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30 p. Ill.

27 p. Ill.

75 p. Ill., INTRODUCTION 8 -- 1.1 OBJECTIVES 8 -- 1.2 THE STUDY TEAM . 8 -- 1.3 RADIOTHERAPY A ND INNOVATION 8 -- 1.4 INNOVATIVE RADIOTHERAPY TECHNIQUES AND THEIR INDICATIONS 9 -- 1.4.1 Novel radiotherapy techniques for treating early breast cancer. 9 -- 1.4.2 Stereotactic body radiation therapy (SBRT). 11 -- 1.4.3 Research funding, registration of activities and clinical outcome. 12 -- 2 METHODOLOGY 14 -- 2.1 WHY AN ABC ANALYSIS? 14 -- 2.2 SELECTION AND PARTICIPATION OF RADIOTHERAPY CENTRES 14 -- 2.3 DEFINITION OF RADIOTHERAPY TREATMENTS 15 -- 2.4 TIME-DRIVEN ABC OF RADIOTHERAPY 15 -- 2.5 ACTIVITIES 15 -- 2.6 COSTS AND RESOURCE USE 16 -- 2.6.1 Personnel cost 19 -- 2.6.2 Equipment costs 19 -- 2.6.3 Indirect material costs 19 -- 2.6.4 Pharmaceuticals, radio-isotopes and gold markers 19 -- 2.6.5 Overhead 20 -- 2.6.6 Direct costs 20 -- 2.7 COST ALLOCATION 20 -- 2.7.1 Time based allocation of personnel and equipment costs to patient related activities 20 -- 2.7.2 Allocating activities, materials and overhead to treatments 21 -- 2.8 TOTAL COST PERTREATMENT .22 -- 2.9 DATA COLLECTION TEMPLATES 22 -- 3 RESULTS 23 -- 3.1 CENTRE’S PROFILE 23 -- AVERAGE COST OVER ALL TREATMENTS 25 -- 3.3 SBRT, FOCUS ON THE LUNG 27 -- 3.4 SBRT OF SPINAL, LIVER, PANCREAS, BONE AND OLIGOMETASTASES 30 -- 3.5 BREAST CANCER 31 -- 3.6 PROSTATE CANCER 36 -- 3.7 HEAD AND NECK CANCER 36 -- 3.8 RECTUM CANCER 37 -- 3.9 PALLIATIVE RADIOTHERAPY 38 -- 3.10 COST DETERMINANTS AND EFFICIENCY 39 -- 4 DISCUSSION OF THE RESULTS 42 -- 4.1 THE 10 CENTRES AND THE OVERALL RESULTS 42 -- 4.1.1 General findings . 43 -- 4.1.2 Cost determinants and efficiency 45 -- 4.2 COST OF SBRT COMPARED WITH OTHER MODALITIES . 46 -- 4.2.1 Focus on the lung 46 -- 4.2.2 SBRT of spinal, liver, pancreas, bone and oligometastases 47 -- 4.3 BREAST CANCER, FOCUS ON APBI AND IORT BOOST 48 -- 4.4 COST OF OTHER COMMON TREATMENTS 50 -- 4.5 COSTS, FINANCING AND BUDGET CONSIDERATIONS 50 -- 4.6 INTRODUCING INNOVATIONS IN HEALTH CARE 51

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p. 267-278 Because it spares many normal tissues and reduces the integral dose, proton therapy (PT) is the preferred tumor irradiation technique for treating childhood cancer. However, to the best of our knowledge, no systematic review of the clinical effectiveness of PT in children has been reported in the scientific literature. A systematic search for clinical outcome studies on PT published between 2007 and 2015 was performed in Medline (through OVID), EMBASE, and the Cochrane Library. Twenty-three primary studies were identified, including approximately 650 patients overall. The median/mean follow-up times were limited (range, 19-91 months). None of the studies were randomized, 2 were comparative, and 20 were retrospective. Most suffered from serious methodologic limitations, yielding a very low level of clinical evidence for the outcomes in all indications. For example, for retinoblastoma, very low-level evidence was found that PT might decrease the incidence of second malignancies. For chondrosarcoma, chordoma, craniopharyngioma, ependymoma, esthesioneuroblastoma, Ewing sarcoma, central nervous system germinoma, glioma, medulloblastoma, osteosarcoma, and rhabdomyosarcoma, there was insufficient evidence to either support or refute PT in children. For pelvic sarcoma (ie, nonrhabdomyosarcoma and non-Ewing sarcoma), pineal parenchymal tumor, primitive neuroectodermal tumor, and "adult-type" soft tissue sarcoma, no studies were identified that fulfilled the inclusion criteria. Although there is no doubt that PT reduces the radiation dose to normal tissues and organs, to date the critical clinical data on the long-term effectiveness and harm associated with the use of PT in the 15 pediatric cancers under investigation are lacking. High-quality clinical research in this area is needed.

