The Role of Surgery in Pediatric Gliomas

Pediatric glial tumors differ from adult gliomas in several ways that are of major therapeutic importance. First, the value of extensive tumor resection, which is controversial for malignant intrinsic brain tumors in adults, has been confirmed for a variety of childhood brain tumors, such as supratentorial high-grade and low-grade gliomas and infratentorial low-grade gliomas, ependymomas, and some medulloblastomas. Second, chemotherapy has been found to be effective in improving overall outcome in several childhood brain tumors, such as medulloblastoma and supratentorial high-grade glioma, but has yet to be proven to have a major benefit for adult tumors. In addition, chemotherapy is increasingly used to delay or avoid radiotherapy in young children with high-grade and incompletely resected low-grade tumors to avoid the morbidity of irradiation on the developing nervous system. Third, the prognosis for histologically similar tumors is often more favorable in children than adults. The present chapter will highlight the unique features of childhood glial tumors, discuss general principles in the clinical presentation, diagnostic evaluation, and treatment of these tumors, and then focus on the surgical management and outcome of the more common types of tumors.     

The changing management of low-grade astrocytomas and oligodendrogliomas

Low-grade gliomas are uncommon primary brain tumors that preferentially affect young to middle-aged adults. Although they are indolent tumors, low-grade gliomas cause considerable and progressive morbidity and are ultimately fatal. Surgery and radiotherapy are the primary therapeutic options for patients with these diseases. Chemotherapy is playing a larger role in the management of patients with low-grade gliomas. Patients with oligodendrogliomas or other low-grade gliomas that harbor a distinct genetic derangement characterized by allelic loss of chromosomes 1p and 19q appear to have a superior prognosis that is due in part to a more predictable and durable response to treatment. For this subset of patients with low-grade gliomas, treatment with initial chemotherapy and deferred radiotherapy is an increasingly attractive therapeutic approach.     

Diffuse brainstem glioma in children: critical review of clinical trials

Diffuse intrinsic brainstem gliomas constitute 15-20% of all CNS tumours in children, and are the main cause of death in children with brain tumours. Many clinical trials have been done over the past three decades, but survival has remained static. More than 90% of children die within 2 years of diagnosis, and conventional fractionated radiation remains the standard treatment. However, median survival differs substantially between clinical trials, suggesting a survival benefit with some strategies. We appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints. Study designs varied substantially, which could explain the differences in outcome, and no treatment has shown a benefit over conventional radiotherapy. However, consistency between protocols (eg, eligibility criteria and outcome measures) is important to measure the progress in management of diffuse pontine gliomas.     

脊髓髓内胶质瘤的外科治疗——附56例临床分析

背景与目的:脊髓胶质瘤的治疗一直为临床难题,对分化良好的低级别髓内星形细胞瘤手术治疗依然可以取得良好效果,但分化差的高级别髓内星形细胞瘤或胶质母细胞瘤预后很差,放疗效果不确定。本文旨在探讨脊髓质瘤的治疗方法及预后。方法:本文总结了56例脊髓髓内胶质瘤的临床资料,对其病理类型、性别比例、年龄构成、发生部位、影像特征、手术技术、术中电生理监护、术后并发症、疗效预后等进行了讨论分析。结果:肿瘤近全切除及大部分切除为26例(46%),其余病例(54%)为部分切除或活检。55例患者行椎板切除减压,1例肿瘤边界清楚,镜下全切除肿瘤,术中行椎板复位。术后随访资料显示:星型细胞瘤Ⅰ~Ⅱ级,术中肿瘤边界相对清楚且近全切除的26例患者,术后3个月运动、感觉等功能有明显改善,其余肿瘤部分切除或活检的患者神经功能无显著改变。55例患者在术后3周至3个月内行普通放疗。脊髓圆锥部位的肿瘤,术后大小便困难发生率高达60%。结论:有相对边界的髓内星形细胞瘤手术治疗为最佳选择,术后辅助放疗,预后良好。恶性髓内胶质瘤手术以明确诊断,部分切除加脊髓减压为原则,手术难以改善神经功能状况,总的预后差。     

