potential indications of hadrontherapy in the sarcomas analysis of the literature
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POTENTIAL INDICATIONS OF POTENTIAL INDICATIONS OF HADRONTHERAPY IN THE SARCOMAS HADRONTHERAPY IN THE SARCOMAS
ANALYSIS OF THE LITERATUREANALYSIS OF THE LITERATURE
Dr Marie Pierre SUNYACH Dr Marie Pierre SUNYACH Dr Pascal POMMIER Dr Pascal POMMIER Centre Léon BérardCentre Léon Bérard
Dr Emmanuel AMSELLEM Dr Emmanuel AMSELLEM Faculté LaënnecFaculté Laënnec
Lyon, FranceLyon, France
Carbon Ions - PerspectiveCarbon Ions - Perspective
RationnalRationnal BalisticBalistic
Bragg peakBragg peak
BiologicalBiological 2 to 3 times 2 to 3 times
more more efficient than efficient than photonphoton
From GSI, Darmstadt, Germany
Hadrontherapy Centers (Carbon Ions)Hadrontherapy Centers (Carbon Ions) Existing CentersExisting Centers
1994: National Institute for Radiological Science (Japan)1994: National Institute for Radiological Science (Japan) 1997: GSI, Darmstadt (Germany) 1997: GSI, Darmstadt (Germany) 2001: Hyogo Ion Beam Medical Center (Japan)2001: Hyogo Ion Beam Medical Center (Japan)
In development (Europe)In development (Europe) GermanyGermany (Heidelberg) (Heidelberg) Italia Italia (CNAO – TERA, Pavi)(CNAO – TERA, Pavi) Austria (Austria (Medaustron, Baden –Vienna)Medaustron, Baden –Vienna) France France (ETOILE, Lyon)(ETOILE, Lyon)
The Medical ProjectThe Medical Project
The «The « medical projectmedical project » » Determine the potential indications of
carbon ions.
FFirst tumor types studied irst tumor types studied Head and neck Sarcoma Glioma
ObjectivesObjectives
To define the situations in which an increased dose To define the situations in which an increased dose (using carbon ions) could be efficient(using carbon ions) could be efficient
To define the survival and local control expected To define the survival and local control expected when the « best treatment » is usedwhen the « best treatment » is used
To evaluate the risk of toxicitiesTo evaluate the risk of toxicities
This is not an exhaustive review of litteratureThis is not an exhaustive review of litterature
DefinitionDefinition of of the the best treatmentbest treatment
Established treatments Treatments assessed by randomized studies
Standard treatments Treatment established by consensus
Innovative treatments Treatments with no validation
No Established treatments for those indications
Local Working Groups
Screening of all topographies and histologies to identify a priori any
potential indication for Hadrontherapy
“Evidence based medicine” approach (methodologists)
screening and analysis of all relevant literature (HT & conc. Therapies)
“Epidemiological landscape” Cancer registry (FRANCIM) and
“One day survey” in French radiation oncology departments
Clinical Trial n° 1 for hadronthérapie
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A portfolio of multicenter clinical trials
2002 - 2003
2003 – 2006
Organ ICD-O2 Localisation Further criteria selection Current tretament; graduated list of concurrent treatment to carbon
Eye, Brain & CNS C70 Meningioma
