Authors' objectives: Anno 2014 there are no hadron facilities in Belgium; Belgian citizens eligible for hadron therapy (i.e. proton beam therapy (PBT) or carbon ion radiotherapy (CIRT)) are sent abroad. From September 2014 on (and until the end of September 2017), the costs related to hadron therapy (i.e. the treatment, transport and accommodation) are reimbursed if the diagnosis is on the list of eligible indicationsa and if the “Agreement Council for Hadron Therapy” (akkoordraad/ conseil d'accord) approves the application. The objective of this study was to evaluate the clinical effectiveness of proton beam (or carbon ion) therapy in those indications in children currently reimbursed by the National Institute for Health and Disability Insurance (RIZIV – INAMI). It concerns the following 16 indications: Proton beam therapy - Skull base chondrosarcoma - Skull base & (para)spinal chordoma - Craniopharyngioma- Ependymoma - Esthesioneuroblastoma - Ewing sarcoma - CNS germinoma - Low-grade glioma (incl. optic pathway) - Medulloblastoma / primitive neuroectodermal tumours (PNET) - Non-resectable osteosarcoma - Pelvic sarcoma - Pineal parenchymal tumours (not pineoblastoma) - Retinoblastoma - Rhabdomyosarcoma - (Para)spinal ‘adult type’ soft tissue sarcoma Carbon ion radiotherapy - Non-resectable or incompletely resected high-grade osteosarcoma with or without metastases

Authors' results and conclusions: RESULTS - After selection, we retrieved 21 primary studies on the 16 potential indications under study. On top of the non-randomized, non-controlled and retrospective nature of the majority of retrieved studies - with the limitations characteristic of these types of studies (e.g. selection bias, recall bias) - all studies suffered from very serious methodological limitations (among others small sample size, long enrolment period, no clear inclusion nor exclusion criteria, variable treatment schemes, short follow-up, no information on the methods and intervals of follow-up, complications only assessed in a subset of patients) and hence when GRADE2 was applied, the level of scientific evidence for all outcomes in all indications was very low. - For retinoblastoma there is very low level scientific evidence that PBT results in a lower risk of developing RT-induced in-field secondary malignancies. However, since radiation-induced solid malignancies need at least five to ten years to develop and for some children in the study the follow-up was short, the results should be interpreted with caution. - For craniopharyngioma there is very low level scientific evidence that PBT compared with intensity modulated radiotherapy (IMRT) did not result in significant differences in overall survival, cystic failure-free survival, nodular failure-free survival, toxicity or cyst dynamics. - For chondrosarcoma, chordoma, ependymoma, esthesioneuroblastoma, Ewing sarcoma, CNS germinoma, glioma, medulloblastoma, non-resectable osteosarcoma (for PBT as well as CIRT) and rhabdomyosarcoma there is insufficient scientific evidence to support or to refute the use of PBT (or CIRT) in children. - For pelvic sarcoma, pineal parenchymal tumour, PNET and (para-)spinal “adult type” soft tissue sarcoma there is no scientific evidence to support or to refute the use of PBT in children. Based on the 2004-2011 data provided by the Belgian Cancer Registry, it can be estimated that in Belgium 37 children (0-14 y.o.) and 14 adolescents (15-19 y.o.) may be eligible for radiotherapy/proton beam therapy on a yearly basis. CONCLUSIONS - Although there is no doubt that proton therapy reduces the radiation dose to normal tissues and organs, to date clinical data on PBT in all paediatric cancers under study is lacking critical information on measures of long-term effectiveness and harm. Prospective comparative clinical trials in the field are urgently needed

Authors' recommendations: To the clinicians: - Patients (or their parents or representatives) should be fully informed that despite the physical underpinning of proton beam therapy, its clinical efficacy for the indications considered in this report has not yet been confirmed in clinical studies. - Children should be referred to proton beam centres with the necessary expertise in treating children with that specific pathology and involved in clinical studies with long-term follow-up (if recruiting in Europe). - The registration in the Belgian Cancer Registry (BCR) database of the chemotherapy regimen and radiotherapy schedule (including hadron therapy) administered in children is recommended. This registration can allow, amongst others, the monitoring of secondary malignancies occurrence. To the Technical Medical Council & the Insurance Committee of the RIZIV - INAMI: - The current reimbursement for PBT should be reevaluated periodically as new scientific evidence on effectiveness and safety becomes available. Meanwhile, the 15-year age limit should be reconsidered for certain indications. - The amount reimbursed for radiotherapy in children should take into account the complexity of treatment administration, including the potential need for anaesthesia. The reimbursement should be made conditional to the registration into the BCR database. To the RIZIV - INAMI, BCR & FANC - AFCN and scientific/professional associations: - Our country should actively promote the set-up of a European Hadron Therapy Registry.

Authors' methods: A systematic search for relevant publications was carried out in Medline, EMBASE, and the Cochrane Library. Reviews and primary studies on proton beam therapy and/or carbon ion therapy published between 2007 (i.e. end date of search strategy of previous KCE Hadron HTA 1 ) up to March 2014 were searched. An overview of the inclusion and exclusion criteria, the search strategy and the flow chart of the selection process are provided in the Supplement. A final update of the search (restricted to Medline) was performed on September 11, 2014.

Authors' identified further research: There is an urgent need for more research, not only on the clinical efficacy, side effects, and harms, but also on the economical aspects, and on the physics and biology. Clinical research should preferentially be conducted in an internationally coordinated way.

Project Status: Completed

Year Published: 2015

URL for published report: https://doi.org/10.57598/R235C

URL for additional information: https://kce.fgov.be/en/publications/all-reports/hadron-therapy-in-children-an-update-of-the-scientific-evidence-for-15-paediatric-cancers

English language abstract: An English language summary is available

Publication Type: Rapid Review

Country: Belgium

DOI: 10.57598/R235C

Organisation Name: Belgian Health Care Knowledge Centre

Contact Address: Administrative Centre Botanique, Doorbuilding (10th floor), Boulevard du Jardin Botanique 55, B-1000 Brussels, Belgium tel: +32 2 287 33 88 fax: +32 2 287 33 85

Contact Name: info@kce.fgov.be

Contact Email: info@kce.fgov.be

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