Intrinsic brainstem tumors in childhood: Surgical indications

Sixty-six children with intrinsic brainstem gliomas diagnosed between 1980 and 1986 underwent radical surgical resection. Retrospective analysis permitted classification of tumors into four categories: diffuse, focal, cystic and cervicomedullary. All 27 patients with diffuse tumors had malignant neoplasms, were not benefitted by surgery and died within 12–18 months. Five of nine cystic tumors, three of five focal tumors and twenty of twenty-four cervicomedullary tumors had low grade histpathology and are alive one to six years postoperatively.The authors propose a clinical-neuroradiological criteria that accurately predict which patients with brainstem tumors are likely to benefit from radical surgical intervention.     

脑恶性胶质瘤放射治疗临床研究进展

脑恶性胶质瘤是成人最常见的颅内原发恶性肿瘤，其致残率和病死率均很高。术后辅助放疗是恶性胶质瘤的标准治疗手段之一，可延长患者的生存期。近年来，随着放疗技术和方法的不断发展，恶性胶质瘤的术后放疗发生了很大的变化。本文将对恶性胶质瘤的放射治疗临床研究进展进行复习。     

A Phase I study of concurrent RMP-7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

BACKGROUND: Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. METHODS: RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3-12 yrs). RESULTS: One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. CONCLUSIONS: The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors.     

Exophytic malignant brainstem mixed glioma in an adult: A case report

Anaplastic mixed gliomas are rare tumors that occur mostly in the cerebral hemispheres. They have a distinctive histological appearance characterized by the presence of two or more glial cellular constituents. The incidence of malignant mixed glioma of the brainstem and posterior fossa is extremely low. The authors report an unusual case of an exophytic malignant mixed glioma. Following subtotal resection, the patient received conventional radiotherapy, but continued to deteriorate, and died five months after surgery. The extensive literature review focuses on histopathology, clinical features, natural history, and possible treatment modalities of this unusual neoplasm.     

Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist

Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons, in which case the tumors are usually called diffuse brainstem gliomas. The diagnosis of supratentorial neoplasms is dependent on their histologic appearance. The maximum possible surgical resection is always attempted since the degree of surgical resection is the main prognostic factor for these patients. Older children (>3 years) with supratentorial neoplasms undergo a multimodality treatment comprised of surgical resection, radiation therapy, and chemotherapy. The addition of chemotherapy seems to improve the survival of a subset of these children, particularly those with glioblastoma multiforme. However, 2-year survival rates remain poor for children with supratentorial neoplasms, ranging from 10%-30%. The diagnosis of a diffuse brainstem glioma is based upon typical imaging, dispensing with the need for surgery in the majority of cases. Radiation therapy is the mainstay of treatment for children with diffuse brainstem gliomas. The role of chemotherapy for these children is not clear, and it is, in general, employed in the context of an investigational study. Less than 10% of children with diffuse brainstem gliomas survive 2 years. Because the outcome for patients with either type of tumor is poor when standard multimodality therapy is used, these children are ideal candidates for innovative treatment approaches.     

Clinical management and outcome of histologically verified adult brainstem gliomas in Switzerland: a retrospective analysis of 21 patients

Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas (BSGs) remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult BSGs. A retrospective chart review of adults (age >18 years) was conducted. BSG was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. Twenty one patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 vs. 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (three in each group), radiochemotherapy (2 vs. 6), chemotherapy alone (0 vs. 2) or no postoperative therapy (3 vs. 1). Median PFS (24.1 vs. 5.8 months; log-rank, p = 0.009) and mOS (30.5 vs. 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. Histologically verification of adult BSGs is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities.     

Improving outcomes for neurofibromatosis 1–associated brain tumors

Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population.     

