Brain Tumors - A Pocket Guide PDF

Brain Tumors A Pocket Guide Nimish A. Mohile Alissa A. Thomas Editors 123 Brain Tumors Nimish A. Mohile Alissa A. Thomas Editors Brain Tumors A Pocket Guide Editors Nimish A. Mohile Alissa A. Thomas Department of Neurology Department of Neurological University of Rochester Medical Sciences Center University of Vermont Larner Rochester, NY, USA College of Medicine Burlington, VT, USA ISBN 978-3-031-41412-1 ISBN 978-3-031-41413-8 (eBook) https://doi.org/10.1007/978-3-031-41413-8 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Paper in this product is recyclable. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Contents Part I Brain Tumor Primer 1 Malignant Glioma 3 Shannon Fortin Ensign and Alyx B. Porter 2 Diffuse Astrocytoma 21 Donna Molaie and Phioanh (Leia) Nghiemphu 3 Oligodendroglioma 39 Oluwatosin Akintola 4 BRAF-Mutated Glioma 51 Karisa C. Schreck and Jean M. Mulcahy Levy 5 Treatment of Meningioma 67 Rimas V. Lukas, Timothy J. Kruser, and Adam M. Sonabend 6 Treatment of Primary CNS Lymphoma 83 Ugur Sener and Lauren Schaff 7 Adult Medulloblastoma 103 Tresa McGranahan and Sonia Partap 8 Treatment of Ependymoma 119 Jing Wu and Surabhi Ranjan v vi Contents Part II Supportive Care Primer 9 Brain Edema and Corticosteroid Toxicity 141 Maninder Kaur and Reena Thomas 10 T umor Related Epilepsy 153 Thomas Wychowski 11 Treatment and Prevention of Venous Thromboembolism 165 Shiao-Pei Weathers and Alexander Ou 12 Management of Neurocognitive Symptoms 177 Christina Weyer-Jamora and Jennie W. Taylor 13 C hemotherapy-Related Toxicities and Management 195 Haroon Ahmad and David Schiff 14 Radiation Related Toxicities and Management 211 Sara J. Hardy and Michael T. Milano 15 Neurosurgical Complications in Brain Tumor Patients 235 Tyler Schmidt 16 Management of Older Patients with Brain Tumors 249 Andrea Wasilewski 17 P alliative Care in Neuro-oncology 267 Young-Bin Song and Lynne P. Taylor Index 283 Part I Brain Tumor Primer Malignant Glioma 1 Shannon Fortin Ensign and Alyx B. Porter WHO CNS Classification: Glioblastoma, IDH-wildtype Astrocytoma, IDH-mutant Grade 3 and 4 Clinical Scenario A 58 year old right handed man came to medical attention due to a focal motor seizure of the left lower extremity. He was found to have a 3 × 3 cm right parieto-occipital homogeneously enhancing cystic mass. He was taken to the operating room where a gross total resection was achieved by right occipital craniotomy. Post- operatively, he had a left homonymous hemianopia. Pathology demonstrated glioblastoma, IDH-wild type, MGMT methylated, ATRX retained. He received chemoradiation to a total dose of 60 Gy over 30 fractions with concomitant temozolomide 75 mg/ m2 days 1 through 42. He completed a total 6 cycles of adjuvant chemotherapy and chose not to wear tumor treating fields. S. F. Ensign Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA A. B. Porter (*) Department of Neurology, Mayo Clinic, Phoenix, AZ, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature 3 Switzerland AG 2023 N. A. Mohile, A. A. Thomas (eds.), Brain Tumors, https://doi.org/10.1007/978-3-031-41413-8_1 4 S. F. Ensign and A. B. Porter He developed distant disease recurrence 7 months after com- pletion of treatment. Neuroimaging revealed a new left parietal lesion and the previously treated right occipital lesion was stable. Since that area was not the primary target of previous radiation, he was presented to tumor board to discuss the safety and feasibility of re-irradiation. A multi-disciplinary team decided to proceed with radiation at a dose of 40 Gy over 15 fractions. Six months later, an MRI demonstrated further growth of the left parietal mass with increased enhancement and surrounding edema. Additionally, he had more clinical symptoms including hemiparesis, aphasia and intractable focal seizures. He underwent resection of the left temporo-parietal mass to relieve pressure, improve symptoms, treat seizures and to determine the extent to which this was recurrent tumor or necrosis. The pathology was consistent with tumor recurrence. He was planned for therapy with bevacizumab beginning 28 days after surgery, but developed a saddle pulmonary embolism requiring hospitalization and sub- sequent decline in performance status. As a result of progressive clinical decline, the patient elected to enroll in hospice care. He spent 5 months in hospice and passed away 28 months from his original diagnosis of glioblastoma. Making the Diagnosis Gliomas arise from glial cells and neuronal precursors. They con- stitute 80% of all malignant primary brain and CNS tumors. Glioblastoma (GBM) is the most invasive, aggressive (grade 4) and common form. Patients can present with various symptoms including seizures, headaches, neurological deficits, and altered mental status. Magnetic Resonance Imaging (MRI) is the diag- nostic modality of choice when a brain lesion is suspected. Computed Tomography (CT) scans are appropriate in emergent situations to evaluate for intracranial hemorrhage or hydrocepha- lus. While certain imaging characteristics are highly suggestive of GBM (heterogeneously enhancing expansile lesion), none are pathognomonic. In fact, many non-neoplastic processes can mimic gliomas, including multiple sclerosis, granulomatous dis- 1 Malignant Glioma 5 eases, infections, and radiation necrosis. Tissue diagnosis is essential to confirming the suspected diagnosis. Surgical approaches can range from a minimally invasive stereotactic biopsy to a craniotomy with gross total resection. A flowchart describing the diagnostic and treatment approach for these tumors is included in Fig. 1.1. The current tenet of glioma surgery is to achieve maximal safe resection. As diffusely infiltrating lesions, the oncologic con- cept of negative-margin resections applicable to other tumor types cannot be applied. Multiple studies over the past decades have demonstrated a survival benefit with gross total resection. Mathematical models applied to retrospective studies revealed a progressive improvement in survival with the extent of resection increasing between 78 and 98%. A systematic review and meta- analysis of the literature revealed a significant improvement in overall and progression-free survival with gross total resection compared to subtotal resection. In glioma surgery, the definition of gross total resection remains controversial. Achieving true gross total resection is impossible due to the far-reaching invasion of tumor cells into the normal brain parenchyma. Therefore, the consensus is that this terminology refers to the enhancing compo- Fig. 1.1 Glioblastoma Treatment Flowchart 6 S. F. Ensign and A. B. Porter nent. The controversy lies in the extent of resection of the T2 hyperintense portion. Subtotal resection and biopsy (open or ste- reotactic) are reserved for tumors in eloquent areas of the brain, for patients with a poor performance status or multiple medical co-morbidities and cannot medically tolerate resective surgery. Once the importance of maximal safe resection was estab- lished, multiple surgical adjuncts promising to optimize efficacy were introduced. These include intraoperative imaging modal- ities such as intraoperative ultrasound and intraoperative MRI. The quality of available data is at best moderate. However, all imaging modalities were found to improve the rate of gross total resection. Intraoperative ultrasound is inexpensive, readily available, easy to use and can localize small areas of residual that might not be vis- ible to the naked eye. Intraoperative MRI on the other hand, requires an expensive infrastructure but can be very helpful in determining the need for further resection. Fluorescence in brain tumor surgery was developed in the 1990s but its use became mainstream only recently. 5-Aminolevulinic acid (5-ALA) is an imaging agent used to detect glioma cells. It is given to patients orally 3 h prior to anesthesia induction at the dose of 20 mg/kg. 5-ALA causes accumulation of fluorescent porphyrin in tumor cells exclusively. These cells then emit a red-pink fluorescent light that is visible in the oculars of the microscope while the normal brain parenchyma appears in blue. This tool is especially valuable at the normal parenchyma/tumor interface. The use of 5-ALA has been shown to improve the abil- ity of to achieve a gross total resection in a randomized study. Another surgical adjunct is direct white matter stimulation. This technique is particularly important when resecting tumors in proximity to the corticospinal tract. During resection, the white matter fibers are directly stimulated at different amplitudes to elicit a motor evoked potential. Depending on the amplitude of the stim- ulation, a positive response indicates the presence of the cortico- spinal tract within a certain distance of the stimulus. Alternatively, awake surgery can be performed with cortical stimulation to mini- mize injury to eloquent areas. The combination of all 3 allows us to safely expand our resection beyond the contrast enhancing por- tion into what is defined as supramarginal resection. 