(all localisations) Inoperable begnin meningiomaPhotons;
IMRT, Protons
Eye, Brain & CNS
C70 Meningioma(all localisations)
Begnin menigioma with risks of surgical sequelae
Photons;IMRT, Protons
Eye, Brain & CNS C70 Meningioma
(all localisations) Malignant meningioma Gr 2-3Photons;
IMRT, Protons
Eye, Brain & CNS C72 Neurinoma Inoperable
Photons;IMRT, Protons
Eye, Brain & CNS C72 Neurinoma Risks of surgical sequelae++
Photons;IMRT, Protons
Eye, Brain & CNS C71
Low grade glioma(3) with bad pronostic :
40 year old, voluminous tumor, symptoms,
inoperable
1st
step : pos t RT tumor relapse with progress ion under
chemotherapy
Photons;
Protons (8)
Eye, Brain & CNS C71
Low grade glioma(3) with bad pronostic :
40 year old, voluminous tumor, symptoms,
inoperable
2nd step : inoperable tumor not previous ly irradiated and
progressive under chemotherapy
Photons;
Protons (8)
Eye, Brain & CNS C71
Low grade glioma(3) with bad pronostic :
40 year old, voluminous tumor, symptoms,
inoperable
3rd s tep : post-operative RTPhotons;
Protons (8)
Eye, Brain & CNS
C71 Glioblastoma1s t step : pos t RT tumor relapse
with progress ion under chemotherapy
Photons;Chemoradiotherapy
The potential indications tables• Indications (topo, stage, pathology..)• Standard and concurrent therapies
International experts
- Validation of the indications for HT (P. and/or C)- Estimation of the therapeutic gain & priorities- Prospective trials
2003 – 2006
Table of potential indicationsTable of potential indicationsLocalisationsLocalisations TreatmentsTreatments
STSSTS R2 M0R2 M0InoperableInoperable
AxialAxiallimblimb
NeutronsNeutrons
STSSTS R1M0R1M0 AxialAxiallimblimb
PhotonsPhotons
STSSTS R1 R2R1 R2 RetroperitonealRetroperitoneal Photons ProtonsPhotons ProtonsCarbon ionsCarbon ions
SurgerySurgery
OsteosarcomaOsteosarcomachondrosarcomachondrosarcoma
InoperableInoperableR2R2
LimbsLimbs Neutrons+chemotherapyNeutrons+chemotherapyPhotons+chemotherapyPhotons+chemotherapy
Carbon IonsCarbon Ions
OsteosarcomaOsteosarcomaChondrosarcomaChondrosarcoma
R2R2inoperableinoperable
Others than limbsOthers than limbs Neutrons+chemotherapyNeutrons+chemotherapyPhotons+chemotherapyPhotons+chemotherapy
Carbon IonsCarbon IonsProtonsProtons
ChordomaChordoma Skull base cervicalSkull base cervical ProtonsProtons
ChordomaChordoma SacrumSacrum ProtonsProtons
ChondrosarcomaChondrosarcoma Skull base cervicalSkull base cervical ProtonsProtons
chondrosarcomachondrosarcoma Lombar sacrumLombar sacrum Protons NeutronsProtons Neutrons
PlanPlan
Soft tissue sarcoma R1 and R2Soft tissue sarcoma R1 and R2
Osteosarcoma and ChondrosarcomaOsteosarcoma and Chondrosarcoma
Skull base Chondrosarcoma and Skull base Chondrosarcoma and ChordomaChordoma
STS: 1524 identified references STS: 1524 identified references 21 analysed in the final document 21 analysed in the final document
1524 References
1389 Exclusions (abstract) : •Language•No indication about treatments•Review:Nb of pts < 10•Publication before 1970•Children•Animals•Resction R0
135 selectionnated
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)STS R1 (extremity or axial)
