Determination of The Potential Indications of Hadronthérapie ...

Determination of The Potential Indications of Hadronthérapie ...

POTENTIAL INDICATIONS OF HADRONTHERAPY IN THE SARCOMAS ANALYSIS OF THE LITERATURE Dr Marie Pierre SUNYACH Dr Pascal POMMIER Centre Lon Brard Dr Emmanuel AMSELLEM Facult Lannec Lyon, France Carbon Ions - Perspective Rationnal Balistic Bragg peak Biological 2 to 3 times more efficient than photon From GSI, Darmstadt, Germany

Hadrontherapy Centers (Carbon Ions) Existing Centers 1994: National Institute for Radiological Science (Japan) 1997: GSI, Darmstadt (Germany) 2001: Hyogo Ion Beam Medical Center (Japan) In development (Europe) Germany (Heidelberg) Italia (CNAO TERA, Pavi) Austria (Medaustron, Baden Vienna)

France (ETOILE, Lyon) The Medical Project The medical project Determine the potential indications of carbon ions. First tumor types studied Head and neck Sarcoma Glioma Objectives To define the situations in which an increased dose (using carbon ions) could be efficient To define the survival and local control expected when the best treatment is used

To evaluate the risk of toxicities This is not an exhaustive review of litterature Definition of the best treatment Established treatments Standard treatments Treatments assessed by randomized studies Treatment established by consensus Innovative treatments Treatments with no validation No Established treatments for those indications 2002 - 2003 Local Working Groups Screening of all topographies and

histologies to identify a priori any potential indication for Hadrontherapy The potential indications tables Indications (topo, stage, pathology..) Standard and concurrent therapies Organ ICD-O2 Localisation Further cr ite ria se le ction Curr ent tr etame nt ; graduate d list of concurr ent t reatme nt t o car bon E y e, Brain & CNS C70 Me ni ng ioma (all l oc al isations) Ino perable b eg nin men ing ioma Pho ton s; IMRT, Pro ton s E y e, Brain & CNS C70

Me ni ng ioma (all l oc al isations) Beg n in men ig ioma wit h risks o f su rg ica l s equ elae Pho ton s; IMRT, Pro ton s E y e, Brain & CNS C70 Me ni ng ioma (all l oc al isations) Ma lig nan t men in gio ma Gr 2-3 Pho ton s; IMRT, Pro ton s E y e, Brain & CNS C72 Ne uri noma Ino pe rab le Pho ton s;

IMRT, Pro ton s E y e, Brain & CNS C72 Ne uri noma E y e, Brain & CNS C71 Low g rade gli oma with bad pr onosti c : 40 ye ar old, volumi nous tumor, symptoms, i noper able E y e, Brain & CNS C71 Low g rade gli oma with bad pr onosti c : 40 ye ar old, volumi nous tumor, symptoms, i noper able

E y e, Brain & CNS C71 Low g rade gli oma with bad pr onosti c : 40 ye ar old, volumi nous tumor, symptoms, i noper able E y e, Brain & CNS C71 Gl ioblas toma Ris ks of su rgic al se qu ela e++ Pho ton s; IMRT, Pro ton s (3) st 1 st ep : p os t RT tumo r re laps e

with p ro gre ss ion un de r ch emoth era py Pho ton s; Prot on s (8 ) (3) nd 2 s tep : inop e rab le tu mor not prev iou sly irrad iate d and progres siv e u nd er che mo th era py Pho ton s; Prot on s (8 ) (3) 2003 2006 Evidence based medicine approach (methodologists) screening and analysis of all relevant literature (HT & conc. Therapies) rd

3 ste p : po st -ope ra tiv e RT 1s t st ep : p os t RT t umor relaps e with p ro gre ss ion un de r ch emoth era py Pho ton s; Prot on s (8 ) Pho ton s; Chemo ra dio the rap y Epidemiological landscape Cancer registry (FRANCIM) and One day survey in French radiation oncology departments International experts 2003 2006 - Validation of the indications for HT (P. and/or C) - Estimation of the therapeutic gain & priorities - Prospective trials A portfolio of multicenter clinical trials Clinical Trial n 1 for hadronthrapie zegqergqeomfhmlqejheqtjheqojhoqejthojetphjqsetophjpqejthoqjethjqethjqptjohqrotjhpqtjhopjqtpohjqet hjpotjhopqtjhopsjthpojsrthojqpetohjqopetjhqopetjhqopejthqopejthopqejthopjqethopjqpetohjpqojhqojethpoqjet

hojqpetohjqpeotjhqopetjhopqejthopqjehopjqethjoqpoerjghpqrjghiohjrgklfhlihbjljhbjhoej Table of potential indications Localisations Treatments STS R2 M0 Inoperable Axial limb Neutrons STS R1M0 Axial limb Photons STS R1 R2 Retroperitoneal Photons Protons