p. 454-461 INTRODUCTION: Despite the lack of randomized evidence, stereotactic body radiotherapy (SBRT) is being accepted as superior to conventional radiotherapy for patients with T1-2N0 non-small-cell lung cancer in the periphery of the lung and unfit or unwilling to undergo surgery. To introduce SBRT in a system of coverage with evidence development, a correct financing had to be determined. METHODS: A time-driven activity-based costing model for radiotherapy was developed. Resource cost calculation of all radiotherapy treatments, standard and innovative, was conducted in 10 Belgian radiotherapy centers in the second half of 2012. RESULTS: The average cost of lung SBRT across the 10 centers (6221&OV0556;) is in the range of the average costs of standard fractionated 3D-conformal radiotherapy (5919&OV0556;) and intensity-modulated radiotherapy (7379&OV0556;) for lung cancer. Hypofractionated 3D-conformal radiotherapy and intensity-modulated radiotherapy schemes are less costly (3993&OV0556; respectively 4730&OV0556;). The SBRT cost increases with the number of fractions and is highly dependent of personnel and equipment use. SBRT cost varies more by centre than conventional radiotherapy cost, reflecting different technologies, stages in the learning curve and a lack of clear guidance in this field. CONCLUSIONS: Time-driven activity-based costing of radiotherapy is feasible in a multicentre setup, resulting in real-life resource costs that can form the basis for correct reimbursement schemes, supporting an early yet controlled introduction of innovative radiotherapy techniques in clinical practice.

24 p. ill. Biedt protontherapie, een nauwkeurige bestralingstechniek, meer voordeel bij de behandeling van kinderen dan klassieke radiotherapie? Bij protontherapie worden de omliggende weefsels minder blootgesteld aan straling. Daardoor zou het risico op bijkomende tumoren en andere problemen, veroorzaakt door bestraling, lager liggen. Op verzoek van het RIZIV onderzocht het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) of dit laatste uiteindelijk ook betere medische resultaten oplevert bij kinderen. De vraag is zeer actueel, omdat dit jaar de bouw van de eerste Belgische protoncentra werd aangekondigd. De vraag is echter onmogelijk te beantwoorden: ondanks de wereldwijde behandeling van duizenden kinderen zijn er geen goede klinische studies bij kinderen uitgevoerd. Het KCE moest dus concluderen dat de meerwaarde van protontherapie voor de behandeling van kanker bij kinderen nog niet is bewezen. VOORWOORD 1 -- SAMENVATTING 2 -- 1 INTRODUCTIE 2 -- 2 METHODEN .3 -- 3 RESULTATEN 3 -- 4 CONCLUSIES .3 -- INHOUDSOPGAVE .2 -- LIJST MET AFBEELDINGEN 3 -- LIJST VAN AFKORTINGEN & ACRONIEMEN 4 -- 1 INTRODUCTIE 5 -- 1.1 RATIONALE & ONDERZOEKSVRAGEN .5 -- 1.2 WAT IS HADRONTHERAPIE? 5 -- 1.2.1 Protontherapie 6 -- 1.2.2 Radiotherapie met koolstofionen 7 -- 1.3 WAAROM PROTONTHERAPIE BIJ KINDEREN? 7 -- 1.4 PROTONTHERAPIE - DE HEILIGE GRAAL IN DE PEDIATRISCHE RADIOTHERAPIE? 8 -- 2 SYSTEMATISCHE LITERATUURSTUDIE 8 -- 2.1 KLINISCHE EFFECTIVITEIT VAN PROTONTHERAPIE EN GEÏNDICEERD VOOR RADIOTHERAPIE/PROTONTHERAPIE, PER TUMORTYPE 9 -- 2.1.1 Chondrosarcoom van de schedelbasis 9 -- 2.1.2 Chordoom van de schedelbasis & (para)spinaal 9 -- 2.1.3 Craniofaryngeoom 9 -- 2.1.4 Ependymoom .10 -- 2.1.5 Esthesioneuroblastoom .10 -- 2.1.6 Ewingsarcoom 11 -- 2.1.7 Germinoom van het centraal zenuwstelsel .11 -- 2.1.8 Laaggradig glioom (incl. van de visuele banen) 12 -- 2.1.9 Medulloblastoom / Primitieve neuro-ectodermale tumor .13 -- 2.1.10 Niet-reseceerbaar osteosarcoom .13 -- 2.1.11 Bekkensarcoom 13 -- 2.1.12 Parenchymale tumoren van de pijnappelklier 14 -- 2.1.13 Retinoblastoom .14 -- 2.1.14 Rhabdomyosarcoom 15 -- 2.1.15 (Para)spinaal wekedelensarcoom van het 'volwassen type' 15 -- 2.2 KLINISCHE EFFECTIVITEIT VAN RADIOTHERAPIE MET KOOLSTOFIONEN EN GESCHIKTHEID VOOR RADIOTHERAPIE/RADIOTHERAPIE MET KOOLSTOFIONEN (CIRT) 16 -- Niet-reseceerbaar osteosarcoom 16 -- 3 DISCUSSIE 17 -- 4 KERNBOODSCHAPPEN18 -- AANBEVELINGEN 19 -- REFERENTIES 20