TREATMENT TREATMENT ToxicityToxicityOS OS LCLC
DFSDFSZagarsZagars 20032003
N=254N=254Photons:Photons:
Med Doses: 64 GyMed Doses: 64 GyNo No
informationinformationLC 10y:73%(67%-79%)LC 10y:73%(67%-79%)DFS 10y:49%(43-56%)DFS 10y:49%(43-56%)
Schmitt GSchmitt G 19891989N=104N=104
Photons 40 GyPhotons 40 GyNeutrons 6.3nGyNeutrons 6.3nGy
No No informationinformation
LC 5y:77%(68-85%)LC 5y:77%(68-85%)DFS 5y:65%(55-74%)DFS 5y:65%(55-74%)
STS R1: propositionSTS R1: proposition
R1 definitive and never resectableR1 definitive and never resectable Hadrontherapy will not replaced good surgeryHadrontherapy will not replaced good surgery
Objective of Carbon IonsObjective of Carbon Ions To decrease local recurrence To decrease local recurrence to near 0 %to near 0 %
Non randomized phase II Non randomized phase II
STS R2 / unresecable (extremity /axial)STS R2 / unresecable (extremity /axial)
AuthorsAuthors YearsYears TreatmentTreatment ToxicityToxicity OS OS LCLC
DFSDFS
SchwartzSchwartz 20012001
N=41N=41
NeutronsNeutrons4.8-22 nGy4.8-22 nGy+/- Photons+/- Photons10-60 Gy10-60 Gy
15% late severe 15% late severe toxicitytoxicity
LC 4y : 61%LC 4y : 61%DFS4y: 59%DFS4y: 59%OS 4y: 66%OS 4y: 66%
SchmittSchmitt 19891989N=94N=94
NeutronsNeutrons16.8 nGy16.8 nGy
No informationNo information LC 5y : 56%(45-66%)LC 5y : 56%(45-66%)DFS 5y:25.5%(17-35%)DFS 5y:25.5%(17-35%)
KamadaKamada 20022002N=57N=57
Carbon ionsCarbon ions52.3 Gy52.3 Gy57.6 Gy57.6 Gy
6/57 6/57 LC 3y:73%(48-98%)LC 3y:73%(48-98%)OS 3y:46%(26-66%)OS 3y:46%(26-66%)
DFS 3y:36%(24-50 %)DFS 3y:36%(24-50 %)
STS R2 or unresecable propositionSTS R2 or unresecable proposition R2 definitive and never resecableR2 definitive and never resecable
Hadrontherapy will not replaced good surgeryHadrontherapy will not replaced good surgery
Non randomized phase II trial Non randomized phase II trial
Photontherapy :Photontherapy : LC 10 %LC 10 %
Neutrontherapy :Neutrontherapy : LC 60% LC 60%
Objective : at least 50% local control with few Objective : at least 50% local control with few toxicitiestoxicities
Unresecable tumor or recurrence with oligo Unresecable tumor or recurrence with oligo metastasis can be treated in this groupmetastasis can be treated in this group
RetroperitonalRetroperitonal STSSTS
Gilbeau Gilbeau TREATMENTTREATMENT OSOSLCLC
Photons Photons +/- +/-
AssociatedAssociatedCTCT
R0R0 Overall survival Overall survival 2 y. : 93%2 y. : 93% 5 y.: 83%5 y.: 83%
LR relapse free survivalLR relapse free survival2 y. : 100 %2 y. : 100 % 5 y. : 53%5 y. : 53%
Photons Photons +/- +/-
AssociatedAssociatedCTCT
R1R1 Overall survival Overall survival 2 y. : 84%2 y. : 84%5 y. : 46% 5 y. : 46%
LR relapse free survival LR relapse free survival 2 y. : 55%2 y. : 55%5 y. : 32%5 y. : 32%
Retroperitonal STSRetroperitonal STSPropositionProposition
Post-operative irradiation is not a standard Post-operative irradiation is not a standard treatmenttreatment
Improving local control is neededImproving local control is needed
Non randomized Phase II for R2 or Non randomized Phase II for R2 or unresecable tumor.unresecable tumor.
