Elsevier

Cancer/Radiothérapie

Volume 19, Issue 8, December 2015, Pages 775-789
Cancer/Radiothérapie

Review article
Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapyTumeurs cérébrales pédiatriques : revue de la littérature en radiothérapie, état de l’art et défis pour l’avenir en ce qui concerne la protonthérapie et la carbonethérapie

https://doi.org/10.1016/j.canrad.2015.05.028Get rights and content

Abstract

Background and purpose

Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits.

Materials and methods

A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy.

Results

A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas.

Conclusion

Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment.

Résumé

Objectifs

Les tumeurs cérébrales sont l’indication de radiothérapie pédiatrique la plus fréquente, avec des effets tardifs fréquents : cognitifs, osseux, visuels, auditifs et hormonaux. En raison de leur balistique exceptionnelle, les faisceaux de particules pourraient apporter une meilleure protection des tissus sains sans diminuer le contrôle local et la survie. Cet article est une revue de la littérature scientifique ayant pour but de proposer les indications de protonthérapie et de thérapie par ions carbone pour les tumeurs cérébrales pédiatriques et d’estimer les bénéfices thérapeutiques escomptés.

Matériel et méthodes

Une revue systématique a été réalisée sur les essais cliniques de radiothérapie des tumeurs pédiatriques en utilisant Medline (de 1966 à mars 2014), selon les critères suivants : patients âgés de 18 ans ou moins, ayant reçu une radiothérapie et comportant des données de survie. Les études sur les fonctions cognitives, la qualité de vie, la comparaison dosimétrique photons–protons ont également été incluses.

Résultats

Sur 7051 références primaires publiées, 40 études cliniques et 60 articles de qualité de la vie et dosimétrie ont été analysés, ainsi que les essais cliniques en cours. Ces documents ont été condensés et présentés dans un document spécifique mis à la disposition des experts participant à un atelier final d’une journée. Il existe de nombreuses indications de protonthérapie pour les tumeurs cérébrales pédiatriques à visée curative : pour le traitement localisé des épendymomes, tumeurs germinales, craniopharyngiomes, gliomes de bas grade, pour l’irradiation pan-ventriculaire des germinomes purs non-sécrétant et pour l’irradiation crâniospinale des médulloblastomes et germinomes purs métastatiques. La thérapie par ions carbone est en train d’émerger et pourrait être étudiée pour les tumeurs très agressives et radiorésistantes, tels les gliomes du tronc cérébral diffus, et les rechutes des gliomes de haut grade.

Conclusion

Pour les tumeurs cérébrales pédiatriques, protonthérapie et thérapie par ions carbone sont prometteuses. L’avantage de diminuer les effets tardifs sans altérer la survie a été décrit pour la plupart des tumeurs cérébrales pédiatriques avec la protonthérapie et est en évaluation dans des essais cliniques en cours. Actuellement, en France, une minorité de patients pédiatriques reçoit une protonthérapie en raison du manque d’équipement.

Introduction

Brain tumours are the most frequent paediatric solid tumours in children. In most cases, treatment includes surgery and radiotherapy with or without chemotherapy. Paediatric brain tumours acutely raise the question of treatments long-term tolerance. According to paediatric brain tumour natural history, the treatment is either addressing the general spreading of the disease or the local invasion and often both. Whenever the local control is the upfront challenge for the cure rate, the role of surgery and radiation therapy is important. The main drawback of radiation therapy is its acute and late toxicity that are particularly serious for central nervous system in childhood. Intelligence quotient impairment and other functional loss are well-documented. The challenge is therefore to improve the local control with less toxicity by identifying very accurately the target and avoiding irradiation of normal tissues outside the target.

