Recent advances in the treatment of childhood brain tumors

Pediatric brain tumors are the commonest cause of cancer-related death in children. The last four decades have seen only a 35% increase in 5-year survival rate of children with these tumors. The therapeutic successes achieved are due to advances in neuroimaging, surgical techniques, radiotherapy, and induction of newer chemotherapeutic agents along with molecular targeted therapy. Neuroimaging advances include the use of MRA, MRS, DSA, and PET scans. With the use of stereotactic surgery, intraoperative mapping, and imaging, surgical resection has improved with significant decrease in morbidity. A major development has been the use of precision guided radiotherapy utilizing technologies like 3D-CRT, SRS, and IMRT, thereby decreasing radiation to normal tissues. Induction of newer drugs and high-dose chemotherapy with peripheral stem cell support has improved survival and delayed radiation in younger children and infants with brain tumors. Intense ongoing research is profiling novel molecular targets for therapeutic intervention. Newer therapeutic strategies like blood brain barrier disruption, immunotherapy, and gene therapy are in clinical trials. This review article intends to give the reader an overview of current therapeutic strategies and research involved in the treatment of children with brain tumors.     

Proton beam irradiation in pediatric oncology: an overview

The greatest challenge for the treatment of children with cancer is to attain the highest probability of cure with the least morbidity. This has stimulated advances in radiotherapy technology. In recent literature published regarding proton radiation therapy (PRT) for pediatric cancer patients, PRT has been shown to have a distinct advantage over conventional photon therapy because of the ability to confine the high-dose treatment area to the tumor volume and minimize the radiation dose to the surrounding tissue. This is particularly important in children, in whom late effects of radiation to normal tissue can include developmental delay and increased risk of second malignant neoplasms. Several proton facilities are operating world-wide, and several medical centers in the United States and Europe are in the midst of planning and constructing new proton facilities. This may enlarge the role of radiation therapy in the multimodal management of children with cancer.     

Pediatric radiation oncology in Germany: a study of availability and application

BACKGROUND: Radiotherapy plays a pivotal role in many multimodal therapy concepts in pediatric oncology. However, the absolute number of irradiated children is estimated to be quite low. The aim of this study was to evaluate the availability and application of pediatric radiation oncology in Germany. METHOD: In summer 2007, a standardized questionnaire was sent to all radiotherapy facilities in Germany. The questions regarded the structure of the departments, the number of irradiated children each year including the distribution of the different diagnoses, the number of curative treatments, inclusion in study trials, and existence of special contact persons for pediatric radiotherapy as well as technical aspects of irradiation of children. RESULTS: Answers to the questionnaires were obtained from 171 departments (77.4%). Of these, 67 (39%) stated to regularly treat children. These departments treated one to nine children in median each year (<5 children/year: 23 departments; >or=20 children: 15 departments). Most of these children suffered from brain tumors, Hodgkin's disease and acute lymphatic leukemia (ALL). Three-dimensional conformal radiotherapy was the most frequent treatment technique; special techniques like intensity-modulated radiotherapy (IMRT) or brachytherapy were rare. CONCLUSIONS: Due to quite low patient numbers treated in most radiotherapy facilities, individual experiences in pediatric radiation oncology can be assumed to be quite limited. As radiotherapy is part of multimodal therapy approaches in pediatric oncology and children treated with radiotherapy are at special risk for potential side effects, pediatric radiation oncology remains a sophisticated area. Therefore radiotherapy reference-institutions implemented by the therapy optimizing protocols are of fundamental importance.     

Current developments in radiotherapy for paediatric brain tumours.

This review summarises current developments in radiation oncology and how they impact on the management of children with brain tumours. Improved understanding of radiobiology has led to attempts to improve the therapeutic ratio with hyperfractionated radiotherapy. Recent advances in planning and delivery of radiotherapy, including three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton therapy allow a more precise localisation of the maximum dose region with maximum sparing of normal brain. Increasingly interactions between drugs and radiotherapy are exploited, but it is important to evaluate toxicity of combined modality therapy. The introduction of models to predict the impact of radiotherapy dose-volume parameters on long-term neuropsychological function will hopefully lead to further benefit with respect to sparing of normal tissue morbidity.     

