Kalifa Chantal, Grill Jacques
Pediatric Department, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif cédex, France.
J Neurooncol. 2005 Dec;75(3):279-85. doi: 10.1007/s11060-005-6752-x.
Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood [1]. Genetic predisposition to infantile malignant brain tumors are known in Gorlin syndrome for example who present with desmoplastic medulloblastoma in about 5% of the affected patients. In addition, sequelae from tumor and its treatment are more severe at this age [2]. Thus, malignant brain tumors represent a true therapeutic challenge in neuro-oncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group. Since the end of the 80s, noninvasive imaging procedures produce accurate diagnosis of brain tumors and improvement in neurosurgery, neuroanesthesia and perioperative intensive care permit safe tumor resections or at least biopsies. Consequently, the pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications [3]. At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors [4]. Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors. Different approaches have been explored: * Prolonged postoperative chemotherapy and delayed irradiation as designed in the POG (Pediatric Oncology Group). * Postoperative chemotherapy without irradiation in the SFOP (Société Française d'Oncologie Pédiatrique) and in the GPO (German Pediatric Oncology) studies. * The role of high-dose chemotherapy with autologous stem cells transplantation was explored in different ways: High-dose chemotherapy given in all patients as proposed in the Head Start protocol. High-dose chemotherapy given in relapsing patients as salvage treatment in the French strategy. In the earliest trials, the same therapy was applied to all histological types of malignant brain tumors and whatever the initial extension of the disease. This attitude was justified by the complexity of the classification of all brain tumors that has evolved over the past few decades leading to discrepancy between the diagnosis of different pathologists for a same tumor specimen. Furthermore, it has become increasingly obvious that the biology of brain tumors in very young children is different from that seen in older children. However, in the analysis of these trials an effort was made to give the results for each histological groups, according to the WHO classification and after a central review of the tumor specimens. All these collected data have brought to an increased knowledge of infantile malignant brain tumors in terms of diagnosis, prognostic factors and response to chemotherapy. Furthermore a large effort was made to study long term side effects as endocrinopathies, cognitive deficits, cosmetic alterations and finally quality of life in long term survivors. Prospective study of sequelae can bring information on the impact of the different factors as hydrocephalus, location of the tumor, surgical complications, chemotherapy toxicity and irradiation modalities. With these informations it is now possible to design therapeutic trials devoted to each histological types, adapted to pronostic factors and more accurate treatment to decrease long term sequelae.
恶性脑肿瘤在婴儿中并不罕见，因为三岁前发生的恶性脑肿瘤占儿童期所有恶性脑肿瘤的20%-25%[1]。例如，在戈林综合征中已知婴儿恶性脑肿瘤的遗传易感性，约5%的受累患者会出现促结缔组织增生性髓母细胞瘤。此外，这个年龄段肿瘤及其治疗的后遗症更为严重[2]。因此，恶性脑肿瘤是神经肿瘤学中一个真正的治疗挑战。在现代影像学和现代神经外科时代之前，由于这个年龄组风险增加，这些恶性脑肿瘤被误诊，或者无法像大龄儿童那样从手术中获益。自80年代末以来，非侵入性成像程序能够准确诊断脑肿瘤，神经外科、神经麻醉和围手术期重症监护的改善使得安全的肿瘤切除或至少活检成为可能。因此，儿科肿瘤学家更常面对需要辅助治疗的非常年幼的儿童。在针对这个年龄组的特定方法出现之前，这些儿童接受的治疗与大龄儿童相同，但他们的生存率和生活质量明显更差。这些不良结果的原因可能部分是由于担心放射治疗引起的晚期效应，导致减少了必要的照射剂量，这增加了治疗失败的几率，同时又无法避免与治疗相关的并发症[3]。80年代末，对年轻的髓母细胞瘤患者进行了术后化疗的试点研究。范·艾伊斯用MOPP方案治疗了12名选定的髓母细胞瘤儿童，未进行放疗；据报道，其中8人是长期幸存者[4]。随后，儿科肿瘤协作组针对非常年幼的恶性脑肿瘤患儿设计了治疗试验。探索了不同的方法：* 如儿科肿瘤学组（POG）所设计的延长术后化疗和延迟放疗。* 法国儿科肿瘤学会（SFOP）和德国儿科肿瘤学（GPO）研究中术后化疗不放疗。* 以不同方式探索了高剂量化疗联合自体干细胞移植的作用：如“启动计划”方案中对所有患者进行高剂量化疗。在法国策略中，对复发患者进行高剂量化疗作为挽救治疗。在最早的试验中，对所有组织学类型的恶性脑肿瘤以及无论疾病的初始范围如何都应用相同的治疗方法。这种态度是合理的，因为在过去几十年中，所有脑肿瘤的分类变得复杂，导致不同病理学家对同一肿瘤标本的诊断存在差异。此外，越来越明显的是，非常年幼儿童的脑肿瘤生物学与大龄儿童不同。然而，在对这些试验的分析中，根据世界卫生组织的分类并在对肿瘤标本进行中央审查后，努力给出每个组织学组的结果。所有这些收集到的数据在诊断、预后因素和化疗反应方面增加了对婴儿恶性脑肿瘤的认识。此外，还做出了很大努力来研究长期副作用，如内分泌病、认知缺陷、外观改变以及长期幸存者的最终生活质量。后遗症的前瞻性研究可以提供有关不同因素影响的信息，如脑积水、肿瘤位置、手术并发症、化疗毒性和放疗方式。有了这些信息，现在有可能设计针对每种组织学类型、适应预后因素并更精确治疗以减少长期后遗症的治疗试验。