1 Malignant Glioma 7 Beyond cytoreduction, the role of surgery is to provide tissue for immunohistochemical and genetic analysis. The prognosis is heavily influenced by the genetics and molecular subtypes. Isocitrate dehydrogenase (IDH) mutation is ubiquitous in low grade gliomas. Malignant astrocytoma with IDH mutations are classified as either grade 3 or grade 4 astrocytomas, depending on histologic features and molecular signature. IDH-mutant infiltra- tive gliomas have a better prognosis than IDH-wild-type. Based on the 2021 WHO Classification of Tumors, the diagno- sis of glioblastoma is achieved in a high grade glioma that is IDH- wild-type. For the purposes of this chapter, treatment recommendations apply to IDH-wild-type glioblastoma and can be extrapolated for treatment of IDH mutant grade 3 and grade 4 astrocytomas, for which there are few randomized trials to clearly define therapy. MGMT (O6-methylguanine-DNA methyltransfer- ase) methylation status is a predictive biomarker that determines the response to temozolomide. MGMT is a DNA repair enzyme. It is particularly effective in repairing damage caused by alkylat- ing agents and therefore confers a resistance to temozolomide. MGMT promoter gene methylation silences it and enhances response to temozolomide. IDH and MGMT status are only 2 of multiple mutations analyzed in GBM tissue. Once the genetic and molecular signatures of the tumor have been defined, the treat- ment paradigm, including clinical trial eligibility, are then deter- mined. Post-operative Treatment Radiation Glioblastoma is characterized by microscopic invasive disease within the brain parenchyma outside the tumor bulk, and most high grade glioma recurrences occur within 2 cm of the initial surgical resection margin. Adjuvant fractionated radiation therapy (RT) targeting this expected relapse field confers an overall sur- vival benefit and comprises standard of care post-operative treat- ment, delivered concurrently with chemotherapy. While there 8 S. F. Ensign and A. B. Porter are several approaches to radiation therapy volume planning (EORTC vs RTOG recommendations), the accepted standard of care is the EORTC contouring approach. Radiation dosing of 60 Gy is delivered as 30 × 2 Gy fractions to the clinical target volumes (CTV), which is comprised of the gross tumor volume (GTV) + 2 cm. GTV encompasses the tumor resection cavity plus areas of residual T1 enhancement. Side effects most encountered include fatigue, cognitive decline, alopecia, and radiation derma- titis. Elderly and frail patients may be considered for short course radiotherapy combined with chemotherapy. GBM survival decreases with advancing age and treatment is limited by toxic side effects and underlying coexisting conditions in the elderly , and patients over age 70 were excluded from the initial phase III study showing a benefit of combined chemoradiation versus radiotherapy alone using fractionated 60 Gy dosing. Instead de-escalated treatment with hypofractionated radiation (40 Gy in 15 fractions) with concurrent and adjuvant temozolomide is a consideration in this population. Alternatively, elderly patients not fit for this strategy may be considered for hypofractionated radio- therapy or temozolomide monotherapy alone, with the latter treat- ment strategy more effective in patients with MGMT promoter methylation [8, 9]. Chemotherapy Temozolomide (TMZ), a pro-drug alkylating agent which methyl- ates DNA at the O6 position of guanine and which is able to pen- etrate the blood-brain barrier, is the current standard chemotherapy utilized in the adjuvant postoperative treatment of GBM [7, 10]. TMZ is delivered orally at a dose of 75 mg/m2 daily during con- current radiotherapy. After completion of RT, TMZ is held for 4 weeks then resumed at 150 mg/m2 and subsequently escalated to 200 mg/m2 days 1–5 of every 28 days for a minimum of 6 months. No study has demonstrated benefit of adjuvant chemotherapy beyond 6 months, but it should be noted that in the CATNON 1 Malignant Glioma 9 study, 12 months of adjuvant therapy were given to individuals with anaplastic astrocytomas. Analysis of the CATNON study also suggested that there may not be additional benefit for concurrent temozolomide in that population. Specific treatment regimens used in malignant gliomas are included in Table 1.1. Given the emetogenicity of TMZ use of ondansetron 8 mg, granisetron 1 mg or prochlorperazine 10 mg orally 30 min before each chemotherapy dose is recommended. During concurrent chemoradiotherapy weekly blood counts may be needed to moni- tor for cytopenias, and liver function testing monitored midway through radiation therapy and subsequently. Lymphopenia places patients at increased risk for Pneumocystis jirovecii pneumonia (PJP), and prophylaxis should be considered in patients still requiring corticosteroids. TMZ should be held for platelet count under 100,000 and ANC 50 with KPS ≥70, age LCA Foramen of Hemorrhage Rare Luschka SHH 60% 70% Cerebellar Strong DWI, 5% hemisphere more edema TP53wt Majority C, DN TP53 mutant Rare LCA Non-WNT/Non-SHH Group 3 Rare C, LCA High Group 4 25% 45% C, LCA Midline Minimal contrast 30–40% OS overall survival, wt wildtype, C classic, LCA large-cell/anaplastic, DN desmoplastic/nodular 105 106 T. McGranahan and S. Partap In adults, the most common etiology of a cerebellar mass is metastasis from a solid cancer (for example lung or breast cancer) and not MB. The radiographic differential also includes ependy- moma, choroid plexus papilloma, hemangioblastoma and glioma. For children, the radiographic differential includes atypical tera- toid rhabdoid tumor, ependymoma, and pilocytic astrocytoma. Staging Chang stage (Table 7.2) is used to document extent of disease and for risk stratification. Given high rates of metastasis in MB, as well as implications for treatment, all MB require CNS staging. An MRI brain should be obtained both preoperative as well as within 48 h after surgery. This is essential for determining the amount of residual disease before post-surgical inflammation changes predominant. Patients also require MRI spine obtained pre-operatively or 2–3 weeks after surgery. If there is no radio- graphic evidence of leptomeningeal spread, CSF should be sam- pled from the lumbar spine 2 weeks postoperatively to reduce the risk of false positive results from surgical debris. Often due to Table 7.2 Chang staging Tumor classification T1 3 cm T3a >3 cm with spread into the aqueduct of Sylvius and/or foramen of Luschka, cerebral subarachnoid space, third or lateral ventricles T3b >3 cm with unequivocal spread into the brainstem; for T3b, surgical staging may be used in the absence of involvement at imaging T4 >3 cm with spread beyond the aqueduct of Sylvius and/or the foramen magnum Metastatic classification M0 GTR and no evidence of CSF or distant spread M1 Tumor cells found in CSF M2 Intracranial tumor beyond primary site M3 Gross nodular seeding in subarachnoid space M4 Metastasis outside of neuroaxis (e.g. bone, bone marrow) 7 Adult Medulloblastoma 107 hydrocephalus, pre-operative lumbar spine sampling of CSF is not considered safe. Due to concerns for dural enhancement following lumbar puncture, MRI of spine should be obtained prior to lumbar sampling of CSF. Systemic staging (PET, CT, bone scan) is only recommended if there are concerning symptoms. Pathologic and Molecular Findings MB is an embryonal tumor with histology of small round blue cells with mitosis. Histologically, MB is divided into three sub- types (classic, large-cell/anaplastic, and desmoplastic/nodular). Large-cell/anaplastic subtype is associated with worse prognosis compared to other groups. As of WHO 2016, MB are also divided into four molecular subtypes (WNT, SHH, Group 3 and Group 4) which overlap with the histological subtypes (Table 7.1). All MB subtypes are WHO grade 4 tumors. WNT-MB subgroup represents 15% of adult MB. This sub- group is characterized by activation of the WNT/beta-catenin pathway and typically has classic histology, however rarely is large-cell/anaplastic. WNT-MB has the best prognosis for both adults and children, however the 5 year survival in adults is 80% compared to over 95% in children. On MRI, the WNT subgroup often arises from the cerebellar peduncle and has higher rates of hemorrhage. Even without suspicion based on family history, 6–8% of patients with WNT-MB had germline APC mutations so all of these patients should have genetics referral. SHH-MB subgroup is the most common subtype in adults repre- senting 60% of adult MB. This subgroup is characterized by muta- tions in the sonic-hedgehog (SHH) pathway and subdivided into TP53 wildtype and mutant. In adult MB, the majority of SHH-MB are TP53 wild-type. All histologic subtypes are seen in SHH-MB, however large-cell/anaplastic is more common in TP53 mutant SHH-MB. The 5-year overall survival is 70% in adults. SHH-MB are more often in the cerebellar hemispheres, although they may be midline in adults. There is often a greater degree of edema sur- rounding SHH-MB compared to other subtypes. Genetics referrals 108 T. McGranahan and S. Partap should also be considered for SHH subgroups with consideration of germline testing for TP53, PALB2 and BRCA2. Non-WNT/Non-SHH subgroup: The 2021 WHO is comprised of the “Group 3” and “Group 4” subtypes that were previously defined in the 2016 WHO, as well as other molecular subtypes that has emerged with more granular methylation and transcrip- tome profiling. Group 3 subgroup is extremely rare in adults with reports ranging from 0 to 5%. This subgroup may have classic or large cell/ anaplastic. Rates of metastasis are high contributing to the poor prognosis of this group for both children and adults. Group 4 subgroup is the second most common subgroup in adults representing 20–25% of adult MB. Histologically this may have classic or large cell/anaplastic morphology. In adults, Group 4 MB is metastatic in 35–40% of patients contributing to the poor prognosis with median overall survival of less than 3 years [3, 6]. Group 4 MB are more often midline and enhance less than other subtypes. First Line Treatment Clinical Risk Stratification The majority of studies have not found the risk stratification used in children (Table 