82 p. ill. 1 INTRODUCTION 2 -- 2 METHODS .3 -- 3 RESULTS 3 -- 4 CONCLUSIONS .3 -- 5 INTRODUCTION 5 -- 5.1 RATIONALE & RESEARCH QUESTIONS 5 -- 5.2 WHAT IS HADRON THERAPY? 5 -- 5.2.1 Proton beam therapy .6 -- 5.2.2 Carbon ion radiotherapy 7 -- 5.3 WHY PROTON BEAM THERAPY IN CHILDREN? .7 -- 5.4 PROTON BEAM THERAPY – THE HOLY GRAIL IN PAEDIATRIC RADIATION ONCOLOGY? 7 -- 6 SYSTEMATIC LITERATURE REVIEW .8 -- 6.1 CLINICAL EFFECTIVENESS OF PROTON BEAM THERAPY AND ELIGIBILITY FOR RADIOTHERAPY/PROTON BEAM THERAPY BY TUMOUR TYPE .8 -- 6.1.1 Skull base chondrosarcoma 8 -- 6.1.2 Skull base & (para)spinal chordoma .9 -- 6.1.3 Craniopharyngioma 9 -- 6.1.4 Ependymoma .10 -- 6.1.5 Esthesioneuroblastoma .10 -- 6.1.6 Ewing sarcoma 11 -- 6.1.7 CNS germinoma 11 -- 6.1.8 Low-grade glioma (incl. optic pathway) .12 -- 6.1.9 Medulloblastoma / primitive neuroectodermal tumours 12 -- 6.1.10 Non-resectable osteosarcoma 13 -- 6.1.11 Pelvic sarcomas 13 -- 6.1.12 Pineal parenchymal tumours .13 -- 6.1.13 Retinoblastoma .14 -- 6.1.14 Rhabdomyosarcoma 15 -- 6.1.15 (Para-)spinal ‘adult type’ soft tissue sarcoma (STS) 15 -- 6.2 CLINICAL EFFECTIVENESS OF CARBON ION RADIOTHERAPY AND ELIGIBILITY FOR RADIOTHERAPY/CARBON ION RADIOTHERAPY .16 -- Non-resectable osteosarcoma .16 -- 7 DISCUSSION 16 -- 8 KEY MESSAGES 17

