High-grade Central Nervous System Tumors Research Articles

NCOG-31. TUMOR TREATING FIELDS: REAL-WORLD SURVIVAL AND QUALITY OF LIFE OUTCOMES ON THE XCELSIOR PLATFORM

Abstract OBJECTIVE xCures operates a direct-to-patient, real-world evidence platform according to the nationwide observational research protocol XCELSIOR (NCT03793088), which aggregates medical data in an FDA-compliant electronic database. We used this platform to analyze advanced registry survival and Quality of Life (QoL) outcomes associated with the use of Tumor Treating Fields (TTFields) for treatment of high grade central nervous system (CNS) tumors. METHODS XCELSIOR participants with high grade CNS tumors were invited weekly to complete the EuroQol 5-Dimension (EQ-5D-5L) QoL questionnaire over the course of one year. A EuroQol-endorsed model was used to estimate health state utilities from patients’ EQ-5D responses. The participating patients’ clinical data was accessed from the XCELSIOR platform to enable study of clinical factors and survival outcomes. RESULTS 225 patients with high grade CNS tumors in total completed at least one EQ-5D questionnaire. 88 patients (39%) had ever used TTFields and 58 of these patients (26%) were currently using TTFields. Patients currently using TTFields had significantly higher average health state utility estimates compared to non-users (p=.00183), with a mean improvement in utility of .14 (SE=.04), indicating significantly higher overall QoL in TTFields users. Mortality events were recorded for 40 participating patients, 14 (35%) of which had used TTFields. From these 40 events the mean/median overall survival (OS) for patients who had used TTFields was 23.39/20.15 months vs 15.77/12.72 months for patients who had not used TTFields, showing significantly higher average OS in patients who had used TTFields (p=.04139). CONCLUSION The XCELSIOR platform has enabled the study of real-world clinical and QoL outcomes for patients with CNS tumors. The results show that use of TTFields is associated with improved survival as well as improved overall Quality of Life for patients in a real-world setting, corroborating results seen in trial settings as well as results seen in other real-world studies.

The Impact of Proactive Gastrostomy Tube Placement on Treatment-related Outcomes in Young Children With High-grade Central Nervous System Tumors.

Young children undergoing treatment with intensive chemotherapy for high-grade central nervous system (CNS) tumors are at risk for malnutrition, yet no guidelines exist for the placement of enteral tubes. Prior studies evaluated the impact of proactive gastrostomy tube (GT) placement with a narrow scope of outcomes, such as weight. To examine the impact of proactive GT on comprehensive treatment outcomes, we performed a single-center, retrospective study of children younger than 60 months of age with high-grade CNS tumors treated per CCG99703 or ACNS0334 between 2015 and 2022. Of 26 patients included, 9 (35%) underwent proactive GT, 8 (30%) had rescue GT, and 9 (35%) had a nasogastric tube (NGT). Clinically significant weight loss occurred in 47% of patients with NGT during induction compared with 22% with proactive GT ( P = 0.274); however, between cohorts, there was no significant difference in antibiotic or parenteral nutrition utilization, weight loss at therapy completion, and duration of hospitalization. Therefore, proactive GT placement was modestly effective at preventing significant weight loss during induction, however, there was no clear benefit for hospitalization duration, antibiotic, or parental nutrition requirements compared with NGT. We recommend an individualized approach to GT placement for young children with CNS malignancies undergoing intensive chemotherapy.

Ultrasensitive detection and monitoring of central nervous system tumors from plasma using personalized whole-genome ctDNA profiling.

2064 Background: Patients with the central nervous system (CNS) tumors are largely followed up by imaging. Current plasma-based liquid biopsy techniques have limited utility in neuro-oncology due to a low circulating cell-free tumor DNA (ctDNA) burden, blood-brain barrier, and low number of mutations in coding regions. Whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a personalized, highly sensitive and specific approach to detect mutations in ctDNA and provide blood-based monitoring in brain tumor patients. Furthermore, it can be performed on lower amount of peripheral blood since WGS requires less sequencing depth compared to targeted ctDNA panels. Methods: We have profiled a cohort of 28 extra- and intra-axial adult and pediatric brain tumors including adult and pediatric low- and high-grade glioma (9), meningiomas (11), medulloblastomas (5), ependymomas (2), neurocytoma (1). Tumor DNA was extracted from archival pathology tissue, normal DNA from unsorted white blood cells, and ctDNA from 1-2 mL of post-surgery plasma. WGS was performed with 40x coverage for Tumor-Normal DNA and 20x for ctDNA. Using WGS of matched Tumor-Normal and plasma samples, we derived a personalized mutational pattern using SNVs, indels, and copy numbers for quantification and ultra-sensitive detection of ctDNA in plasma samples. An AI-based error suppression model was implemented to filter out the noise in the cell-free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal to determine the Tumor Fraction at the time of diagnosis, during the therapy or surveillance period. The ctDNA Tumor Fraction (TF) was compared to the clinical status and MRI-based imaging. Results: All subtypes of brain tumors contained enough mutations to derive personalized mutational signatures. Most mutations were distributed in the noncoding DNA. TF correlated with clinical status and with the disease course on imaging at given time points reaching a 10-4 minimal residual disease detection sensitivity. We were able to detect ctDNA across all WHO grades ranging from WHO 1 meningioma to WHO 4 glioblastoma and medulloblastoma. Furthermore, we were able to detect tumor-specific copy number aberrations such as MYCN amplification in plasma samples and mutational signatures. Conclusions: Here we demonstrate that patient-specific WGS tumor signature in ctDNA from plasma can be used for sensitive monitoring of adults and children with primary low- and high-grade CNS tumors.