7.3) to be prognostic in adults. As a result, mul- tiple definitions have been used to characterize high and average Table 7.3 Childhood clinical staging of medulloblastoma High risk Average risk Age of child Less than 3 years Older than 3 years Extent of resection STR or biopsy GTR/NTR Presence of metastatic Metastatic disease M0 disease (M1–3) Histology Large cell/Anaplastic Classic GTR gross total resection, NTR near total resection, STR subtotal resection 7 Adult Medulloblastoma 109 risk MB in adults. The majority of studies have found metastasis (Chang M1–4), anaplastic histology and brainstem involvement to be associated with worse prognosis. Risk stratification based on age or residual disease remains unclear in adult MB especially since the identification of molecular subgroups. Surgery Surgery is an essential component for diagnosis and management of MB. The goal of surgery is removal of as much visible tumor as can be done safely without resulting in new neurologic deficits. Residual tumor volume of less than 1.5 cm2 is considered a gross total resection (GTR). In the setting of brain stem involvement, leaving residual tumor volume is considered safe. In adults with group 4 tumors there is a progression free survival benefit to GTR however maximal safe resection in all patients is recom- mended. In addition to diagnosis and debulking, surgery may also be needed for management of hydrocephalus. Obstructive hydro- cephalus is common at presentation of MB and patients may require CSF diversion even prior to initial work up. For many patients, debulking surgery can relieve obstruction, however some may require shunt placement for treatment of the hydrocephalus. Regardless of initial hydrocephalus management, development of signs and symptoms related to elevated ICP should lead to prompt evaluation for hydrocephalus with head imaging and funduscopic examination. Craniospinal Irradiation Surgery and radiation remain the cornerstone of treatment for adult MB while the role of chemotherapy is questioned in adults. The standard of care is to start craniospinal irradiation (CSI) within 4 weeks of surgery and retrospective data have found that adult patients who started radiation after this window trend towards worse survival. Proton CSI is favored over photon CSI due to data that found adult MB patients had less weight loss, 110 T. McGranahan and S. Partap nausea, vomiting, hematologic toxicities and esophagitis when treated with protons. The range of dose for CSI is between 23.4 and 39.6 Gy and tumor bed is boosted to between 54 and 55.8 Gy. Despite the limitations to risk stratification noted above, CSI to a dose of 36 Gy in 20 fractions is typically used for patients determined to be high risk due to the presence of metastasis, ana- plastic histology or brainstem involvement. For patients without these high risk features, a CSI dose of 23.4 Gy in 13 fractions with the same tumor bed boost to 54–55.8 Gy is used. Focal radiation to sites of metastatic disease vary based on location and tolerance of tissues. Typical doses are 50.4 Gy for intracranial metastasis or below the conus and 45 Gy for focal spinal metastasis above the conus. In the setting or radiographic leptomeningeal disease, the dose of CSI is increased to 39.6 Gy. While dose reduction is being studied in average risk WNT tumors in patients up to 21 years of age (NCT02724579, NCT01878617), this is not recommended for adults outside of clinical trials. Systemic Therapy MB is sensitive to chemotherapy, however at this time there is no standard chemotherapy regimen for adult MB. Most chemother- apy regimens have been adopted from pediatric studies as only three prospective, single arm, adult MB clinical trials have resulted and none included molecular subtypes. Most retrospec- tive studies have not found benefit to chemotherapy, however a recent meta-analysis did find improved survival combining a wide variety of chemotherapy protocols (neoadjuvant, concurrent and adjuvant). As a result, treatment guidelines from EANO- EURACAN recommend treatment of all patients with chemother- apy in addition to CSI regardless of risk factors or molecular subtype. The role of chemotherapy in adult MB is an area in need of prospective clinical trials. Whenever possible patients should be referred for participation in clinical trials. The treatment recom- mendations differ between NCCN and EANO-EURACAN; these authors’ recommendations are reflected. Neoadjuvant chemo- 7 Adult Medulloblastoma 111 Table 7.4 First line chemotherapy following irradiation Packer—42 day cycle CVP—28 day cycle D1: Lomustine 75 mg/m2 D1–4: Cisplatin 25 mg/m2 D1: Cisplatin 70 mg/m2 (consider D1–4: Etoposide IV 40 mg/ carboplatin AUC 4 as alternative) m2 D1, D8, D15: Vincristine 1.5 g/m2 (2 mg D4: Cyclophosphamide max) 1000 mg/m2 4–8 cycles pending tolerability Goal: 4 cycles AUC Area under the curve therapy is not recommended. Given toxicity and unclear benefit, chemotherapy concurrent with radiation (vincristine or carbopla- tin) are not recommended. It is important to note that other groups do advocate for use of concurrent chemotherapy. NCCN guidelines support adjuvant chemotherapy of either the “Packer Protocol”, consisting of platinum agent (carboplatin or cisplatin), lomustine and vincristine , or “CVP” with cyclophospha- mide, etoposide, cisplatin. In fit adult MB patients, adjuvant chemotherapy with “Packer Protocol” should be considered (Table 7.4). There are several older multi-drug regimens that have been reported but are not favored as first line therapy. Surveillance Most adult MB recurrences are reported within 6 years of diagno- sis, however, the high rate of late recurrences in adult MB man- dates lifelong surveillance. The median time to tumor progression is 24–50 months, however there is an increased risk of recurrence in adults after 7 years and recurrences have been reported after 14 years from diagnosis. During treatment, patients should have an MRI of the brain and spine completed one month following CSI. For patients who have metastatic disease to the spine or systemic metastasis, all surveil- lance imaging should include known sites of disease. For patients without metastatic disease, the role of spine surveillance is debat- able as 50% relapses occur in posterior fossa and absence of intra- 112 T. McGranahan and S. Partap cranial progression is predictive of absence in spine. Systemic surveillance (bone surveillance and PET imaging) have been dis- cussed but at this time are not recommended for adults. These authors recommend MRI brain and spine every 3 months for the first year. If no spine involvement, MRI brain alone can be moni- tored every 3 months for the second year after diagnosis though there is no standard. In children, spine MRI is obtained serially as well until 5 years from diagnosis. During years 3–7, imaging fre- quency can be spaced to every 6 months. Annual MRI surveil- lance for the known sites of disease should be continued indefinitely. Prognosis True prognosis and survival data are limited given rarity of dis- ease, wide variations in treatment and limited prospective studies. For adults, the SEER and CBTRUS databases estimate 2, 5 and 10 year survival as 85–89%, 74–78% and 67–68% [13, 14]. Molecular subtypes help with stratifying prognosis with WNT having the best prognosis of 5 year survival of 80%, followed by SHH with a 5 years survival of 70% and Group 4 of 5 year sur- vival of less than 50%. Recurrent Disease Treatment At the time of recurrent disease, repeat staging should be com- pleted with MRI spine, CSF sampling and survey of systemic symptoms with consideration of CT chest and abdomen or PET scan. There is very limited data to guide treatment of recurrent MB and estimated survival after recurrence is 15 months. For this reason, all patients should be evaluated at a comprehensive brain tumor center for consideration of clinical trials. Local treatment options at recurrence include, re-resection and re-irradiation. While there are increased risks of toxicity with re- irradiation, stereotactic radiosurgery has been reported to result in an 89% disease control rate. 7 Adult Medulloblastoma 113 Table 7.5 Recurrent treatment options First choice Enroll in a clinical trial Other options Dosing reference Local therapyRe-resection Re-irradiation Brandes et al. (2015) Chemotherapy Bevacizumab and temozolomide Temozolomide MOPP (methotrexate, Kunschner et al. (2001) procarbazine, vincristine, prednisone) Lomustine + Gill et al. (2008) platinum ± vincristine CVP (cisplatin- See Table 7.4 cyclophosphamide-etoposide) Tandem autologous stem cell Gill et al. (2008) transplant Targeted Vismodegib Li et al. (2019) therapy Sonidegib Li et al. (2019) Chemotherapy is favored for multifocal relapse however there have been no studies comparing efficacy of various treatments. Responses have been reported with several treatments listed in Table 7.5. For patients with SHH- MB, SMO inhibitors vismodegib and sonidegib are well tolerated and should be considered for recur- rent SHH- MB. There are current prospective trials studying these agents in newly diagnosed SHH disease as well (NCT01878617, EORTC-1634-BTG). Survivorship The survivorship issues for adult MB parallel those for other malignant brain tumors with complications of neurologic injury from site of disease as well as long term effects of radiation and chemotherapy. Fertility: All patients should be offered referral to fertility pres- ervation clinics prior to start of treatment. 