成人新诊断高危低级别胶质瘤术后治疗的现状及争议

高危低级别胶质瘤为世界卫生组织（WHO）Ⅱ级是一组起源于中枢神经系统胶质细胞的异质性肿瘤。手术通常作为首选的治疗方法,然而术后最佳治疗方法暂无共识。术后放疗、化疗可以提高部分患者的局部控制率和总生存率（overall survival,OS）,但对于高危低级别胶质瘤术后最佳放疗时机、放疗的剂量、化疗药物的选择、靶向治疗和免疫治疗等目前尚存争议。本文就国内外文献进行归纳总结,并对高危低级别胶质瘤术后辅助治疗的现状及争议进行探讨。      

Leptomeningeal gliomatosis as the initial presentation of gliomatosis cerebri

Leptomeningeal gliomatosis is a known, yet uncommon, complication of malignant gliomas. In rare instances it can present with non-specific symptoms prior to the development of detectable intraparenchymal lesions, posing a diagnostic challenge. Gliomatosis cerebri is also a rare disease, characterized by extensive diffuse infiltration of neoplastic glial cells. For both entities, limited data exist to guide treatment and prognosis is poor. We describe the case of a patient who presented with symptoms of increased intracranial pressure and diffuse leptomeningeal enhancement in the brain and spinal cord on MRI. After a period of surveillance, intraparenchymal lesions developed in association with widespread diffuse infiltration. The diagnosis of gliomatosis cerebri with diffuse leptomeningeal gliomatosis was established in hindsight. Initial treatment consisted of six cycles of temozolomide chemotherapy. Following radiological progression, the patient received craniospinal radiotherapy. Four months later the patient’s symptoms had resolved and MRI demonstrated near complete response of leptomeningeal enhancement and intraparenchymal lesions. Six months after radiotherapy, the patient remains clinically well without radiographic recurrence.     

Results of the treatment of children with recurrent gliomas with lomustine and vincristine

Gliomas comprise over 50% of all childhood brain tumors. Treatment of recurrent childhood gliomas has been disappointing and the effectiveness of therapy has been difficult to judge because of the variable natural history of the disease. Information gathered recently has suggested that treatment with [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)] (CCNU) and vincristine (VCR) after radiotherapy is effective in prolonging survival in children with newly diagnosed anaplastic gliomas. The authors have used these same drugs--CCNU (100 mg/m2) and VCR (1.5 mg/m2 up to a maximum dose of 2 mg)--in 6-week cycles for a maximum of eight cycles in children with recurrent gliomas. To date, 15 patients have been treated; five patients had malignant gliomas and ten low-grade gliomas. Three children showed improvement, five had stable disease, and seven had progressive disease. Of the five patients with malignant gliomas, four progressed within two cycles of treatment and one had stable disease for 7 months on treatment and then relapsed. Seven of ten children with low-grade gliomas benefitted from treatment and six remain in continuous remission a median of 16 months after initiation of therapy. Three of these children are off all therapy 21, 30, and 30 months after treatment, respectively. Therapy was well tolerated and toxicity consisted primarily of reversible bone marrow suppression. The authors conclude that CCNU and VCR chemotherapy is effective in children with recurrent low-grade gliomas and can result in relatively long-term disease stabilization. In limited experience of the authors, it is not of benefit in children with recurrent anaplastic lesions.     

Actualités dans la biologie,l’imagerie et le traitement des gliomes de l’adulte

A better understanding of gliomas biology is now leading to a combined histo-molecular classification of these tumors. In anaplastic gliomas ongoing studies depend on 1 p/19 q codeletion status and in glioblastomas on MGMT methylation status. Advanced brain tumor imaging elicits a better identification of gliomas evolutive potential of. In low-grade gliomas, the importance of maximal resection and the role of chemotherapy are being increasingly recognized. In anaplastic gliomas, phase III studies have clarified the respective roles of chemotherapy and radiotherapy. In glioblastomas concomitant chemoradiotherapy is the standard. Most targeted therapies, namely anti-EGFR therapies have failed to demonstrate efficacy but anti-angiogenics are promising. The aim of this review is to discuss the main advances in adults’ gliomas biology, imaging and treatment.     

SEOM clinical guideline of diagnosis and management of low-grade glioma (2017)

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk–benefit ratio of adjuvant treatment must be weighed for each individual.     