Transition of Care for Children with High-Grade Central Nervous System Tumors

AbstractThe increase in survival rates of children with high-grade central nervous system tumors has highlighted the necessity for and challenges associated with transition of care as these children grow into adult life. Late recurrence and treatment effects are some of the conditions that require care after transition. Several models of transition have been proposed in the literature. An effective transition will not only ensure adequate continuity of care but will also include assessment of effectiveness of the transition by health care personnel and the patient/patient's family themselves.

The utility of routine surveillance screening with magnetic resonance imaging to detect tumor recurrence/progression in children with high-grade central nervous system tumors: a systematic review.

Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.

Abstract 5846: The use of sodium sulfide, a hydrogen sulfide donor, to sensitize glioblastoma multiforme to photon and proton radiotherapy

Abstract Glioblastoma multiforme (GBM) is the most common glial tumor accounting for 12-15% of all brain tumors worldwide. It is a rapidly progressing, life-threatening disease with a median survival of 3-6 months when left untreated. Minimal advancements in the treatment of GBM have limited its management. Conventional treatment with surgical resection of the primary tumor followed by photon radiation (60 Gy in 2 Gy fractions) in combination with adjuvant chemotherapy can limit recurrence and prolong median survival to 15 months. Proton radiotherapy has received increased attention in recent years due to its more precise energy deposition and 10% higher relative biological effectiveness (RBE) when compared to photon therapy. Several clinical trials have shown that high dose photon/proton therapy reduces central recurrence rate and extends median survival of GBM patients to 21.6 months. Unfortunately, the high rate of radionecrosis has limited its widespread adoption. Radiosensitization agents may overcome this problem by allowing for the use of lower radiation doses to achieve comparable cytotoxic effects; however, no radiosensitizers are currently approved for the treatment of GBM. The current study examines the use of sodium sulfide (Na2S), a hydrogen sulfide donor, as a radiosensitizing agent for both photon and proton therapy in two human glioblastoma cell lines, T98G and U87-MG. Survival curves were generated for T98G cells using a colony forming assay. Protons had an increased RBE of 1.18, which is in close agreement to the accepted RBE of 1.1. Na2S (0 μM, 10 μM, 100 μM, 500 μM, 1000 μM) was given as a pre-treatment in two 2-hour incubations: 2 hours prior to radiation and again immediately before radiation. Na2S alone exhibited a concentration dependent cytotoxic effect with maximal killing of approximately 50% at 500 μM. Further increases in sodium sulfide up to 1000μM had no effect on cell survival. Similar killing was not observed in a non-cancer mouse retinal endothelial cell line even at extremely high doses of 1000 μM suggesting that Na2S cytotoxicity is specific and limited to cancer cells. Na2S increased killing in both photons and protons at 6 Gy by decreasing the surviving fraction from 27.7% to 20% and 16% to 3% respectively. Initial studies into the mechanism of radiosensitization using bleomycin as a radiomimetic agent have suggested Na2S increases the number of DNA double strand breaks (DSB), a highly cytotoxic form of DNA damage, as seen by γH2AX staining in both T98G and U87-MG cells. The benefits of high dose radiation therapy, particularly with proton boost, in the treatment of high-grade central nervous system tumors such as GBM are apparent, but the increased risk of radionecrosis has limited its use. While further studies need to be conducted to elucidate the exact mechanism, preliminary results strongly suggest that sodium sulfide can act as a radiosensitizing agent by increasing DNA DSB formation. Citation Format: Adam Xiao, Rajesh Pidikiti, Matthew Maynard, Nader Sheibani, Lynn Harrison. The use of sodium sulfide, a hydrogen sulfide donor, to sensitize glioblastoma multiforme to photon and proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5846. doi:10.1158/1538-7445.AM2017-5846