Abdominopelvic mesh compartmentalization reduces the complications of radiotherapy in children: a preliminary report.

AIM: The aim of this report was to assess the effects of radiotherapy (RT) in children with abdominopelvic tumours in whom a biodegradable (Polyglactin 910) mesh had been inserted prior to commencement of radiotherapy. METHODS: Retrospective analysis was carried out of four patients with abdominopelvic tumours who underwent radiotherapy between 2000 and 2002 as part of their management. RESULTS: All children tolerated radiotherapy well with no evidence of acute or chronic radiation enteritis. One child developed prolonged postoperative ileus and a second child developed infective diarrhoea and fever, not related to radiation. CONCLUSION: We have highlighted a good tolerance of radiotherapy in children following the insertion of a Polyglactin 910 mesh prior to starting radiation and would recommend further larger studies with longer follow-up to support this.     

The correction of unilateral aphakia in children treated for orbital rhabdomyosarcoma

The survival rate of children with localized orbital rhabdomyosarcoma is now greater than 90% 3 years after diagnosis as a result of advances in radiation and chemotherapy. Ninety percent of these children develop cataracts within 1 to 4 years after the completion of radiotherapy. The correction of aphakia in these children is complicated by the concurrent keratoconjunctivitis and dryness associated with radiotherapy. Three patients with a diagnosis of orbital rhabdomyosarcoma underwent treatment for uniocular cataract. Two of the patients were unable to use extended wear contact lenses. Both underwent epikeratophakia with poor results. One patient who had clinically significant ocular drying prior to cataract extraction underwent successful implantation of an intraocular lens as a primary procedure, with excellent visual results. Clinicians should be aware of the difficulties associated with contact lens wear and epikeratophakia tissue lenses in children who have had high doses of radiation for orbital rhabdomyosarcoma. Such patients are probably best served by primary intraocular lens implantation or by preservation of the posterior capsule at the time of cataract extraction to allow secondary lens implantation if contact lens wear is unsuccessful.     

Brachytherapy for solid tumors in children

The standard treatment after surgery and chemotherapy in pediatric solid tumors is external beam to the tumor with a generous (5 cm) margin for local control. This treatment is given over a five to six-week period, requires use of repeated deep sedation, and leads to unacceptable morbidity (especially organ and bone-growth retardation) in infants and younger children. Limited volume irradiation by brachytherapy over a few days may be sufficient therapy for children treated with aggressive chemotherapy. Brachytherapy allows high doses of radiation to be limited accurately to the tumor bed, spares the surrounding normal tissues, and thus minimizes late sequelae. Manually afterloaded removable iridium-192, iodine-125, and cesium-137 have been used with good results. The major disadvantages of LDR brachytherapy are: the necessary sedation and immobilization of younger children to prevent accidental removal of the implants during the entire period, radiation exposure to the medical personnel and the parents, and the psychological effect of separating parents from their child. Using a low energy radionuclide such as iodine-125, or remote afterloading technology with LDR and PDR reduces radiation exposure hazards, but prolonged sedation and immobilization are still required. HDR brachytherapy not only eliminates the radiation exposure hazards but, in addition, eliminates the other disadvantages of brachytherapy thereby extending treatment to the infants and younger children. The long term effects of brachytherapy need further study.     

Long-term effect of chemotherapy–intensity-modulated radiation therapy (chemo-IMRT) on dentofacial development in head and neck rhabdomyosarcoma patients

Dentofacial developmental abnormalities have been reported in head and neck rhabdomyosarcoma (HNRMS) patients treated with conventional radiotherapy technique and chemotherapy. This current study investigates dentofacial long-term effects among HNRMS survivors managed with intensity-modulated radiotherapy (IMRT) and chemotherapy. In general, IMRT is a more effective 3D-conformal radiotherapy technique, which delivers high doses of radiation to the tumor target while minimizing doses received by the surrounding normal tissues. The medical records and radiographs of thirteen patients were reviewed to identify the following: 1. Facial asymmetry and jaw hypoplasia. 2. Effects on the dental tissue causing tooth agenesis/hypodontia, root agenesis/stunting/malformation, and/or enamel hypoplasia. 3. Trismus, hyposalivation/xerostomia. Seven patients presented with facial asymmetry and jaw hypoplasia, 9 patients presented with effects on the dental tissue [root agenesis/stunting/malformation (9), tooth agenesis/hypodontia (7) and enamel hypoplasia (3)] and 7 patients developed trismus and /or xerostomia. All patients with facial asymmetry and jaw hypoplasia also developed dental abnormalities. Patients with dentofacial developmental abnormalities were ≤7 years of age at treatment. Our study shows that dentofacial developmental abnormalities are still a burden in the era of IMRT and as prognosis of childhood malignancy improves and more patients survive, these late dentofacial sequelae among childhood cancer survivors will become more common. Dental oncologists should be integral members in the management of children with head and neck cancers.     