152 p. ill. 1. SEARCH STRATEGIES 7 -- 1.1. ELECTRONIC REFERENCE DATABASES: MEDLINE (THROUGH OVID), EMBASE AND THE COCHRANE LIBRARY 7 -- 1.2. HTA AGENCIES 17 -- 1.2.1. Methods 17 -- 1.2.2. List of consulted HTA agencies and related websites 18 -- 1.2.3. Retrieved publications 20 -- 1.3. CLINICAL TRIALS.GOV 23 -- 1.3.1. Methods 23 -- 1.3.2. List of (ongoing) studies 23 -- 1.4. FLOW CHART FOR SELECTION PROCEDURE 35 -- 2. QUALITY APPRAISAL 37 -- 2.1. QUALITY APPRAISAL TOOLS 37 -- 2.2. STUDY SELECTION AND QUALITY APPRAISAL 38 -- 2.2.1. Skull base chondrosarcoma & skull base and (para)spinal chordoma 38 -- 2.2.2. Craniopharyngioma 44 -- 2.2.3. Ependymoma 47 -- 2.2.4. Esthesioneuroblastoma 49 -- 2.2.5. Ewing sarcoma 50 -- 2.2.6. CNS Germinoma 51 -- 2.2.7. Low-grade glioma 54 -- 2.2.8. Medulloblastoma & PNET 57 -- 2.2.9. Non-resectable osteosarcoma 59 -- 2.2.10. Pelvic sarcomas 60 -- 2.2.11. Pineal parenchymal tumours 61 -- 2.2.12. Retinoblastoma 61 -- 2.2.13. Rhabdomyosarcoma 64 -- 2.2.14. (Para-)spinal ‘adult type’ soft tissue sarcoma 66 -- 2.3. EVIDENCE TABLES BY INDICATION 67 -- 2.3.1. Skull base chondrosarcoma & skull base and (para)spinal chordoma 67 -- 2.3.2. Craniopharyngioma 71 -- 2.3.3. Ependymoma 79 -- 2.3.4. Esthesioneuroblastoma 84 -- 2.3.5. Ewing sarcoma 87 -- 2.3.6. CNS Germinoma 90 -- 2.3.7. Low-grade glioma 92 -- 2.3.8. Medulloblastoma & PNET 97 -- 2.3.9. Non-resectable osteosarcoma 104 -- 2.3.10. Retinoblastoma 110 -- 2.3.11. Rhabdomyosarcoma 112 -- 2.4. GRADE PROFILES & SUMMARY OF FINDINGS TABLES 119 -- 2.4.1. Skull base chondrosarcoma & skull base and (para)spinal chordoma 119 -- 2.4.2. Craniopharyngioma 124 -- 2.4.3. Ependymoma 126 -- 2.4.4. Esthesioneuroblastoma 128 -- 2.4.5. Ewing sarcoma 130 -- 2.4.6. CNS Germinoma 133 -- 2.4.7. Low-grade glioma 135 -- 2.4.8. Medulloblastoma & PNET 137 -- 2.4.9. Non-resectable osteosarcoma 139 -- 2.4.10. Retinoblastoma 144 -- 2.4.11. Rhabdomyosarcoma 146 -- 3. BELGIAN INCIDENCE DATA - DESCRIPTION OF THE SELECTION CRITERIA PER TUMOUR TYPE 149 -- 4. REFERENCES 151