Although surgery could be improved by postoperative assessment and sophisticate imaging, more improvement could come from altered radiotherapy technics as particle therapy. Actually, the better dose localization of particle therapy opens the possibility to increase target dose and to decrease organs at risk dose in the same time. Even more, in case of really very radioresistant tumours, heavy ions could be used with the same possibility of organs at risk sparing. Actually, protontherapy is a highly conformal treatment, able to reduce the absorbed dose to the normal brain parenchyma, the optic pathways, hypothalamus and sensorial organs.

However, one should consider also the risk of undue relapses while changing from larger integrated dose with photons to more localized dose of protons, due to uncertainties of the microscopic extend of the disease [1]. Similarly, uncertainties are remaining about the relative biological efficiency of particle therapy especially for children normal brain, and for tumours.

Thus, a complex figure of multiple parameters is existing in the domain of paediatric tumours including pattern of spreading and relapse, targets nature and location, tumour sensitivity, age of the patients, side-effects risk, that are influencing the possibilities of improvement by the use of particle therapy.

In France, presently, there is only one high-energy protontherapy center (ICPO, Orsay) able to treat such tumours [2]. The other French protontherapy center (Impact/Médicyc, Nice) is getting upgraded to access high energy, and there are several other projects. There is a need to determine how many regional referral centres, equipped with such technique, are necessary in France. An analysis of all indications for adults and children must be performed. This prompted the radiotherapy committee of the French society of childhood cancers (Société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent [SFCE]), to join the France Hadron consortium to define the indications of particle therapy for paediatric brain tumours. The France Hadron consortium includes existing particle therapy centres (ICPO in Orsay and Impact/Medicyc in Nice), as well as projects (centre Étoile in Lyon, Archade in Caen, Périclès in Toulouse).

The present paper reviews the toxicity and impairment data regarding paediatric central nervous system tumours, then details, for each type of paediatric brain tumours, the present challenges, the contribution of radiotherapy as a treatment component and the possibilities to improve it including by the use of particle therapy, and, how to assess this by evidence-based medicine approaches.

Cognitive dysfunction and endocrinopathy are the most frequent side effects of brain radiation therapy. Depending on tumour location; auditive and visual impairment are also frequent. Vasculopathy with stroke and second cancers are much less frequent.

Additionally, in case of craniospinal irradiation, decreased bone growth is constant, risks on lung and heart function do exist [3], [4], [5].

Moreover, the use of anticancer agent is a cause of second cancer.

Section snippets

Methods

Prior to the literature research, an expert group identified the potential indications for hadrontherapy (proton and carbon) in terms of tumour location and/or histology according to basic principle. These principles were: radioresistant unresectable tumours surrounded by organ at risk, with mainly local–regional spreading for patients lacking heavy comorbidities.

The Medline database and Cochrane Library (from January 1966 to March 2014) were used to perform the search. The query equation was

Gliomas

Glioma, according to their pathological grade and anatomic location, are of different level of life-threatening seriousness which is described thereafter (Table 1).

Low-grade gliomas are the most commonly diagnosed brain tumour in children and the most common cause of child brain irradiation. The overall survival rate being rather good, the main concern is the treatment related late toxicity, which justifies the search for alternatives to the use of radiotherapy.

High-grade glioma are rare in

Discussion

Paediatric radiotherapy is often considered as a two-edged weapon. On one edge, a necessary and efficient treatment for children's solid tumour, particularly brain tumours, on the other edge, a source of mild to severe late effects: cognitive, endocrinal, auditory and visual. In the everyday practice of paediatric radiation oncology, the question of referral to a protontherapy centre is frequent but resources are scarce and no national guidelines exist for paediatric brain tumour. This prompted

Conclusion

In France, 600 children every year receive a radiotherapy and brain tumours radiation therapy is the most frequent indication. To this, we can add the adolescents and young adults population. The number of indications for protons in a curative setting in paediatric and adolescents and young adults with brain tumours is 410 per year. Therefore, the need for protontherapy for such internationally acknowledged development, added to the other recognized and reimbursed indications (other paediatric

Disclosure of interest

The authors declare that they have no competing interest.

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