Osteosarcoma, Chondrosarcoma (Limbs or Sacrum):Osteosarcoma, Chondrosarcoma (Limbs or Sacrum):1635 identified references 1635 identified references
11 analysed in the final document 11 analysed in the final document
1635 References
1521 Exclusions (abstract): •Langage•No indication about treatment•Review: Nb of pts < 10•Publication before 1970
114 selectionnated
103 Exclusions (article): •No clinical data•Resection R0•No RTE•RTE < 50 Gy•Nb < 10 pts•No indication about treatment
11 definitively selectionnated
Chondrosarcoma Chondrosarcoma R2 or unresecable R2 or unresecable
TreatmentTreatment ToxicityToxicityOS OS LCLC
DFSDFS
BubachBubach 19901990N=18N=18
NeutronsNeutrons 16 nGy16 nGy
29%29% LC 3y:61%(35-82%)LC 3y:61%(35-82%)DFS 3y:33%(13-59%)DFS 3y:33%(13-59%)OS 3y: 50%(26-74%) OS 3y: 50%(26-74%)
MunzenriderMunzenrider19991999SpineSpineN=17N=17
Protons Protons 66-83 66-83 CGECGE
LC 4y : 54%LC 4y : 54%OS 5y : 48%OS 5y : 48%
R2 or unresecable Osteosarcoma R2 or unresecable Osteosarcoma
TreatmentTreatment ToxicityToxicity OS OS LCLC
DFSDFS
HugHug
19951995Osteo n=15Osteo n=15
ProtonsProtonsOsteosarcomaOsteosarcoma
69.8 CGE69.8 CGE+ Chemotherapy+ Chemotherapy
8.6%8.6%
OsteosarcomaOsteosarcomaOS 3.2y :53% (27-79%)OS 3.2y :53% (27-79%)LC 3.2y : 73% (12-92%)LC 3.2y : 73% (12-92%)
CohenCohen19841984
Osteo n=16Osteo n=16Neutrons 18-26Neutrons 18-26 32%32%
OsteosarcomaOsteosarcomaOS 4y : 11% (0.3-48%)OS 4y : 11% (0.3-48%)LC 4y : 22% (3-60%)LC 4y : 22% (3-60%)
KamadaKamada 20022002osteosarcomaosteosarcoma
N=15N=15
Carbon IonsCarbon Ions52.8 GyE-57,6 52.8 GyE-57,6
GyEGyE+ chemotherapy+ chemotherapy
6 grade 36 grade 3 Osteosarcoma Osteosarcoma OS 3y 45%OS 3y 45% (7-83%)(7-83%)LC3y 73%LC3y 73% (44-99%)(44-99%)
R2 or Unresectable R2 or Unresectable Osteosarcoma and Osteosarcoma and ChondrosarcomaChondrosarcoma: : PropositionProposition
Phase II Stratification according to histology and Phase II Stratification according to histology and tumor gradetumor grade
Unresecable tumor or recurrence with oligo metastasis can Unresecable tumor or recurrence with oligo metastasis can be treated in this groupbe treated in this group
Chordoma of the skull base, Chondrosarcoma of the Skull Chordoma of the skull base, Chondrosarcoma of the Skull base:base:
1077 identified references 1077 identified references 19 analysed in the final document 19 analysed in the final document
1077 References
958 Exclusions (abstract): •Language•No indication about treatment•Review: Nb of pts < 10•Publication before 1970
119 selectionnated
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 ChordomaSkull Base Chordoma
TREATMENTTREATMENT Toxicity Toxicity OS OS LCLC
DFSDFSMunzenriderMunzenrider 19991999
N=290N=290Protons 66-83 CGEProtons 66-83 CGE OS 5y :80%OS 5y :80%
LC 5y :73%LC 5y :73%
NoelNoel 20032003N=47N=47
Protons 67 CGEProtons 67 CGE 49%49% OS 4 y:88% (78%-98%)OS 4 y:88% (78%-98%)LC 3 y:71% (54%-88%)LC 3 y:71% (54%-88%)
HugHug 19991999N=47N=47
Protons: 66-79 CGEProtons: 66-79 CGE 20%20% OS 5y: 79%OS 5y: 79%LC 5y: 59%LC 5y: 59%
Schulz-Schulz-ErtnerErtner
20042004N=44N=44
Carbon: 60 GyECarbon: 60 GyE 13%13% OS 3y: 91%OS 3y: 91%LC 3y: 81%LC 3y: 81%
Skull Base ChondrosarcomaSkull Base Chondrosarcoma
TREATMENTTREATMENT
MunzenriderMunzenriderMGHMGH
19991999N=229N=229
Protons Protons 66-83 CGE66-83 CGE LC 5y: 98% LC 5y: 98%
OS 5 y: 91% OS 5 y: 91%
NoelNoelOrsayOrsay
2003 2003 n=18n=18
Protons Protons 67 CGE67 CGE
LC 3y: 85% (66-99%)LC 3y: 85% (66-99%)Os 4y: 75% (58-92%)Os 4y: 75% (58-92%)
HugHug 19991999N=25N=25
ProtonsProtons66-79 CGE66-79 CGE
OS 5y: 100% OS 5y: 100% LC 5y:75 %LC 5y:75 %
Chordoma (Spine or Sacrum)Chordoma (Spine or Sacrum)
TREATMENTTREATMENT
OS OS LCLC
DFSDFS
BreteauBreteauOrleansOrleans
19981998N=12N=12
Photons 40 GyPhotons 40 GyNeutrons Neutrons
15-2515-25