114 T. McGranahan and S. Partap Cognitive: Consistent with other studies of whole brain radia- tion in adults, survivors of adult MB have cognitive impairment. Studies have identified the cognitive domains most impacted are learning, memory, visuospatial skills and reasoning. Differences in cognitive outcomes between proton and photon radiation have never been proven for adults. In pediatric MB how- ever, there is retrospective data that suggests superior global IQ, perceptual reasoning and working memory with protons com- pared to photons. Both groups had impaired processing speed. Endocrine: Treatment with CSI places patients at risk for pitu- itary dysfunction as well as primary endocrine organs. The major- ity of data for endocrinopathies following treatment for MB are based on childhood survivors. The risk of thyroid dysfunction (primary or second) for children treated with CSI range from 20 to 69%. Patients who underwent CSI should have annual surveillance for endocrine dysfunction with TSH and free T4, gonadal steroids and AM cortisol. There should be a low threshold for shorter intervals of endocrine screening if patients clinically decline with unexplained weight loss, excessive fatigue, nausea or orthostatic symptoms. Ototoxicity: Ototoxicity develops in 48% of patients treated for MB most often as a complication from treatment. Platinum based chemotherapies, particularly cisplatin, cause ototoxicity that should be monitored during treatment as well as long term. Carboplatin can be considered in lieu of cisplatin as it has less ototoxic effects. Cochlear dose of radiation can also impact ototoxicity and studies in children have found that reducing the cochlear dose of radiation reduces grade 3 and 4 ototoxicity. Neuropathy: Multiple studies in adult MB highlight the risk of peripheral neuropathy with vincristine [8, 10]. Given the high risk of neuropathy with vincristine, as noted above these authors do not support including concurrent vincristine during radiation in adults. If vincristine is used in adjuvant chemotherapy, close mon- itoring is necessary and discontinuation if grade 2 motor or sen- sory neuropathy develops. 7 Adult Medulloblastoma 115 Radiation related neurologic injury (radiation necrosis): Brain and spinal radiation injury can occur in MB similar to other brain tumors. Radiation injury in the brain stem can be particularly toxic presenting with weakness, dysarthria or dysphagia. With proton radiation, these changes occur 8–18 months following the start of radiation. Genetic screening: A high prevalence of genetic predisposition were found in WNT and SHH subtypes of both childhood and adult MB. Current recommendations are that all patients with WNT and SHH MB should be referred for genetic counseling and testing as standard of care. Secondary Malignancy: Patients treated with radiation and chemotherapy remain at risk for secondary malignancies. There is no standard accepted screening however the risks include (but are not limited to) skin cancer, secondary brain tumor (meningioma, glioma), sarcomas, leukemia and thyroid malignancy. Vascular Complications: CSI may result in a multitude of radi- ation induced/accelerated vascular complications in the brain as well as cardiovascular system. Cerebral microhemorrhages have been reported to occur in 67% of patients by 4 years after treat- ment. Other vascular complications include radiation vascu- lopathy and resulting ischemic strokes as well as cavernomas. Additionally, spinal radiation may place cardiac structures at increased risk, for this reason childhood cancer survivor guide- lines recommend echocardiogram every 5 years following spine radiation. Future Directions Adult MB is a rare adult malignancy and at this time there are limited prospective clinical trials to guide treatment. All patients with MB should be referred to a comprehensive brain tumor cen- ter for consideration of clinical trials even inquiring at pediatric centers for clinical trial options. Table 7.6 includes samples of patient-facing education in lay terms to help patients understand their condition and options. 116 T. McGranahan and S. Partap Table 7.6 Patient education Patient question Patient information Type of Adult medulloblastomas are rapidly growing brain tumors. tumor They develop from cells in the posterior fossa, or back lower area of the brain. They are extremely rare in adults and more common in children Symptoms Often adult patients with medulloblastoma present with headache, vision changes, dizziness or imbalance Next steps These tumors have a high risk of spreading in the fluid surrounding the brain and spinal cord. MRI of the patient’s spinal cord and a sample of the spinal fluid is necessary to see if the tumor has spread Treatment Because these are rare tumors, referral to a center that specializes in brain tumors is recommended Surgery is the first step of diagnosis and treatment This is followed by radiation to the area the tumor was seen on the MRI as well as the whole brain and spinal cord. This radiation is typically delivered 5 days a week over 6 weeks Chemotherapy may be given after radiation. Side effects Tumor resection: Often after surgery patients will need to work with a therapist to improve speech or movement Radiation: Risks include hair loss, nausea/vomiting, decrease in blood counts and headaches however full discussion of side effects should occur with treating radiation oncologist Monitoring These tumors have a high risk of growing back. For that reason, patients will need to be monitored with MRIs for life. Initially these will be every 3 months but overtime the frequency of MRIs will decrease Genetic Multiple genetic syndromes have been reported in testing association with medulloblastoma. All patients should be considered for genetic counseling and patients with WNT and SHH subtypes will need genetic testing Prognosis Medulloblastomas are potentially curable, however may recur even more than a decade from the time of diagnosis. Over 70% of patients who undergo treatment live longer than 5 years 7 Adult Medulloblastoma 117 Current clinical trials are exploring the role of molecular strat- ification and incorporation of targeted agent. Given improved out- comes in WNT subgroup MB, reduced doses of radiation are also being explored in patients up to 21 years of age. The role of che- motherapy in treatment of adult MB remains unclear but may con- fer a benefit. There have only been three prospective adult MB clinical trials that have results [10, 12, 23]. None of these studies used molecular stratification. There is urgent need for a prospective randomized clinical trial in adult MB of adjuvant che- motherapy. References 1. Waszak SM, Northcott PA, Buchhalter I, et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol. 2018;19:785–98. 2. Chang CH, Housepian EM, Herbert C Jr. An operative staging system and a megavoltage radiotherapeutic technique for cerebellar medulloblasto- mas. Radiology. 1969;93:1351–9. 3. Zhao F, Ohgaki H, Xu L, et al. Molecular subgroups of adult medullo- blastoma: a long-term single-institution study. Neuro Oncol. 2016;18:982–90. 4. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20. 5. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medul- loblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123:473–84. 6. Remke M, Hielscher T, Northcott PA, et al. Adult medulloblastoma com- prises three major molecular variants. J Clin Oncol. 2011;29:2717–23. 7. Franceschi E, Hofer S, Brandes AA, et al. EANO–EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. Lancet Oncol. 2019;20:e715– 28. 8. De B, Beal K, De Braganca KC, et al. Long-term outcomes of adult medulloblastoma patients treated with radiotherapy. J Neurooncol. 2018;136:95–104. 9. Brown AP, Barney CL, Grosshans DR, et al. Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma. Int J Radiat Oncol Biol Phys. 2013;86:277–84. 118 T. McGranahan and S. Partap 10. Beier D, Proescholdt M, Reinert C, et al. Multicenter pilot study of radio- chemotherapy as first-line treatment for adults with medulloblastoma (NOA-07). Neuro Oncol. 2018;20:400–10. 11. Kunschner LJ, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998. Neuro Oncol. 2001(3):167–73. 12. Brandes AA, Franceschi E, Tosoni A, Blatt V, Ermani M. Long-term results of a prospective study on the treatment of medulloblastoma in adults. Cancer. 2007;110:2035–41. 13. Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS statistical report: pri- mary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21:v1–v100. 14. Li Q, Dai Z, Cao Y, Wang L. Comparing children and adults with medul- loblastoma: a SEER based analysis. Oncotarget. 2018;9:30189–98. 15. Brandes AA, Bartolotti M, Marucci G, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol Hematol. 2015;94:348–59. 16. Gill P, Litzow M, Buckner J, et al. High-dose chemotherapy with autolo- gous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system. Cancer. 2008;112:1805–11. 17. Li Y, Song Q, Day BW. Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systematic review and meta-analysis. Acta Neuropathol Commun. 2019;7:123. 18. Harrison RA, Kesler SR, Johnson JM, Penas-Prado M, Sullaway CM, Wefel JS. Neurocognitive dysfunction in adult cerebellar medulloblas- toma. Psychooncology. 2019;28:131–8. 19. Kahalley LS, Peterson R, Ris MD, et al. Superior intellectual outcomes after proton radiotherapy compared with photon radiotherapy for pediat- ric medulloblastoma. J Clin Oncol. 2020;38:454–61. 20. Packer RJ, Zhou T, Holmes E, Vezina G, Gajjar A. Survival and second- ary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children’s Oncology Group trial A9961. Neuro Oncol. 2013;15:97–103. 21. Roongpiboonsopit D, Kuijf HJ, Charidimou A, et al. Evolution of cere- bral microbleeds after cranial irradiation in medulloblastoma patients. Neurology. 