82 p. ill. LIST OF FIGURES 4 -- LIST OF TABLES 4 -- LIST OF ABBREVIATIONS & ACRONYMS 5 -- SCIENTIFIC REPORT 9 -- 1 INTRODUCTION 9 -- 1.1 CANCER IN CHILDREN AND ADOLESCENTS 9 -- 1.1.1 The burden of cancer in children and adolescents 9 -- 1.1.2 Prognosis 10 -- 1.1.3 Sequelae of cancer (therapy) in paediatric cancer survivors 12 -- 1.2 HADRON THERAPY 14 -- 1.2.1 Radiotherapy and radiation effects 14 -- 1.2.2 History of hadron therapy 14 -- 1.2.3 Photon versus hadron (charged particle) therapy 15 -- 1.2.4 Radioprotection 17 -- 1.2.5 Carbon ion therapy 17 -- 1.2.6 Proton beam therapy 18 -- 1.2.7 Conclusions 23 -- 1.3 CONCLUSIONS OF THE 2007 KCE REPORT ON HADRON THERAPY 24 -- 1.4 HADRON THERAPY IN BELGIUM 24 -- 1.5 OBJECTIVE OF THIS STUDY 25 -- 2 METHODS 26 -- 2.1 LITERATURE SEARCH 26 -- 2.2 QUALITY APPRAISAL 27 -- 2.3 DATA EXTRACTION 27 -- 2.4 STATISTICAL ANALYSIS 27 -- 2.5 GRADING EVIDENCE 27 -- 2.6 VALIDATION 29 -- 3 RESULTS 30 -- 3.1 NUMBER OF (POTENTIAL) PATIENTS PER INDICATION UNDER STUDY 30 -- 3.2 CHORDOMA & CHONDROSARCOMA 32 -- 3.2.1 Background 32 -- 3.2.2 What is the clinical effectiveness of proton beam therapy in children with skull base and (para)spinal chordoma or with skull base chondrosarcoma? 33 -- 3.3 CRANIOPHARYNGIOMA35 -- 3.3.1 Background 35 -- 3.3.2 What is the clinical effectiveness of proton beam therapy in children with craniopharyngioma? 36 -- 3.4 EPENDYMOMA 38 -- 3.4.1 Background 38 -- 3.4.2 What is the clinical effectiveness of proton beam therapy in children with ependymoma? 38 -- 3.5 ESTHESIONEUROBLASTOMA 40 -- 3.5.1 Background 40 -- 3.5.2 What is the clinical effectiveness of proton beam therapy in children with esthesioneuroblastoma? 40 -- 3.6 EWING SARCOMA 42 -- 3.6.1 Background 42 -- 3.6.2 What is the clinical effectiveness of proton beam therapy in children with Ewing sarcoma? 43 -- 3.7 CNS GERMINOMA 44 -- 3.7.1 Background 44 -- 3.7.2 What is the clinical effectiveness of proton beam therapy in children with CNS germinoma? 44 -- 3.8 LOW-GRADE GLIOMA (INCL. OPTIC PATHWAY GLIOMA) 45 -- 3.8.1 Background 45 -- 3.8.2 What is the clinical effectiveness of proton beam therapy in children with low-grade glioma? 46 -- 3.9 MEDULLOBLASTOMA & OTHER PRIMITIVE NEUROECTODERMAL TUMOURS (PNET) 48 -- 3.9.1 Background 48 -- 3.9.2 What is the clinical effectiveness of proton beam therapy in children with medulloblastoma and PNET? 49 -- 3.10 NON-RESECTABLE OSTEOSARCOMA 51 -- 3.10.1 Background 51 -- 3.10.2 What is the clinical effectiveness of proton beam therapy in children with non-resectable osteosarcoma? 52 -- 3.10.3 What is the clinical effectiveness of carbon ion radiotherapy (CIRT) in children with nonresectable or incompletely resected high-grade osteosarcoma? 53 -- 3.11 PELVIC SARCOMAS 54 -- 3.11.1 Background 54 -- 3.11.2 What is the clinical effectiveness of proton beam therapy in children with pelvic sarcomas? 55 -- 3.12 PINEAL PARENCHYMAL TUMOURS 55 -- 3.12.1 Background 55 -- 3.12.2 What is the clinical effectiveness of proton beam therapy in children with pineal parenchymal tumours? 56 -- 3.13 RETINOBLASTOMA 56 -- 3.13.1 Background 56 -- 3.13.2 What is the clinical effectiveness of proton beam therapy in children with retinoblastoma? 57 -- 3.14 RHABDOMYOSARCOMA 58 -- 3.14.1 Background 58 -- 3.14.2 What is the clinical effectiveness of proton beam therapy in children with rhabdomyosarcoma? 59 -- 3.15 (PARA-)SPINAL ‘ADULT TYPE’ SOFT TISSUE SARCOMA 61 -- 3.15.1 Background 61 -- 3.15.2 What is the clinical effectiveness of proton beam therapy in children with (para)spinal adulttype soft tissue sarcomas? 62 -- 3.16 SUMMARY OF SELECTED STUDIES 63 -- 4 DISCUSSION & CONCLUSIONS 69 -- 5 RECOMMENDATIONS 72 -- REFERENCES 73