Carbon ions Surgery Osteosarcoma chondrosarcoma Inoperable R2 Limbs Neutrons+chemotherapy Photons+chemotherapy Carbon Ions Osteosarcoma Chondrosarcoma R2 inoperable Others than limbs Neutrons+chemotherapy Photons+chemotherapy Carbon Ions Protons Chordoma Skull base cervical Protons

Chordoma Sacrum Protons Chondrosarcoma Skull base cervical Protons chondrosarcoma Lombar sacrum Protons Neutrons Plan Soft tissue sarcoma R1 and R2 Osteosarcoma and Chondrosarcoma Skull base Chondrosarcoma and Chordoma

STS: 1524 identified references 21 analysed in the final document 1524 References 135 selectionnated 1389 Exclusions (abstract) : Language No indication about treatments Review:Nb of pts < 10 Publication before 1970 Children Animals Resction R0 114 Exclusions (article) No clinical data Resection R0 No RTE RTE < 50 Gy Nb < 10 pts No indication about treatment Dosimetric studies 21 definitively selectionnated STS R1 (extremity or axial) TREATMENT Toxicity

OS LC DFS Zagars 2003 N=254 Photons: Med Doses: 64 Gy No information LC 10y:73%(67%-79%) DFS 10y:49%(43-56%) Schmitt G 1989 N=104 Photons 40 Gy Neutrons 6.3nGy No information LC 5y:77%(68-85%) DFS 5y:65%(55-74%) STS R1: proposition

R1 definitive and never resectable Hadrontherapy will not replaced good surgery Objective of Carbon Ions To decrease local recurrence to near 0 % Non randomized phase II STS R2 / unresecable (extremity /axial) Authors Years Treatment Toxicity OS LC DFS Schwartz 2001 Neutrons 4.8-22 nGy +/- Photons 10-60 Gy 15% late severe

toxicity LC 4y : 61% DFS4y: 59% OS 4y: 66% N=41 Schmitt 1989 N=94 Neutrons 16.8 nGy No information LC 5y : 56%(45-66%) DFS 5y:25.5%(17-35%) Kamada 2002 N=57 Carbon ions 52.3 Gy 57.6 Gy 6/57 LC 3y:73%(48-98%)

OS 3y:46%(26-66%) DFS 3y:36%(24-50 %) STS R2 or unresecable proposition R2 definitive and never resecable Hadrontherapy will not replaced good surgery Non randomized phase II trial Photontherapy : Neutrontherapy : LC 10 % LC 60% Objective : at least 50% local control with few toxicities

Unresecable tumor or recurrence with oligo metastasis can be treated in this group Retroperitonal STS Gilbeau TREATMENT OS LC Photons +/Associated CT R0 Overall survival 2 y. : 93% 5 y.: 83% LR relapse free survival 2 y. : 100 % 5 y. : 53% Photons +/Associated CT R1 Overall survival 2 y. : 84% 5 y. : 46%

LR relapse free survival 2 y. : 55% 5 y. : 32% Retroperitonal STS Proposition Post-operative irradiation is not a standard treatment Improving local control is needed Non randomized Phase II for R2 or unresecable tumor. Osteosarcoma, Chondrosarcoma (Limbs or Sacrum): 1635 identified references 11 analysed in the final document 1635 References 114 selectionnated 1521 Exclusions (abstract): Langage No indication about treatment Review: Nb of pts < 10 Publication before 1970

103 Exclusions (article): No clinical data Resection R0 No RTE RTE < 50 Gy Nb < 10 pts No indication about treatment 11 definitively selectionnated Chondrosarcoma R2 or unresecable Bubach Munzenrider 1990 N=18 1999 Spine N=17 Treatment Toxicity Neutrons 16 nGy

29% Protons 66-83 CGE OS LC DFS LC 3y:61%(35-82%) DFS 3y:33%(13-59%) OS 3y: 50%(26-74%) LC 4y : 54% OS 5y : 48% R2 or unresecable Osteosarcoma Treatment 1995 Osteo n=15 Hug Protons Osteosarcoma 69.8 CGE + Chemotherapy Toxicity 8.6% 1984 Cohen