2017;88:789–96. 22. Franceschi E, Bartolotti M, Paccapelo A, et al. Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients? J Neurooncol. 2016;128:235–40. 23. Moots PL, O’Neill A, Londer H, et al. Preradiation chemotherapy for adult high-risk medulloblastoma: a trial of the ECOG-ACRIN Cancer Research Group (E4397). Am J Clin Oncol. 2018;41:588–94. Treatment of Ependymoma 8 Jing Wu and Surabhi Ranjan The Clinical Scenario A 43-year old woman presented with 4 months of progressive head- aches and neck pain. A brain MRI image with gadolinium contrast revealed a large homogeneously enhancing mass within the fourth ventricle extending through the foramina of Luschka and Magendie and inferiorly to the lower aspect of C2 vertebrae. These lesions caused mass-effect on the brainstem and upper cervical cord (Fig. 8.1). The patient underwent a resection of the intraventricular mass. A postoperative MRI of the brain showed a 1 cm × 0.8 cm residual tumor. An MRI image of the cervical, thoracic and lumbar spine was obtained for staging, which showed no signs of tumor dis- semination. A lumbar puncture was performed 2 weeks after the surgery and no malignant cell was found in the cerebrospinal fluid. The patient’s pathology report was reviewed and showed a well delineated tumor with monomorphic cells of variable density and round to oval nuclei with speckled chromatin. Perivascular pseudorosettes were observed. The patient was diagnosed with a grade 2 ependymoma. She received involved field radiation ther- J. Wu (*) · S. Ranjan Department of Neurology, Cleveland Clinic Florida, Weston, FL, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature 119 Switzerland AG 2023 N. A. Mohile, A. A. Thomas (eds.), Brain Tumors, https://doi.org/10.1007/978-3-031-41413-8_8 120 J. Wu and S. Ranjan a b c Fig. 8.1 (a) Axial T1 post-contrast MRI revealing an irregular hyperintense mass within the fourth ventricle and compressing the surrounding brainstem. (b) Appearance of the lesion on T2 FLAIR sequence. (c) Sagittal T1 post- contrast sequence a b Fig. 8.2 Sagittal T2 sequence (a) and T1 post-contrast sequence (b) of the thoracic MRI showing sausage-shaped intradural and extramedullary masses at the T10 and T12 levels apy to the residual tumor and tumor bed to a total dose of 59.4 Gy in 33 fractions. Three years later, the patient started complaining of progressive back pain radiating to the lower anterior abdomen. An MRI of the spine revealed intradural extramedullary masses at T10 and T12 level (Fig. 8.2). These tumors were resected and a pathological exam confirmed a grade 2 ependymoma. No evi- 8 Treatment of Ependymoma 121 dence of recurrence was found in the brain or cerebrospinal fluid (CSF). Postoperatively, she received focal radiation to the T10 and T12 regions. Her low back pain was resolved after the treat- ment and she remained symptom-free and without disease pro- gression for 30 months following the focal radiation to the lower thoracic spine. Making the Diagnosis Surgical Role Surgical resection is the mainstay of the current treatment of ependymoma. The surgical procedure is essential to establish a pathological diagnosis and collect tissue for genomic analysis to determine each case’s unique molecular features. If the tumor cannot be resected safely due to its location, a biopsy of the lesion is still required to confirm the pathological diagnosis prior to the treatment. The extent of surgical resection has been consistently shown as a prognostic marker in pediatric and adult studies [1–4]. Patients with gross total resection (GTR) have improved out- comes with a lower rate of local recurrence and improved overall prognosis. Patients who underwent subtotal resection, even with the addition of radiation therapy, have an increased chance to have disease progression. Myxopapillary ependymoma was previ- ously classified as a grade 1 tumor due to long survival time and potential for cure after gross total resection, but some myxopapil- lary ependymomas may present with late recurrence or dissemi- nation and have been upgraded to grade 2 in the 2021 WHO Classification of CNS Tumors. A postoperative MRI obtained within 24–48 h of surgery is recommended to determine the extent of the resection. GTR is defined as no residual contrast-enhanced or non-enhanced lesion seen on postoperative MRI and a report of no residual tumor by the operating surgeon. If there is extensive residual disease showing on the immediate postoperative MRI and the lesions can be resected readily, a second-look surgery can be beneficial [6, 7]. 122 J. Wu and S. Ranjan Ependymomas are known for a high rate of CSF dissemination as compared to other gliomas with studies reporting a rate of 7–10% [8, 9]. CSF analysis is recommended as staging in addi- tion to imaging of the entire neuroaxis. However, a lumbar punc- ture should be deferred by at least 2 weeks postoperatively to avoid confusing findings in the CSF. A CSF analysis positive for malignancy should be repeated after another week to rule out false positive CSF dissemination as it will change the treatment para- digm. Key Pathologic and Molecular Findings The pathognomonic features of ependymoma are perivascular pseudorosette and true ependymal rosettes. Pseudorosettes are characterized by tumor cells arranged radially around a blood vessel with a perivascular anuclear zone of fine fibrillary pro- cesses. Ependymal rosettes are formed when cuboidal or colum- nar tumor cells are arranged around a central lumen. An overview of WHO classification will be in a separate chap- ter. Briefly, ependymomas are classified from grades 1 to 3. Grade 1 ependymomas include subependymomas. Myxopapillary epen- dymoma is a WHO grade 2 tumor which arises in the region of the conus medullaris, cauda equina and filum terminale. Tumor cells are radially arranged in papillary fashion around vascularized, mucoid, fibrovascular cores. When resected en bloc, these tumors have excellent prognosis. However, 34–40% of the cases will have local recurrent and dissemination along the neuraxis [12, 13]. Grade 2 and 3 ependymomas are designated based on tumor location: spinal, supratentorial, or posterior fossa; and further des- ignated based on molecular findings. Supratentorial ependymo- mas include ZFTA-fusion positive and YAP1-fusion positive. The entity formerly known as ependymoma RELA fusion position, in the 2016 WHO, is now included in the ZFTA-fusion positive sub- group. Posterior fossa ependymomas include group PFA and group PFB. Spinal ependymomas include a distinct subgroup of spinal ependymoma, MYCN-amplified. In the 2021 WHO, the designation of “anaplastic” ependymoma has been removed, 8 Treatment of Ependymoma 123 however ependymoma may be classified by pathologists as grade 2 or grade 3 according to histopathological features. Subependymomas are WHO grade I tumors, which are slow growing, exophytic and consist of bland to mildly pleomorphic mitotically inactive cells embedded in a fibrillary matrix. These tumors are characterized by intraventricular location and are most commonly found in the fourth ventricle. Subependymomas have excellent prognosis. The above case represents a posterior fossa ependymoma. The pathognomonic features of ependymoma are perivascular pseudo- rosette and true ependymal rosettes. Pseudorosettes are character- ized by tumor cells arranged radially around a blood vessel with a perivascular anuclear zone of fine fibrillary process. Ependymal rosettes are formed when cuboidal or columnar tumor cells are arranged around a central lumen. Ependymomas have three distinct histopathological variants without clinicopathological significance. These are papillary ependymoma, characterized by well-formed papillary, clear-cell ependymomas which have oligodendrocytes-like appearance and tanycytic ependymoma, which have elongated cells with spindle- shaped nuclei. It is important to know that geographic necrosis is not a diagnostic feature by itself without association with high proliferation index and vascular proliferation. Non-pallisading necrosis can be seen in grade 2 ependymoma, while pseudopalli- sading necrosis and microvascular proliferation are common in grade 3 ependymomas. Transcriptome and methylome profiling have recently identi- fied nine molecular subgroups of ependymoma, each into three central nervous system (CNS) compartments of supratentorial, posterior fossa and spinal compartments. These molecular subgroups have a better clinical and prognostic association than the histological classification and form the basis of the 2021 WHO integrated molecular classification. Supratentorial ependymomas are divided into ZFTA-fusion positive, which includes the RELA fusion gene and a poor outcome, and YAP1-fusion positive, which has a relatively good prognosis. Posterior fossa ependymomas are categorized into PFA and PFB. PFA are found in infants, have balanced genomes, a higher extent of CpG island methylation and 124 J. Wu and S. Ranjan have poor prognosis [16, 17]. PFB are found in children and adults, have genome-wide polyploidy, low CpG island methylation and good outcomes. Posterior fossa subependymoma has a bal- anced genome and a good outcome. Ependymomas occuring in the spine include are spinal ependymoma, myxopapillary ependy- moma, and subependymoma. Spinal ependymomas have frequent NF2 gene mutation and frequently occur in neurofibromatosis type 2 patients. These have good outcomes. Spinal myxopapillary ependymomas have genome-wide polyploidy and good progno- sis. Spinal subependymomas are associated with 6q deletion and have good prognosis. Post-operative Treatment Radiation Therapy Due to a lack of prospective studies and