate these in this review. Appropriate initial clinical evaluations facilitate optimal therapeutic management for patients with primary CNS lymphoma. This is of particular importance because primary CNS lymphoma is a potentially curable disease, despite the high likelihood of recurrence.

Adjuvant treatment of resectable biliary tract cancer with cisplatin plus gemcitabine: A prospective single center phase II study

Abstract: Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3–100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50–100) for cisplatin and 100% (IQR 75–100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0–33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8–62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study

Abstract: Ipilimumab, an immune checkpoint inhibitor, is approved for treatment metastastic melanoma and is a promising agent against other malignancies. There is some preliminary evidence from case reports that ipilimumab treatment may be associated with pulmonary side effects. However, data from prospective studies on ipilimumab-related pulmonary toxicity are still scarce. Serial spirometries and measurements of CO-diffusion capacity (DLCO) in patients with metastatic melanoma before and during treatment with ipilimumab were performed. A reduction from baseline of forced vital capacity (FVC) of ≥ 10%, or ≥ 15% of DLCO was defined as clinically meaningful and indicative for pulmonary toxicity. Of 71 patients included in this study, a clinically meaningful lung function decline was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and 9 weeks of treatment initiation, respectively. Even after adjusting for age, concomitant melanoma treatment, progressive pulmonary metastases, and baseline pulmonary function values, mean ± SD DLCO decreased significantly during follow-up (−4.3% ± 13.6% from baseline, p = 0.033). Only 7% of patients reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis was diagnosed only in one patient (1.4%). DLCO decline maybe an early indicator of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function testing including DLCO measurement during treatment might help for risk stratification to screen for ipilimumab-related pneumonitis.

Associations of anticoagulant use with outcome in newly diagnosed glioblastoma.

Abstract: e14070Background: To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of a

A phase 1, multicenter, open-label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed WHO grade IV malignant glioma (glioblastoma, ndGBM): Dose-escalation results.

Abstract: e14083Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with

Developing an Integrative Treatment Program for Cancer-Related Fatigue Using Stakeholder Engagement – A Qualitative Study:

Abstract: Background: Although cancer-related fatigue (CRF) has gained increased attention in the past decade, it remains difficult to treat. An integrative approach combining conventional and complementary medicine interventions seems highly promising. Treatment programs are more likely to be effective if the needs and interests of the people involved are well represented. This can be achieved through stakeholder engagement. Objectives: The aim of the study was to develop an integrative CRF treatment program using stakeholder engagement and to compare it to an expert version. Method: In a qualitative study, a total of 22 stakeholders (4 oncologists, 1 radiation-oncologist, 1 psycho-oncologist, 5 nurses/nurse experts, 9 patients, 1 patient family member, 1 representative of a local Swiss Cancer League) were interviewed either face-to-face or in a focus group setting. For data analysis, qualitative content analysis was used. Results: With stakeholder engagement, the integrative CRF treatment program was adapted to usual care using a prioritizing approach and allowing more patient choice. Unlike the expert version, in which all intervention options were on the same level, the stakeholder engagement process resulted in a program with 3 different levels. The first level includes mandatory nonpharmacological interventions, the second includes nonpharmacological choice-based interventions, and the third includes pharmacological interventions for severe CRF. The resulting stakeholder based integrative CRF treatment program was implemented as clinical practice guideline at our clinic (Institute for Complementary and Integrative Medicine, University Hospital Zurich). Conclusion: Through the stakeholder engagement approach, we integrated the needs and preferences of people who are directly affected by CRF. This resulted in an integrative CRF treatment program with graded recommendations for interventions and therefore potentially greater sustainability in a usual care setting.

Primary Central Nervous System Lymphoma—PART 2: Modern Therapeutic Management and Future Directions

Abstract: Primary central nervous system (CNS) lymphoma, a rare CNS neoplasm associated with high mortality, is responsive to therapeutic interventions. In Part 1 of our two-part coverage of this entity, we provided an overview of the epidemiology of primary CNS lymphoma, followed by a discussion of the diagnostic and staging evaluation, and a review of current prognostication systems. In Part 2, we discuss the management of primary CNS lymphoma, focusing in particular on systemic therapies and radiation. With respect to systemic therapies, we provide details of a variety of regimens built around a backbone of high-dose methotrexate. Future directions for the treatment of primary CNS lymphoma are reviewed as well. These include optimization of consolidation regimens and the pursuit of novel agents.

B cell-rich non-neoplastic sentinel lesion preceding primary central nervous system lymphoma.

Abstract: Primary central nervous system lymphoma (PCNSL) is an uncommon tumor in the brain. Although most PCNSL are readily diagnosed as diffuse large B cell lymphoma (DLBCL) on the first biopsy, very rare cases have been described in which the first detected intracerebral lesions are non-neoplastic, and are composed mostly of perivascular T cells, not B cells. This phenomenon is known as “sentinel lesions.”

Hospital volume and group expertise in newly diagnosed glioblastoma management

Abstract: Unfortunately, the report does not provide any information on whether chemotherapy was omitted more frequently in low volume centers than high volume centers. Optimal selection of therapy and adaptation to molecular markers requires a multidisciplinary team including neuro-oncologists (neurologists, oncologists and radiation oncologists), specialized neurosurgeons, experienced neuroradiologists and expertise in neuropathology including molecular diagnostics. The report by Koshy and colleagues is valuable in providing insights into outcome of patients in daily practice. Better understanding on challenges and limitations of delivering care in the real life setting will allow for improvement in care and outcome of patients. New models of collaboration, exchange, but also facilitated patient referral is needed in order to provide optimal care to patients suffering from rare [2] tumors. The multidisciplinary expertise and dedicated Neuro-Oncology Tumor Boards at specialized centers have the potential to offer a broad palette of therapeutic options. Individually tailored treatments based on modern molecular neuropathology and investigational protocols have to be weighed against the practical convenience of treatment close to home. A combined and collaborative patient care approach with treatment oversight by the expert in the subdiscipline while treatment delivery is delegated to an affiliated facility may be an appropriate and patient-friendly way to compensate for the missing volume and expertise.