27 p. ill. La protonthérapie, une technique de radiothérapie ultra-précise, offre-t-elle plus d’avantages que la radiothérapie classique lorsqu’il s’agit de traiter des enfants ? Elle permet en effet de délivrer une dose de rayons moins élevée aux tissus entourant la tumeur, ce qui devrait diminuer le risque de nouveaux cancers et autres effets secondaires de l’irradiation. L’INAMI a demandé au Centre fédéral d’Expertise des Soins de santé (KCE) de s’assurer que la technique donne de bons résultats chez les enfants. La question est d’actualité en Belgique, avec l’annonce, au début de cette année, de la construction des premiers centres de protonthérapie. Mais c’est aussi une question à laquelle il est quasi impossible de répondre parce que, malgré des milliers d’enfants traités dans le monde, l’application de cette technique aux cancers pédiatriques n’a fait l’objet d’aucune étude clinique internationale de qualité. Le KCE doit donc conclure que la valeur ajoutée de la protonthérapie n’est pas encore établie dans le traitement des cancers pédiatriques. PRÉFACE 1 -- RÉSUMÉ 2 -- 1. INTRODUCTION 2 -- 2. MÉTHODES 3 -- 3. RÉSULTATS 3 -- 4. CONCLUSIONS 3 -- SYNTHÈSE 4 -- 1. INTRODUCTION 7 -- 1.1. JUSTIFICATION ET QUESTIONS DE RECHERCHE 7 -- 1.2. QU'EST-CE QUE L'HADRONTHÉRAPIE ? 7 -- 1.2.1. Protonthérapie 8 -- 1.2.2. Radiothérapie par ions carbone 9 -- 1.3. POURQUOI UTILISER LA PROTONTHÉRAPIE CHEZ LES ENFANTS ? 10 -- 1.4. PROTONTHÉRAPIE : LE SAINT-GRAAL DE LA RADIO-ONCOLOGIE PÉDIATRIQUE ? 10 -- 2. REVUE SYSTÉMATIQUE DE LA LITTÉRATURE 11 -- 2.1. EFFICACITÉ CLINIQUE DE LA PROTONTHÉRAPIE ET ÉLIGIBILITÉ À LA -- RADIOTHÉRAPIE/PROTONTHÉRAPIE PAR TYPE DE TUMEUR 11 -- 2.1.1. Chondrosarcome de la base du crâne 11 -- 2.1.2. Chordome de la base du crâne et (para)spinal 12 -- 2.1.3. Craniopharyngiome 12 -- 2.1.4. Épendymome 12 -- 2.1.5. Esthésioneuroblastome 13 -- 2.1.6. Sarcome d'Ewing 13 -- 2.1.7. Germinome du SNC 14 -- 2.1.8. Gliome de bas grade (y compris des voies optiques) 14 -- 2.1.9. Médulloblastome/tumeurs neuroectodermiques primitives 15 -- 2.1.10. Ostéosarcome non résécable 15 -- 2.1.11. Sarcome du bassin 16 -- 2.1.12. Tumeurs parenchymateuses pinéales 16 -- 2.1.13. Rétinoblastome 17 -- 2.1.14. Rhabdomyosarcome 17 -- 2.1.15. Sarcome des tissus mous (STS) de « type adulte » (para)spinal 18 -- 2.2. EFFICACITÉ CLINIQUE DE LA RADIOTHÉRAPIE PAR IONS CARBONE ET ÉLIGIBILITÉ À LA RADIOTHÉRAPIE/RADIOTHÉRAPIE PAR IONS CARBONE 18 -- Ostéosarcome non résécable 19 -- 3. DISCUSSION 19 -- 4. MESSAGES PRINCIPAUX 21 -- RECOMMANDATIONS 22 -- RÉFÉRENCES 23

vi, 101 p. ill.

vi, 101 p. ill.

vi, 101 p. ill.