rarity of ependymomas, there is a wide variation in radiation treatment recommendation among experts. The decision for adjuvant radiation in treatment of ependymoma depends on the tumor grade, extent of resection and status of tumor dissemination. In general, patients with anaplastic ependymoma, patients with subtotal resection and disseminated tumors are treated with upfront adjuvant radiation. Cranio-spinal irradiation (CSI) is not recommended unless the patient has evi- dence of wide-spread dissemination. The role of radiation therapy is unclear for WHO grade 2 ependymomas with gross total resec- tion, and general consensus is that patients can be observed clini- cally and radiographically after complete removal of a grade 2 ependymoma. Patients with spinal cord grade 2 ependymo- mas with subtotal resection generally undergo upfront radiation therapy. A recent retrospective study on 1058 patients found improved progression free survival, but no improvement in over- all survival with the use of adjuvant radiation therapy in WHO grade 2 spinal ependymoma. Similarly, another study evalu- ating 348 patients with spinal cord ependymoma showed an improvement in PFS with adjuvant radiation but no improvement in OS. A total dose of 59.4 Gy to the involved field using 8 Treatment of Ependymoma 125 conventional fractionation of 1.8 Gy per day in 33 fractions can be used. Children between 12 and 18 months with a gross total resection have been treated with a total dose of 54 Gy. The dose to the optic chiasm and spinal cord should be limited to 54 Gy or less. Patients with myxopapillary ependymoma which have been resected en bloc (without the breach of capsule) are associated with very low risk of recurrence (0–10%) do not require any adju- vant radiation [22, 23]. Local radiation to the spinal lesion is administered in patients with sub-totally resected myxopapillary ependymoma. In contrast to adults, pediatric myxopapillary epen- dymomas do not have a benign course and a majority of patients present with disseminated spinal disease. In fact, a pediatric myxopapillary ependymoma study found that patients who under- went a subtotal resection followed by radiation fared better than patients who underwent GTR alone. For disseminated ependymoma, debulking of the primary tumor should be attempted. Craniospinal irradiation may be con- sidered in patients using a dose of 36 Gy in 1.8 Gy fractions with a boost of 59.4 Gy to the primary tumor and metastases. A combi- nation of chemotherapy and focal irradiation can also be used. Subependymomas are considered WHO grade I benign tumors and no adjuvant radiation treatment is recommended after surgi- cal resection. Proton therapy has been considered more in the management of ependymomas due to its feature of sparing normal tissues. It may be the most beneficial for young patients with tumors that require radiotherapy near critical structures. Prospective studies with extended follow-up are warranted to investigate the effect of proton versus photon therapies in both pediatric and adult ependy- momas. Chemotherapy The role of chemotherapy is not established in ependymoma. Chemotherapy has been most investigated in pediatric studies. Due to the concern for severe radiation toxicity to the developing 126 J. Wu and S. Ranjan brain among infants, chemotherapy has been used in an attempt to defer the radiation to the developing nervous system [26, 27]. Alternating procarbazine and, carboplatin, etoposide and cispla- tin, cyclophosphamide and vincristine that are used postopera- tively have been found to be active antineoplastic regimen but no tumor has shown more than 50% reduction. The second prospec- tive AIEOP protocol for pediatric patients investigated four courses of vincristine, etoposide and cyclophosphamide after radiation in patients with anaplastic ependymoma. The VEC regimen used vincristine at 1.5 mg/m2 on day 1, cyclophospha- mide 1 g/m2 infused in one hour for 3 doses, 3 h apart on day 1 and etoposide 100 mg/m2 infused in 2 h, days 1, 2 and 3. Each cycle was of 3–4 weeks duration, for a total of 4 cycles. The children’s oncology group has an ongoing Phase 3 trial COG ACNSS0831 evaluating maintenance chemotherapy versus observation, following induction chemotherapy and radiation therapy in treating children with newly diagnosed ependymoma. One of its experimental arms uses a chemotherapy regimen con- sisting of vincristine on day 1 and 8, of courses 1 and 2, carbopla- tin on day 1 of courses 1 and 2, and cyclophosphamide on day 1–2 of course 1 only. Etoposide is administered on day 1–3 of course 2. Another experimental arm uses vincristine on day 1, 8 and 15 of course 1–3 only, etoposide on days 1–3, cisplatin on day 1, cyclophosphamide on days 2 and 3. The role of chemotherapy was not studied prospectively in adults until a clinical trial by The Collaborative Ependymoma Research Network (CERN) investigators, where they rationalized to test a dose-dense temozolomide regimen in combination with lapatinib in recurrent ependymoma. Some evidence of treatment efficacy as disease control and objective response were found. However, the survival benefit cannot be determined. Given the positive correlation between patients with no resid- ual tumor and prognosis, a bridge chemotherapy approach has been used in several studies [7, 28]. This approach uses chemo- therapy as a conduit to reduce the bulk of residual tumor, after the first surgery so that a second-look surgery or irradiation can be undertaken (Table 8.1). 8 Table 8.1 Upfront pediatric chemotherapy regimens for ependymoma Patient age group Clinical trial and number Treatment Chemo regimen PFS OS Second 3–21 years with Group 1: Residual tumor, any VEC Grade II, Grade II, AIEOP, 2016 intracranial grade—VEC chemo (upto vincristine at 1.5 mg/m2 D1, 5-year: 5-year: ependymoma, 4 cycles), possible second cyclophosphamide 1 g/m2 D1 and 75.3% 90.5% N = 160 surgery, RT + boost etoposide 100 mg/m2, days 1, 2 Grade III, Grade III, Group 2: No residual tumor, and 3 for 4 cycles of 3–4 weeks 5-year: 57% 5-year: WHO grade II—RT Supportive treatment: granulocyte 73.3% Group 3: No residual tumor, colony stimulating factor Treatment of Ependymoma WHO grade III—RT followed by VEC × 4 UKCCSG/ Children under Surgery, followed by four Course 1, carboplatin 550 mg/ 3-year event 3-year SIOP study, 3 years, N = 89 courses of alternating m2 + vincristine 1.5 mg/m2 free overall 2007 myelosuppressive and Course 2, methotrexate 8000 mg/ survival, survival, non-myelosuppressive drugs m2 + vincristine 1.5 mg/m2 42.7% 76.8% repeated every 56 days for a Course 3, cyclophosphamide 5-year event 5-year total of 7 cycles 1500 mg/m2 with mesna free overall Course 4, cisplatin 40 mg/m2 survival, survival, 37.5% 60% (continued) 127 Table 8.1 (continued) 128 Patient age group Clinical trial and number Treatment Chemo regimen PFS OS French Children under Surgery, chemo (3 courses in Course A: Carboplatin 15 mg/kg, 2-year PFS, 2-year Society of 5 years with of 21 days each, 7 cycles) day 1 + procarbazine 4 mg/kg/day 33% OS, 79% Pediatric intracranial Salvage radiation for disease on days 1–7 4-year PFS, 4-year Oncology, ependymoma, progression or relapse Course B: 22% OS, 59% 2001 N = 73 following chemotherapy Etoposide 5 mg/kg/day on days 22 and 23 + cisplatin 1 mg/kg/day on days 22 and 23 Course C: Vincristine 0.05 mg/kg on day 43 + cyclophosphamide 50 mg/kg on day 43 German HIT Pediatric HIT 88/89: Sandwich chemo: 2 cycles of 45 months 3-year study, 2000 anaplastic Surgery, sandwich chemo, ifosfamide, etoposide, OS: ependymoma, radiation methotrexate, cisplatin and 75.6% N = 55 HIT 91: cytarabine Surgery followed by Maintenance chemo: 8 cycles of randomization to either methotrexate, cisplatin and RT + weekly vincristine and vincristine maintenance chemo OR Sandwich chemo followed by RT J. Wu and S. Ranjan 8 Treatment of Ependymoma 129 There is no role for upfront chemotherapy in adult patients with ependymoma, other than in a clinical trial setting. Other Modalities With more identified unique molecular features and genomic alterations are discovered, targeted therapies regimen has been tested in the setting of clinical trials. For example, it was discov- ered that co-expression of ERBB2 and ERBB4 is elevated in more than 75% of ependymomas and a high expression of ERBB receptors is associated with an aggressive tumor behavior. Therefore, lapatinib, an inhibitor of ERBB2 receptor, has been tested in a clinical trial of recurrent ependymoma when com- bined with temozolomide, a commonly used alkylating agent (NCT00826241). Another example is that VEGF inhibition was tested as a therapeutic approach given the elevated VEGF expres- sion in most of the ependymoma. A combination of VEGF mono- clonal antibody and carboplatin has been tested in the recurrent ependymoma (NCT01295944). More recently, marizomib, a second-generation irreversible proteasome inhibitor which pen- etrates the blood brain barrier has been tested in recurrent epen- dymomas with a characteristic signature C11orf95-RELA fusion, which drives tumorigenesis in 70% of supratentorial ependymo- mas by activating the NF-KB transcription pathway (NCT03727841). Surveillance Surveillance guidelines for ependymoma patients are rather arbi- trary and extrapolated from clinical trials. Patients with intracra- nial ependymoma should be followed with an MRI brain with and without contrast every 3 months for the first year after treatment, then every 3 months for the second year, and every 4–6 months afterwards. It is reasonable to add a contrast-enhanced MRI of the entire spine every 6–12 month in the first year for staging, or if symptoms attributed