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