LC 4y: 61%LC 4y: 61%OS 4y: 54 %OS 4y: 54 %
MunzenriderMunzenrider 19991999N=85N=85
Protons 66-83 CGEProtons 66-83 CGE LC 5y: 69%LC 5y: 69% OS 5y: 80%OS 5y: 80%
Skull of base Chordoma and ChondrosarcomaSkull of base Chordoma and Chondrosarcoma
Skull Base ChordomaSkull Base Chordoma Encouraging Local ControlEncouraging Local Control
Phase II randomized Study: Proton/CarbonPhase II randomized Study: Proton/Carbon
Skull Base ChondrosarcomaSkull Base Chondrosarcoma Association surgery and protontherapyAssociation surgery and protontherapy Excellent resultsExcellent results This is not an indication for Carbon ionsThis is not an indication for Carbon ions
Excepted for large tumor volumeExcepted for large tumor volume
SummarySummary
Difficulty to assess the efficiency of standard Difficulty to assess the efficiency of standard treatments to be compared with carbon ionstreatments to be compared with carbon ions
Small studiesSmall studies
Few Few homogenous series of patients treated with homogenous series of patients treated with adequate doses of radiation therapy adequate doses of radiation therapy
Survival data not reported by subgroup of Survival data not reported by subgroup of treatmentstreatments
IndicationsIndications InterestInterest Evaluation Evaluation
STS R1STS R1 Excepted Excepted retroperitonealretroperitoneal
AA Phase IIPhase II
STS R2 MO M+STS R2 MO M+ Excepted Excepted retroperitonealretroperitoneal
AA Phase IIPhase II
RetroperitonealRetroperitoneal R2 unresecableR2 unresecableAA
Phase IIPhase II
Osteosarcoma Osteosarcoma ChondrosarcomaChondrosarcoma
M0/M+M0/M+
R2 unresecableR2 unresecableLimbsLimbsOthersOthers
AAPhase IIPhase II
ChondrosarcomaChondrosarcoma Skull base Skull base BB ProtonProton
Chordoma Chordoma Skull base Skull base AA Protons vs CarbonProtons vs Carbon
ChordomaChordoma Sacrum Sacrum AA
Protons vs CarbonProtons vs Carbon
Physic rationnalPhysic rationnal
Pic de Bragg
Pic de Bragg étalé
Protons, light ions
Projet médical Projet médical « Hadronthérapie »« Hadronthérapie »
Objectif:Objectif: projet médical français et européen* commun pour projet médical français et européen* commun pour l’hadronthérapie (protons – carbone)l’hadronthérapie (protons – carbone)
PrincipesPrincipes::MultidisciplinaritéMultidisciplinarité (oncologues , chirurgiens, spécialistes (oncologues , chirurgiens, spécialistes d’organes, anapaths, épidémiologistes, ..)d’organes, anapaths, épidémiologistes, ..)Fondée sur une analyse rigoureuse de la littérature Fondée sur une analyse rigoureuse de la littérature et l’avis d’experts indépendantset l’avis d’experts indépendants
* ENLIGHT * ENLIGHT ERANET ERANET
Schema of the analysis of literattureSchema of the analysis of literatture
To do the synthesis of liTo do the synthesis of litterature in selectionnated erature in selectionnated situationssituations
To defineTo define the survival and local control expected when the « best the survival and local control expected when the « best treatment » is usedtreatment » is used
This is not an exhaustive review of litteratureThis is not an exhaustive review of litterature
To present this document to a group of expertTo present this document to a group of expertss
Validation of Validation of the the potential indicationpotential indicationss Stratification of those indicationsStratification of those indications To define the modality of evaluationTo define the modality of evaluation
List of clinical situations
to be evaluated
Studies research :type of tumorstype of treatmentscharateristic of studies
Medline Cochrane data base institutionnal web sites
Reference manager
Selection of studies-summary-integral text
Document
Report sudmitted to a group of experts
Definitive list of potential indications
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