to spinal cord involvement are suspected. For patients with disseminated ependymoma, the entire neuraxis 130 J. Wu and S. Ranjan is imaged with contrasted MRI brain and spine every 3 months for the first 2 years after treatment, then every 4 months for the next 2 years and every 6 months thereafter. Treatment at Recurrence Most patients develop tumor recurrence at the primary site. At the time of recurrence, staging for dissemination and CSF should be performed. Treatment approaches for recurrent ependymoma, again rely on surgery and radiation. Patients should undergo a maximal safe surgical resection followed by involved field radia- tion or reirradiation. Stereotactic radiosurgery or focal fraction- ated reirradiation is often used. Craniospinal irradiation is sometimes utilized but best avoided. A retrospective study on 101 pediatric patients showed that brain radiation was well-tolerated by most patients. After irradiation, the median progression free survival was 27.3 months and the median overall survival was 75.1-months. The 10-year cumulative incidence of severe radia- tion necrosis after reirradiation was 7.9%. Opportunities should be investigated for clinical trial enrollment. Prognosis and Survivorship Rather than the tumor grade, the prognosis of ependymoma depends on age and tumor location. A retrospective study on 123 patients with adult ependymoma found an overall survival of 221 months for all intracranial ependymomas and 67 months for anaplastic ependymoma. The overall survival for spinal tumors was longer and could not be calculated due to the small number of events. In this study, the median time to first recurrence was 21 months for intracranial ependymomas, versus 25 months for spinal tumors. Supratentorial ependymal tumors have a worse prognosis in adults. A meta-analysis of 183 adult patients with intracranial ependymomas showed that supratentorial ependymoma has had a progression-free survival of 24 months and overall survival of 8 Treatment of Ependymoma 131 61 months, as compared to a median progression free survival of 144 months in infratentorial ependymoma, whose median overall survival could not be calculated. Patients with group A posterior fossa ependymomas have a significantly poor prognosis as compared to group B posterior fossa ependymomas. Patients with group A posterior fossa epen- dymomas are significantly younger (median age of 4 versus a median age of 39 for group B posterior fossa ependymomas), commonly male, more frequently classified as WHO grade 3 ependymoma and a higher incidence of metastasis at the time of recurrence. For group A tumors, the progression free and overall survival rates are 24% and 48% respectively, in contrast to 92% and 98% for group B tumors. Subependymomas are benign tumors, most commonly arising from the floor of the fourth ventricle and lateral ventricles and often discovered at autopsy. Symptomatic patients are managed with maximal safe tumor resection and restoration of the normal CSF flow. Long-term outcomes are excellent, provided there are no postoperative complications. Adult myxopapillary ependymomas have good outcomes. Encapsulated myxopapillary ependymomas, which were treated with a gross total resection with and intact capsule have a low recurrence rate of 10%, whereas those with a piecemeal resection or a subtotal resection have a higher recurrence rate of up to 19%. Overall survival with a gross total resection is 19 years and with subtotal resection 14 years. The 10-year overall survival of patients with myxopapillary ependymoma is 92–93% and the median time to recurrence is 26–30 months [35, 36]. While age less than 36 years was a negative prognostic marker, the use of adjuvant RT and a greater extent of surgical resection increased progression free survival. Pediatric myxopapillary ependy- momas have a less favorable outcome as compared to adults. A large retrospective study of 95 pediatric patients less than 20 years of age, reveals a 5-year progression free survival rate at 73.7% and a 5-year overall survival rate of 98.9%. In the pediatric population, addition of radiation therapy following resection sig- nificantly improves progression free survival. 132 J. Wu and S. Ranjan As survival for childhood central nervous system cancers have improved, there is an increasing focus on their long-term effects in children and adolescents. Patients may have received surgery, focal or cranio-spinal radiation therapy and chemotherapy. Neurological, cognitive, auditory and endocrine dysfunctions are common in this population, especially among children who were treated at a young age. Patients who receive craniospinal radiotherapy experience significant decline in IQ over time as compared to patients who received focal radiation or surgery alone. Children younger than 3 or 4 years may experience a dev- astating longitudinal decline in IQ. Apart from radiation therapy, hydrocephalus and posterior fossa syndrome contributes to a neu- rocognitive decline. Adult patients with intracranial or spinal ependymomas have a high symptom burden. Adult patients with intracranial ependy- moma commonly have problems with vision, language, and con- centration whereas patients with spinal ependymoma developed limb weakness, sexual dysfunction, radiating pain and change in bowel pattern. Trends and Future Directions Better understanding of ependymoma biology and molecular fea- tures will provide more opportunities of developing targeted and personalized therapeutic strategies. Robust preclinical studies and clinical trials are essential for the development of novel therapy. Collaborations between scientists and clinicians specializing in adult and pediatric neuro-oncology should foster rapid translation of laboratory science into clinical trials. The rarity of ependymo- mas makes it challenging to perform large scale or randomized clinical trials. A collaborative effort between academic centers should be the future direction to advance the care for ependy- moma patients (Table 8.2). 8 Treatment of Ependymoma 133 Table 8.2 Patient information What type of tumor do I have? Ependymoma is a primary central nervous system tumor, which means it begins in the brain or spinal cord. Ependymoma arises from the ependymal cells that line the brain cavities (ventricles) and the fluid-filled space which runs through the spinal cord. Ependymomas occur in both children and adults. Tumors in the lower half of the brain are more common in children, but those in the spinal cord are more common in adults. The cause of ependymoma is not fully understood Based on how cancer cells appear under the microscope, the World Health Organization (WHO) grades ependymomas into grades 1, 2 and 3. A lower grade indicates a slow-growing cancer and a higher grade means that the cancer is more aggressive. There are different types of ependymoma depending on the tumor location, the mutations in the tumor, and the grade of the tumor. Subependymomas are WHO grade 1 tumors Spinal ependymomas are ependymomas are ependymomas that occur in the spinal cord. These include – Spinal ependymoma (WHO grade 2 or 3) – Spinal ependymoma MYCN-amplified (WHO grade 2 or 3) – Myxopapillary ependymoma (WHO grade 2) Posterior fossa ependymomas are ependymomas that occur in the back part of the brain. These include – Posterior fossa ependymoma (WHO grade 2 or 3) – Posterior fossa ependymoma, group PFA (WHO grade 2 or 3) – Posterior fossa ependymoma, group PFB (WHO grade 2 or 3) Supratentorial ependymomas are ependymomas that occur in the upper part of the brain. These include – Supratentorial ependymoma (WHO grade 2 or 3) – Supratentorial ependymoma, ZFTA fusion-positive (WHO grade 2 or 3) – Supratentorial ependymoma, YAP1 fusion-positive (WHO grade 2 or 3) Your medical team will determine which type and grade of ependymoma you have, based on pathological and molecular study on the tumor tissues obtained from a surgery or biopsy. Ependymoma rarely grow or metastasize outside of the central nervous system (brain and spinal cord), but may spread to other areas of the central nervous system through the cerebrospinal fluid (continued) 134 J. Wu and S. Ranjan Table 8.2 (continued) How do I treat it? The first goal in treating an ependymoma is to have surgery to remove as much of the tumor as can be done safely. Sometimes, your medical team may recommend a second surgery if there is tumor that can still be seen on an MRI scan after your first surgery. In some patients, a complete surgical removal of the tumor isn’t possible if the tumor is located in a critical location of the brain or spinal cord. In these cases, a biopsy is still recommended so that your medical team can make an accurate diagnosis of the type of ependymoma It is important to know that the treatment recommendation for ependymoma may differ even among ependymoma experts. As ependymomas are rare tumors, patients should be preferably treated at a brain and spine tumor center, which have experience in treating this type of tumor. Grade 2 ependymomas with a complete surgical removal may be observed with serial MRIs and clinic visits. Grade 2 ependymomas that are not completely removed and Grade 3 ependymomas will need to be treated with radiation after you heal from surgery. Your team will also perform MRIs of the brain and entire spine to find the extent of tumor spread. A spinal tap will also be done to find out if there are microscopic tumor cells in your brain and spinal fluid. In rare circumstances, if there is an extensive spread of the tumor, the entire brain and spine may need to be treated with radiation Some centers will offer you a clinical trial for voluntary participation. It is