Novel immunotherapeutic approach

Malignant astrocytoma is the most common primary brain tumor in adults. The median survival time of patients with high-grade malignant astrocytoma is about 1 year, despite aggressive treatment with surgical resection, radiotherapy, and cytotoxic chemotherapy. Novel therapeutic approaches are therefore needed to prolong survival. Immunotherapy is one such novel approach that has been investigated for application with different types of tumors, including brain tumors. The author reviews immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. A number of potentially targetable antigens have been identified in gliomas. Both tenascin and epidermal growth factor receptor (EGFR) have been studied extensively as targets for direct immune attack via specific antibodies. As a novel target, interleukin 13 receptor alpha 2-chain (IL-13 R alpha 2) has been identified. IL-13 R alpha 2 is abundantly and specifically overexpressed in glioblastoma multiforme, and recently a MHC class I-restricted CTL epitope has been identified. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that have a unique potency for activating T cells. DCs have been investigated in several clinical trials in patients with malignant tumors including malignant gliomas. So far, seven papers concerning immunotherapy with DCs against malignant gliomas have been published. These reports demonstrate that immunotherapy with DCs induces immune responses and clinically antitumor effects in some patients with malignant glioma. In addition, none of these studies reported evidence of autoimmune neurotoxicity.     

Chemotherapy of low-grade gliomas

Histologic subtypes of low-grade gliomas include pilocytic astrocytomas (World Health Organization [WHO] grade I), diffuse infiltrating astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas (WHO grade II). Although extended survival is typical with these tumors, most patients eventually succumb to recurrent or progressive disease despite receiving either adjuvant radiation therapy or radiation at the time of recurrence. Not surprisingly, chemotherapy for low-grade gliomas has primarily been evaluated in the salvage setting of postradiotherapy progression in both adults and children. Unfortunately, the published body of literature describing chemotherapy for these tumors is small and subject to a number of confounding methodologic limitations. Nonetheless, some guidelines for the use of chemotherapy in these patients can be inferred from the published experience. The data reviewed clearly identifies a potential benefit for PCV chemotherapy (procarbazine, CCNU, and vincristine) in at least a subset of patients with low-grade oligodendroglial tumors. Nitrosoureas and platinum agents appear to have modest efficacy in recurrent oligodendroglial tumors and in some patients with newly diagnosed or progressive low-grade astrocytomas; however, surgery and radiation remain the primary treatment modalities for this group of malignancies. Until new data becomes available, chemotherapy still should be used only as a salvage option in previously irradiated patients with recurrent or progressive low-grade gliomas.     

Temozolomide after radiotherapy in recurrent “low grade” diffuse brainstem glioma in adults

Diffuse brainstem glioma is a rare disease in adults. Radiotherapy (RT) is usually considered to be the standard treatment. However, the role of chemotherapy in treating relapses after RT is unclear, and this study aimed to assess the use of temozolomide (TMZ) in this situation. We conducted a retrospective analysis of patients from our database with “low grade” adult diffuse infiltrating brainstem glioma who received TMZ at relapse after failing RT. The patients were diagnosed by histology or MRI criteria compatible with a low-grade glioma. The tumors were localized in the pons, medulla oblongata or midbrain, excluding supratentorial or infratentorial tumors that had infiltrated the brainstem secondarily. The patients’ clinical and radiological responses were assessed, and their progression free survival (PFS) and overall survival (OS) time were estimated. Fifteen adult patients (median age 34 years) fulfilled the inclusion criteria. Histological analysis was available in 5 cases and showed grade II oligodendroglioma (2 cases), grade II oligoastrocytoma (2 cases), and grade II astrocytoma (1 case). Ten patients were selected by MRI criteria only. All patients received RT as initial treatment and had a median PFS of 34.2 months (95 % CI 24.1–44.2). The median KPS at the time of relapse was 80. TMZ was administered orally at 150–200 mg/m² for 5 days, every 28 days. Clinical improvement after TMZ was observed in 9 cases (60 %), whereas radiological assessment detected responses in 6/15 cases, including 4 partial and 2 minor responses. The estimated median PFS after TMZ was 9.5 months (95 % CI 7.9–11), and the median OS was 14.4 months (95 % CI 10.5–18.2). Grade 3 thrombopenia was observed in 26 % of cases. TMZ could be useful after RT failure in adult patients with recurrent diffuse “low grade” brainstem glioma.     

Advances toward an understanding of brainstem gliomas

The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.