Management of hemophilic pseudotumor of thumb in a child

A case of hemophilic pseudotumor of the thumb in a child is reported. Combined treatment with radiation therapy and factor VIII replacement resulted in complete resolution of the lesion with no recurrence at the 6-month follow-up. The combination of radiotherapy and factor replacement should be strongly considered in the treatment of bone pseudotumors in children.     

Radiotherapeutic management of intracranial ependymoma

Ependymomas comprise about 10% of all pediatric brain tumors. The most consistent prognostic factor for cure has been the extent of surgical resection. Radiation therapy is considered the standard adjuvant treatment, although there has been no randomized trial comparing surgery alone to surgery and postoperative radiotherapy. Craniospinal irradiation has been used in the past to treat these tumors; however, current data indicate that the most common pattern of failure is an isolated local relapse. Furthermore, prophylactic spinal irradiation has not been shown to prevent spinal dissemination. For this reason, most radiation oncologists currently employ localized radiotherapy fields. Available data indicate that doses greater than 45-50 Gy are needed and associated with better local control. Preliminary data using hyperfractionated radiotherapy doses of greater than 65 Gy indicate an improvement in progression-free survival for subtotally respected ependymoma. Chemotherapy can be used to delay institution of radiotherapy in children less than 3 years of age. The role of chemotherapy in older children needs to be further defined.     

Radiotherapy in the SIOP (international society of pediatric oncology) nephroblastoma studies: A review

For decades radiation has generally been accepted as a valuable supplement to surgery in the treatment of Wilms' tumor; unfortunately, it may produce undesirable late effects. It turned out, however, that when treatment is adjusted to known variables, the risk for late sequelae can be diminished in some groups of children. SIOP clinical trials have been based on children with unilateral tumors of standard histology and free of metastasis at diagnosis. The first two clinical trials, SIOP-1 (started in 1971) and SIOP-2 (started in 1974), established the beneficial effect (such as less ruptures, lower stage) of preoperative radiation and actinomycin D (AMD) in SIOP-2, with all children having radiation therapy either pre-operatively, postoperatively, or both. In the SIOP-5 trial (started in 1977), preoperative radiation therapy and AMD were compared with preoperative chemotherapy resulting in only 50% of children having radiation. The result permitted disuse of preoperative radiation in the SIOP-6 trial (started in 1980), where only one-third of the patients received postoperative radiation therapy. At present, in the SIOP-9 trial (started in 1987), fewer than 20% of children are having radiotherapy. The survival rates meanwhile have been increasing steadily from 64% in SIOP-1 to 84% in SIOP-6 for stages I, II, and III combined. © 1994 Wiley-Liss, Inc.     

Management of retinoblastoma with radiation

OBJECTIVE: To evaluate the role of radiation therapy in the management of retinoblastoma. DESIGN: Retrospective analysis. METHOD: From January 1993 to March 1994, one hundred and eleven children (150 eyes) of retinoblastoma were referred for radiotherapy. The diagnosis was based on clinical examination and ocular ultrasonogram for both the eyes. The radiation treatment policy involved 40 Gy in 20 fractions over 4 weeks delivered with sedation for children under 1 year of age, 36 Gy in 9 fractions over 3 weeks under ketamine anesthesia for 1-4 years of age and for >4 years of age, a dose of 50 Gy in 25 fractions over 5 weeks. The initial tumor regression was evaluated by A and B mode ultrasonography and/or CT scan. RESULTS: The age distribution ranged from two months to six years (median - 20 months). Bilaterality was observed in 39 out of 111 cases (35%). The male to female ratio was 1.8:1. Eighty two of the 111 children were treated by definitive external beam radiation to one or both eyes. Fifteen cases received adjuvant radiotherapy after enucleation, and 14 had extensive disease for which palliative radiotherapy was offered. We observed a complete response in 54% of cases, partial response in 32%, and none in 14% of cases. Forty per cent (40%) eye survival was documented at the end of 28 months. The complication rate encountered was about 15%. CONCLUSION: Radiotherapy is an effective modality of treatment in significant number of patients with retinoblastoma. However, it requires appropriate fractionation, precise colimation and careful immobilization with general anesthesia.     