advised to discuss all options with your oncologist, the expectations from treatment, and possible side effects What can I expect to experience during treatment? Symptoms depend on the location of the ependymoma and type of planned treatment. Patients with ependymoma in the brain may experience headaches, memory difficulty, speech problems, seizures and balance issues. Patients with ependymoma of the spine may feel neck or back pain, numbness, pain in the arms or legs, and weakness in arm or leg During treatment with radiation, patients may experience fatigue, sleep disturbance, memory impairment (if tumor is in the brain), pain from the tumor location and sometimes swelling of the tumor. You may need treatment with steroids to control the swelling Most patients with ependymoma get treatment from a team of experts such as a neurosurgeon, a neuro-oncologist, a radiation-oncologist, nurse practitioner or a physician assistant and a nurse. Sometimes, you may be referred to see a neuropsychologist for memory testing and palliative care for pain. Your medical team will work closely with you to improve your symptoms and quality of life 8 Treatment of Ependymoma 135 Table 8.2 (continued) How will we keep an eye on this? Patients have MRIs and evaluation in a doctor’s office every 3 months for the first 2 years of treatment and then every 4–6 months thereafter. These MRIs and clinic visits are usually conducted with a neuro-oncologist. It is very important for ependymoma patients to continue follow-up with their neuro-oncologist as these tumors usually recur, sometimes after many years from initial treatment What is my prognosis? The prognosis of ependymoma depends on many factors such as the patient’s age, the location of tumor, extent of surgical removal, the tumor grade, tumor’s genetic profile and the type of treatment received. Patients live longer and with lesser recurrence if the tumor is fully removed with surgery. Patients with spinal cord ependymomas have better outcomes as compared to ependymomas in the brain References 1. Rodriguez D, Cheung MC, Housri N, Quinones-Hinojosa A, Camphausen K, Koniaris LG. 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Cancer. 1985;56(4):883–93. https://doi.org/10.1002/1097- 0142(19850815)56:43.0.co;2-6. 24. Fassett DR, Pingree J, Kestle JR. The high incidence of tumor dissemina- tion in myxopapillary ependymoma in pediatric patients. Report of five cases and review of the literature. J Neurosurg. 2005;102(1 Suppl):59– 64. https://doi.org/10.3171/ped.2005.102.1.0059. 25. Kukreja S, Ambekar S, Sin AH, Nanda A. Cumulative survival analysis of patients with spinal myxopapillary ependymomas in the first 2 decades of life. J Neurosurg Pediatr. 2014;13(4):400–7. https://doi.org/10.3171/201 4.1.peds13532. 26. Grill J, Le Deley M-C, Gambarelli D, Raquin M-A, Couanet D, Pierre- Kahn A, et al. Postoperative chemotherapy without irradiation for epen- dymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol. 2001;19(5):1288–96. 27. Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, et al. 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Armstrong TS, Vera-Bolanos E, Gilbert MR. Clinical course of adult patients with ependymoma: results of the Adult Ependymoma Outcomes Project. Cancer. 2011;117(22):5133–41. https://doi.org/10.1002/ cncr.26181. Part II Supportive Care Primer Brain Edema and Corticosteroid Toxicity 9 Maninder Kaur and Reena Thomas Principles of Treatment In Neuro-oncology, steroids are generally used to relieve symp- toms secondary to edema that affects the brain, spinal cord, and possibly nerves and nerve roots. Cerebral edema can be due to the tumor itself or can be a consequence of treatments such as radia- tion therapy. Cerebral edema can be classified as vasogenic edema, cytotoxic edema or hydrocephalic edema. Characteristics of each type of edema are described in Table 9.1. The primary method of treatment is with corticosteroids. It is important to treat the patient for their symptoms and not based decisions on the MRI appearance alone. We rarely recommend the use of steroids for asymptomatic patients. The rare exception is the patient with extensive vasogenic edema due to tumor or related to treatment effect, leading to midline shift or near obstruction of the fourth ventricle. In these cases, a course of steroids to prevent the patient from becoming symptomatic may be deemed reasonable. Graphics: Rosyli Miramontes, MS IV. M. Kaur Loma Linda University Health, Loma Linda, CA, USA R. Thomas (*) Stanford University, Palo Alto, CA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature 141 Switzerland AG 2023 N. A. Mohile, A. A. Thomas (eds.), Brain Tumors, https://doi.org/10.1007/978-3-031-41413-8_9 142 M. Kaur and R. Thomas Table 9.1 Characteristics of each type of edema Hydrocephalic Vasogenic Cellular edema edema edema (Cytotoxic) (Interstitial) Pathogenesis Increased Cellular swelling; Increased brain capillary glial, neuronal, fluid from permeability endothelial blockage of CSF absorption Location Chiefly white Gray and white Chiefly matter matter periventricular white matter; hydrocephalus Edema fluid Plasma filtrate Increased CSF composition including intracellular water plasma sodium proteins Extracellular fluid Increased Decreased Increased volume Capillary Increased Normal Normal permeability to large molecules (insulin, albumin) Clinical causes Brain Hypoxia Obstructive tumor hydrocephalus Abscess Ischemia Purulent meningitis Infarction/ Ischemic hemorrhage hypo-osmolality (water intoxication) Purulent Dysequilibrium meningitis syndrome (granulocytic edema) Purulent meningitis Reye syndrome EEG Focal slowing Generalized Normal (often) slowing 9 Brain Edema and Corticosteroid Toxicity 143 Table 9.1 (continued) Hydrocephalic Vasogenic Cellular edema edema edema (Cytotoxic) (Interstitial) Treatment 1. Steroids 1. Beneficial 1. Not effective 1. Uncertain possibly in pseudotumor or meningitis) 2. Osmotherapy2. Reduces 2. Reduces brain 2. Rarely volume of volume acutely useful, normal brain improves tissue only, compliance acutely 3. Acetazolamide 3. May be 3. No direct 3. Minor useful effect usefulness 4. Furosemide 4. May be 4. No direct 4. Minor useful effect usefulness Fig. 9.1 Glucocorticoid Pathophysiology Corticosteroids are generally divided into glucocorticoids, mineralocorticoids and adrenal sex hormones. Commonly used corticosteroids and their dosing regimens are listed in Table 9.1. Synthetic Glucocorticoids are the most widely used in cerebral edema The proposed mechanisms of glucocorticoids include the inhibition of release of several biochemical substances which have been known to increase vascular permeability or induce vasodilation (which leads to increased permeability secondary to increased hydrostatic pressure (Fig. 9.1) The key factors that regulate the BBB are VEGF, Angiopoietin-1 (Ang-1) and angio- poietin-2 (Ang-2).The exact mechanism of action of steroids 144 M. Kaur and R. Thomas is not well understood. One proposed mechanism is the upregula- tion of Ang-1, which is a strong BBB stabilizing factor and downregulation of VEGF a strong permeabilizing factor. It is also proposed that glucocorticoids may also aid by moving the edema- tous fluid into the ventricular system. It is always the goal to use the lowest needed dose of steroids in order to minimize side effects, which are dose dependent. It is also important to keep in mind the anti-edema effects are also dose dependent, thus require individualization based on the patient’s clinical scenario. anagement of Acute Increased Intracranial M Pressure In patients with acute onset of severe symptoms and signs of increased intracranial pressure, higher doses of steroids should be considered. Symptoms might include severe headaches, charac- terized by pressure-like feelings that are worse in the morning with associated nausea and vomiting. Patients may also complain of headache, dizziness or syncopal episode during activities that transiently increase ICP, such as standing, sneezing, coughing or straining during bowel movements. In these scenarios, there is a concern for symptomatic plateau waves which result from elevated ICP and can lead to intermittent drop in cerebral perfu- sion. In such acute presentations, we recommend an initial load- ing dose of Dexamethasone 10–20 mg to be given intravenously. We follow this loading dose with Dexamethasone 4–6 mg two to four times a day. Decisions on dosing need to be made on a case by case basis, but in general, patient rarely get additional benefit from doses exceeding 16 mg per day. Chronic Steroid Use and Tapering Despite the wide use glucocorticoids, there is limited consensus regarding the dosing, duration as well as tapering protocol. This holds true as there is limited evidence from clinical trials provid- 9 Brain Edema and Corticosteroid Toxicity 145 ing any guidance. Below are the recommendations from our general practice. For patients requiring chronic dosing of steroids, doses should rarely exceed 8 mg per day. Twice daily dosing is ideal, with the second dose given in the early afternoon to prevent insomnia. Patients who are started on steroids but otherwise have mini- mal or no symptoms, should be tapered off rapidly. For patients who have been on steroids for a short period, the rapid taper should not cause any steroid withdrawal symptoms and they can be tapered off within a few days. The effects of a taper are typi- cally noticeable 72 h after a dose change and tapers should involve dose adjustments every 3 days. If they have been on steroids for more than 2 weeks, then doses should by dropped by 2 mg e

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