Neutrons 18-26 32% Carbon Ions 52.8 GyE-57,6 GyE + chemotherapy 6 grade 3 Osteo n=16 Kamada 2002 osteosarcoma N=15 OS LC DFS Osteosarcoma OS 3.2y :53% (27-79%) LC 3.2y : 73% (12-92%) Osteosarcoma OS 4y : 11% (0.3-48%) LC 4y : 22% (3-60%) Osteosarcoma OS 3y 45% (7-83%) LC3y 73% (44-99%) R2 or Unresectable Osteosarcoma and

Chondrosarcoma: Proposition Phase II Stratification according to histology and tumor grade Unresecable tumor or recurrence with oligo metastasis can be treated in this group Chordoma of the skull base, Chondrosarcoma of the Skull base: 1077 identified references 19 analysed in the final document 1077 References 119 selectionnated 958 Exclusions (abstract): Language No indication about treatment Review: Nb of pts < 10 Publication before 1970 100 Exclusions (article): No clinical data Resection R0 No RTE RTE < 50 Gy Nb < 10 pts No indication

about treatment 19 definitively selectionnated Skull Base Chordoma TREATMENT Toxicity OS LC DFS Munzenrider 1999 N=290 Protons 66-83 CGE OS 5y :80% LC 5y :73% Noel 2003 N=47 Protons 67 CGE 49%

Hug 1999 N=47 Protons: 66-79 CGE 20% OS 5y: 79% LC 5y: 59% SchulzErtner 2004 N=44 Carbon: 60 GyE 13% OS 3y: 91% LC 3y: 81% OS 4 y:88% (78%-98%) LC 3 y:71% (54%-88%) Skull Base Chondrosarcoma TREATMENT Munzenrider MGH Noel

Orsay Hug 1999 N=229 Protons 66-83 CGE LC 5y: 98% OS 5 y: 91% 2003 n=18 Protons 67 CGE LC 3y: 85% (66-99%) Os 4y: 75% (58-92%) 1999 N=25 Protons 66-79 CGE OS 5y: 100% LC 5y:75 % Chordoma (Spine or Sacrum)

TREATMENT Breteau Orleans 1998 N=12 Munzenrider 1999 N=85 Photons 40 Gy Neutrons 15-25 Protons 66-83 CGE OS LC DFS LC 4y: 61% OS 4y: 54 % LC 5y: 69% OS 5y: 80% Skull of base Chordoma and Chondrosarcoma Skull Base Chordoma

Encouraging Local Control Phase II randomized Study: Proton/Carbon Skull Base Chondrosarcoma Association surgery and protontherapy Excellent results This is not an indication for Carbon ions Excepted for large tumor volume Summary Difficulty to assess the efficiency of standard treatments to be compared with carbon ions Small studies Few homogenous series of patients treated with adequate doses of radiation therapy

Survival data not reported by subgroup of treatments Indications Interest Evaluation STS R1 Excepted retroperitoneal A Phase II STS R2 MO M+ Excepted retroperitoneal A Phase II Retroperitoneal R2 unresecable Phase II

A Osteosarcoma Chondrosarcoma M0/M+ R2 unresecable Limbs Others Phase II A Chondrosarcoma Skull base B Proton Chordoma Skull base A Protons vs Carbon Chordoma Sacrum

Protons vs Carbon A Physic rationnal Pic de Bragg Protons, light ions Pic de Bragg tal Projet mdical Hadronthrapie Objectif: projet mdical franais et europen* commun pour lhadronthrapie (protons carbone) Principes: Multidisciplinarit (oncologues , chirurgiens, spcialistes dorganes, anapaths, pidmiologistes, ..) Fonde sur une analyse rigoureuse de la littrature et lavis dexperts indpendants * ENLIGHT ERANET Schema of the analysis of literatture To do the synthesis of literature in selectionnated situations

To define the survival and local control expected when the best treatment is used This is not an exhaustive review of litterature To present this document to a group of experts Validation of the potential indications Stratification of those indications To define the modality of evaluation List of clinical situations to be evaluated Report sudmitted to a group of experts Studies research : type of tumors type of treatments charateristic of studies Medline Cochrane data base institutionnal web sites Reference manager Selection of

studies -summary -integral text Document Definitive list of potential indications

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