Germ cell tumours of the central nervous system in children-controversies in radiotherapy

BACKGROUND: Primary germ cell tumours (GCT) of the central nervous system (CNS) are rare tumours of children and adults. As few prospective, randomised trials have been published, management decisions are often based on retrospective and historical studies, histology, age, performance status, and extent of disease at diagnosis. This article reviews the current controversies in the radiotherapeutic management of primary GCT of the CNS. PROCEDURE: A computerised literature search was performed using the Medline database from 1975 to 2000, this being limited to publications written in the English language on CNS GCT in children up to the age of 16 years. RESULTS: Issues in radiation therapy currently undergoing review include the role of cranio-spinal irradiation (CSI), radiation therapy field sizes, the radiation therapy dose, the extent of surgery in combination with radiotherapy, and the role and timing of chemotherapy in combination with radiotherapy. CONCLUSIONS: The excellent outcome in children with pure germinoma of the CNS and the long-term morbidity associated with standard therapy justifies attempts to limit both the total radiation dose and field sizes, with or without the addition of chemotherapy. The poorer outcome associated with non-germinoma GCT justifies a more aggressive approach in children, combining chemotherapy, surgery and virgule, or radiation therapy, based on known prognostic factors.     

RADIOTHERAPEUTIC MANAGEMENT OF INTRACRANIAL EPENDYMOMA

Ependymomas comprise about 10% of all pediatric brain tumors. The most consistent prognostic factor for cure has been the extent of surgical resection. Radiation therapy is considered the standard adjuvant treatment, although there has been no randomized trial comparing surgery alone to surgery and postoperative radiotherapy. Craniospinal irradiation has been used in the past to treat these tumors; however, current data indicate that the most common pattern of failure is an isolated local relapse. Furthermore, prophylactic spinal irradiation has not been shown to prevent spinal dissemination. For this reason, most radiation oncologists currently employ localized radiotherapy fields. Available data indicate that doses greater than 45-50 Gy are needed and associated with better local control. Preliminary data using hyperfractionated radiotherapy doses of greater than 65 Gy indicate an improvement in progression-free survival for subtotally respected ependymoma. Chemotherapy can be used to delay institution of radiotherapy in children less than 3 years of age. The role of chemotherapy in older children needs to be further defined.     

24例儿童高危神经母细胞瘤调强适形放疗的近期疗效分析

目的 总结分析高危神经母细胞瘤患儿调强适形放疗（intensity-modulated radiotherapy,IMRT）疗效、安全性及相关经验。方法 回顾性选取2018年4月至2020年12月于湖南省人民医院儿童血液肿瘤科进行诊治并完成IMRT的高危组神经母细胞瘤患儿24例,收集相关资料,包括年龄、放疗剂量、放疗次数、实验室检查结果、不良反应、生存情况,分别进行归纳总结。结果 24例患儿均接受IMRT,其中男14例、女10例;平均年龄（65±23）个月,中位年龄59个月;原发瘤灶23例位于腹部,1例位于纵隔。放疗时患儿中位年龄41.5个月。放疗辐射剂量范围为14.4~36.0 Gy,平均剂量为（22±3）Gy,每日剂量为1.8~2.0 Gy,总次数8~20次,平均次数11.9次。其中6例接受了残留灶或转移灶放疗。放疗过程中3例出现咳嗽,2例出现腹泻,1例出现呕吐。放疗后2周,血肌酐范围值2.3~70.1 μmol/L,丙氨酸氨基转移酶范围值9.1~65.3 U/L,放疗开始后1~2周出现骨髓抑制Ⅲ度10例,Ⅳ度2例;放疗开始后3~4周出现骨髓抑制Ⅲ度4例,Ⅳ度1例。随访中位时间为13.5个月,其中23例（96%）疾病稳定,1例死亡,截至随访日期,未发现第2次恶性肿瘤及脏器功能异常。结论 IMRT能有效提高神经母细胞瘤局部控制率。IMRT治疗神经母细胞瘤患儿,短期内无明显不良反应,安全性高。     

