Sophie E. M. Veldhuijzen van Zanten

Erasmus MC

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Dannis G. van Vuurden

Princess Máxima Center

Gertjan J.L. Kaspers

Princess Máxima Center

Christof M. Kramm

Universitätsmedizin Göttingen

Darren Hargrave

Great Ormond Street Hospital

Joshua Baugh

Princess Máxima Center

André O. von Bueren

University Hospital of Geneva

Esther Hulleman

Princess Máxima Center

Maura Massimino

Fondazione IRCCS Istituto Nazionale dei Tumori

Gerrit H. Gielen

University Hospital Bonn

Veronica Biassoni

Fondazione IRCCS Istituto Nazionale dei Tumori

Cooperative Institutions

Amsterdam University Medical Centers

Amsterdam UMC Location VUmc

Princess Máxima Center

Vrije Universiteit Amsterdam

Erasmus MC

University Medical Center

Erasmus University Rotterdam

University of Colorado Denver

University College London

University of Amsterdam

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DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology (2020)

Joshua Baugh Niclas Colditz Geert O. Janssens Stefan Dietzsch Darren Hargrave

Abstract BACKGROUND Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate? PATIENTS AND METHODS We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily. RESULTS Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months. CONCLUSIONS Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.

Progression-free survival

Hematology

10.1093/neuonc/noaa222.119

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New trial of convection enhanced drug delivery (CED) in DIPG- applying the SIOPe DIPG survival prediction model for power calculation.

Neuro-Oncology (2019)

Elwira Szychot Peter Collins Hannah Cassidy Mohammed Desai Harpreet Hyare

Abstract Background In diffuse intrinsic pontine glioma (DIPG) drug resistance is in part due to inadequate penetration of blood-brain barrier (BBB) by systemically administered drugs. Convection-enhanced drug delivery (CED) techniques have been established to bypass BBB. Trial design to measure efficacy requires evidence to justify power calculation. Aims To apply SIOPe DIPG registry survival prediction tool to pilot cohort of children with DIPG treated with CED of carboplatin and sodium valproate. Methods Case note and imaging review of 9 children with typical DIPG on imaging who were treated on compassionate basis with CED intra-tumoural infusions of carboplatin (0.12 mg/ml) and sodium valproate (14.4 mg/ml), after radiotherapy (n=9) and chemotherapy (n=4). Each had Renishaw device placed with 4 micro-catheters located within tumour mass. Up to 8 treatment cycles of CED infusions delivered through 2 pairs of catheters on 2 days to encompass pontine tumour volume. Survival prediction was performed using clinical criteria: age, sex, duration of symptoms, prior chemotherapy; and radiological criteria: absence of distant metastases; disease involving more than 50% of, and confined to, pons, ring enhancement at diagnosis. Results Cases were categorized as intermediate or high-risk using SIOPe risk scoring with predicted median overall survival (OS) of 9.7, and 7.0 months, respectively. Four patients, categorized as high-risk, had median overall survival (OS) of 14.2 months. Five children, categorized as standard-risk, had median OS of 16.0 months. Conclusions Results justify a phase 2 trial of CED carboplatin and sodium valproate powered to detect at least 4-month prolongation of survival.

Carboplatin

10.1093/neuonc/noz167.046

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Molecular Drug Imaging: ⁸⁹Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

Journal of Nuclear Medicine (2016)

Marc H.A. Jansen Sophie E. M. Veldhuijzen van Zanten Dannis G. van Vuurden Marc C. Huisman Daniëlle J. Vugts

Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0-6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter- and intratumoral heterogeneity of uptake, and 89Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P = 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion:89Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.

Biodistribution

10.2967/jnumed.116.180216

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Pediatric high-grade gliomas and the WHO CNS Tumor Classification—Perspectives of pediatric neuro-oncologists and neuropathologists in light of recent updates

Neuro-Oncology Advances (2022)

Gerrit H. Gielen Joshua Baugh Dannis G. van Vuurden Sophie E. M. Veldhuijzen van Zanten Darren Hargrave

The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG).We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists.465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri.Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact.

Clinical Significance

Brain tumor

10.1093/noajnl/vdac077

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Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

Journal of Neuro-Oncology (2019)

Fatma E. El‐Khouly Sophie E. M. Veldhuijzen van Zanten Vicente Santa‐María López N. Harry Hendrikse Gertjan J.L. Kaspers

Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines.Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively.Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials.This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

Health Professionals

10.1007/s11060-019-03287-9

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Citations (57)

International consensus on the initial diagnostic workup of cancer of unknown primary

Critical Reviews in Oncology/Hematology (2022)

Iris van der Strate Fatemeh Kazemzadeh Irıs D. Nagtegaal Debbie Robbrecht A. van de Wouw

Guideline

Delphi Method

10.1016/j.critrevonc.2022.103868

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The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors

International Journal of Molecular Sciences (2020)

Ilanah J. Pruis Guus A.M.S. van Dongen Sophie E. M. Veldhuijzen van Zanten

This review highlights the added value of PET imaging in Central Nervous System (CNS) tumors, which is a tool that has rapidly evolved from a merely diagnostic setting to multimodal molecular diagnostics and the guidance of targeted therapy. PET is the method of choice for studying target expression and target binding behind the assumedly intact blood–brain barrier. Today, a variety of diagnostic PET tracers can be used for the primary staging of CNS tumors and to determine the effect of therapy. Additionally, theranostic PET tracers are increasingly used in the context of pharmaceutical and radiopharmaceutical drug development and application. In this approach, a single targeted drug is used for PET diagnosis, upon the coupling of a PET radionuclide, as well as for targeted (nuclide) therapy. Theranostic PET tracers have the potential to serve as a non-invasive whole body navigator in the selection of the most effective drug candidates and their most optimal dose and administration route, together with the potential to serve as a predictive biomarker in the selection of patients who are most likely to benefit from treatment. PET imaging supports the transition from trial and error medicine to predictive, preventive, and personalized medicine, hopefully leading to improved quality of life for patients and more cost-effective care.

PET Imaging

Personalized Medicine

Molecular Imaging

Targeted Therapy

Drug Development

10.3390/ijms21031029

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Citations (29)

A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

Journal of Neuro-Oncology (2017)

Sophie E. M. Veldhuijzen van Zanten Fatma E. El‐Khouly Marc H.A. Jansen Dewi P. Bakker Esther Sánchez Aliaga

Tolerability