Inhibin-A Immunoreactivity in Nervous System Lesions

To evaluate inhibin-A immunoreactivity and its utility in the differential diagnosis of nervous system neoplasms and non-neoplastic lesions. An immunohistochemical study of 252 central and peripheral nervous system tumors and 40 non-neoplastic lesions was undertaken. Brain lesions included the basic spectrum of astrocytic, oligodendroglial, and ependymal neoplasms, as well as glioneuronal, pineal parenchymal, choroid plexus, and embryonal. Meningeal neoplasms, basic peripheral nerve tumors, and uncommon sellar lesions were also assessed. Non-neoplastic lesions included demyelinating disease, progressive multifocal leukoencephalopathy, organizing infarct, and reactive gliosis. Diffuse cytoplasmic, membranous, and perinuclear cytoplasmic staining patterns were observed. Significant immunoreactivity was noted in glioblastoma (12 of 20), pleomorphic xanthoastrocytoma (6 of 10), ganglioglioma (8 of 10), meningioma (14 of 20), and hemangioblastoma (10 of 10). Peripheral nerve and sellar tumors as well as non-neoplastic lesions were entirely immunonegative. In our study that investigated the inhibin-A immunoreactivity in a broad spectrum of nervous system lesions, inhibin-A positivity was established in various low-grade and high-grade central nervous system tumors. Thus, inhibin-A is not a specific marker of hemangioblastoma and may be of limited utility in the differential diagnosis of astrocytic and meningothelial neoplasms. Its pathophysiologic role in these various tumors remains to be determined. Further evaluation of the possible significance of staining patterns and degrees of reactivity relative to pathobiology and/or prognosis significance is required.

A Review of the Use of Antiepileptic Drugs in High-Grade Central Nervous System Tumors

Seizures are a common complication in patients with central nervous system (CNS) tumors. Optimal management is unclear with no defined guidelines and pharmacological management poses many controversies. Due to a hypothesized lack of consistency, we aimed to retrospectively review seizure management in patients with high-grade CNS tumors in our institution. The medical records of patients with high-grade CNS tumors referred to the specialist palliative medicine service in our institution from January-June 2008 were retrospectively reviewed. Seizure incidence, antiepileptic drug (AED) choice, neurology input, medication interactions, and appropriate drug level monitoring were assessed. Twenty-seven patients were included for analysis. Fifteen (56%) were female. The mean age was 58.8 years (range 31-82 years). Three (11%) patients presented with seizures and 8 (30%) developed seizures subsequently. Eight (73% of those with seizures) were on monotherapy AED. Six different agents were used as first-line agents. Phenytoin was the most common AED used (n = 4). Three (27%) patients were on combination AEDs. Five (45.5%) patients had been seen by neurology and 6 (54.5%) had appropriate drug level monitoring performed. Six (55%) patients had potential AED-non-AED interactions. None of the patients had instructions documented in the clinical notes against driving. Seizure management in patients with CNS tumors is not consistent and remains very much a neglected area. Appropriate choice of AED is crucial. Physicians should be aware of potential drug interactions. Ownership and regular follow-up of this group is required to ensure optimum patient management.

Incidence of atypical teratoid/rhabdoid tumors in children

Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population-based data on the incidence of these tumors are not yet available. A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status. A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469). Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors.

Liver grafts from donors with central nervous system tumors: A single-center perspective

Traditionally, patients who die with a malignancy have been excluded from donation. However, it has become a common practice to accept organs from donors that have low-grade tumors or tumors with low metastatic potential. The aim of this study was to analyze our experience with the use of liver grafts from donors with central nervous system (CNS) tumors. A retrospective review of 1173 liver transplants performed between 1992 and 2006 identified 42 donors diagnosed with a CNS tumor. Thirty-two tumors were malignant, and 10 tumors were benign. Forty-two liver transplant recipients received livers from these donors. All patients were followed until May 2007 with a mean follow-up of 29 +/- 17 months. Among 42 donors, there were 28 males and 14 females. The mean donor risk index was 1.78 +/- 0.39. Twenty (47.6%) of the CNS tumors were glioblastoma multiforme (astrocytoma grade IV), 11 (26.2%) were other astrocytomas, and 1 (2.4%) was an anaplastic ependymoma. Twenty (62.5%) neoplasms were grade IV tumors, 8 (25%) were grade II tumors, and 4 (12.5%) were grade III tumors. Over 80% of the patients had at least 1 kind of invasive procedure violating the blood-brain barrier. The rate of recurrence for the entire group was 2.4% (all CNS tumors). There were 7 (7.2%) deaths in all. The most common cause of death was sepsis (n = 3, 7.2%). There was no difference in survival between recipients of grafts from donors with CNS tumors and recipients of grafts from donors without CNS tumors (1 year: 82% versus 83.3%, P = not significant; 3 years: 77.4% versus 72%, P = not significant). In conclusion, in our experience, despite violation of the blood-brain barrier and high-grade CNS tumors, recurrence was uncommon. Grafts from these donors are often an overlooked source of high-quality organs from younger donors and can be appropriately used, particularly in patients who, despite low Model for End-Stage Liver Disease scores, carry a high risk of mortality.