显微外科为主的综合治疗对小儿髓母细胞瘤预后的影响

目的 分析显微手术辅以放疗、化疗对小儿髓线细胞瘤治疗效果及其预后的影响。方法 将髓母细胞瘤患儿分为二组。手术全切除组和手术未全切除组。前才术后只接受全神经轴放射治疗，后者术后辅以放疗和化疗，观察二组治疗效果和预后的差异。结果 手术全切除组术后肿瘤复发率２９．３％，１、２、５年生存率分别为１００％、９４．１％、８２．４％；手术未全切出生率且术后肿瘤复发率８５．７％、１、２、５年的生存率分别为７１．４     

Clinical outcome in children with craniopharyngioma treated with primary surgery and radiotherapy deferred until relapse

BACKGROUND: To report the clinical outcome in children with craniopharyngioma following primary surgery and deferred radiotherapy at relapse. PROCEDURE: Twenty-five children with craniopharyngioma were treated with primary surgery. Total resection was achieved in 19 children (76%), while in 24% total resection was not achieved due to tumor adhesion to adjacent critical structures. None of these children received radiation therapy immediately after total or sub-total resection. Radiotherapy was delivered at the time of relapse in 11 patients (44%). RESULTS: The median follow-up from primary surgery was 10 years (3-16 years). The 14 year overall survival was 100%. Tumor recurrence was observed in (12/25) 48% at a median interval of 17 months. Tumor recurrence following total resection was 6/19 (32%) compared to 100% (6/6) following sub-total resection, and radiotherapy. The 2, 3, and 6 years relapse-free survival following initial surgery was 72, 55, and 50%, respectively. Univariate analysis revealed only extent of surgery to be significant for local recurrence (P < 0.0001). The sequelae observed in these patients included panhypopituitarism (100%), appetite disorders and hypothalamic obesity (32%), neuropsychological and behavioral disorders (20%), and sleep disorders (12%). Majority of children with non-endocrine complications had a local recurrence requiring further surgery and radiotherapy. CONCLUSIONS: The two standard treatment options in children with craniopharyngioma are primary surgery and sub-total resection followed by radiotherapy. In certain subgroups of patients such as those with large tumors and hypothalamic extension, primary surgery is associated with a high incidence of complications and high failure rates. We recommend utilization of an individualized risk-based treatment approach, that attempts to maximize cure rates without compromising long-term functional outcome in children with craniopharyngiomas.     

Radiation-sensitive genetically susceptible pediatric sub-populations

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.     

HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report

BACKGROUND: The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children with progressive low grade glioma at an age under 5 years and in older children upon individual decision. PATIENTS AND METHOD: Until October 10th., 1999, 402 patients from 69 hospitals were registered. 130 children with progressive tumors were treated after a median observation time of 5 months: 46 patients received primary radiotherapy and 84 primary chemotherapy. A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1, 4, 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53. RESULTS: Of 84 patients in the chemotherapy arm of the study (49 male, 35 female, 23 NF I, median age 2.99 years) 36 received treatment at diagnosis and 43 after a median observation time of 19.7 months. 94.3% achieved a clinical and neuroradiological response according to protocol criteria (5 CR, 30 PR/OR, 31 SD) after a median of 5.1 months. 4 tumors showed primary progression (9 too early, 5 not known). Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy, after a median delay of 25.6 months at a median age of 6.0 years. At a median observation time of 21.0 months, 6 children are in CR, 11 in PR, 48 have SD, 4 tumors are progressive and 3 children died of their tumor. (9 too early, 3 not known). PFS is at 72% after 36 months. 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely. CONCLUSIONS: Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children with progressive low-grade glioma. The high rate of hypersensitivity reactions has to prompt future modifications of treatment.