Indicazioni,*dosi*e*volumi*clinici*in* radioterapia ...
Transcript of Indicazioni,*dosi*e*volumi*clinici*in* radioterapia ...
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Indicazioni,*dosi*e*volumi*clinici*in*radioterapia*onco4ematologica:**
stato*dell’arte.*
Andrea'Riccardo'Filippi''
Dipar0mento'di'Oncologia'Università'di'Torino'
XXIV Congresso Nazionale AIRO 2014 Padova, 8-11 Novembre
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DICHIARAZIONE
Relatore ANDREA RICCARDO FILIPPI
Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario.
• Posizione di dipendente in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE / NOME
AZIENDA)
• Consulenza ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE / NOME AZIENDA)
• Fondi per la ricerca da aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE / NOME
AZIENDA)
• Partecipazione ad Advisory Board (NIENTE DA DICHIARARE / NOME AZIENDA)
• Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario (NIENTE DA
DICHIARARE / NOME AZIENDA)
• Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE / NOME
AZIENDA)
• Altro
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Role'of'radia0on,'volumes'and'techniques'for:'
• Early'Stage'Hodgkin’s'Lymphoma'• Early'Stage'Diffuse'Large'BJCell'Lymphomas'• Early'Stage'Follicular'Lymphomas'
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Early'Stage'HL'
• Is'Chemotherapy'alone'an'op0on?'• Radia0on'Volumes'and'Technique'• Could'FDGJPET'result'aQer'chemotherapy'guide'the'treatment'strategy?'
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GHSG* EORTC* NCIC*and*ECOG* Stanford*
Risk*factors**
a)'Large'medias0nal'mass'b)'Extranodal'disease'c)' ESR' ≥' 50' without' BJsymptoms' or' ≥30' with' BJsymptoms'd)'≥'3'nodal'areas'
a)' Large' medias0nal'mass'b)'Age'≥50'years'c)' ESR' ≥' 50'without' BJsymptoms'or'≥'30'with'BJsymptoms'd)'≥'4'nodal'areas'
a)' Histology' other' than'LP/NS'b)'Age'≥'40'years'c)'ESR'≥'50'd)'≥'4'nodal'areas''
a)'BJsymptoms'b)' Large' medias0nal'
mass'
Favourable**
CS'IJII'without'risk'factors' CS' IJII' without' risk'factors'
CS'IJII'without'risk'factors''
CS' IJII' without' risk'factors'
Unfavourable**
CS' I' or' CS' IIA' with' ≥' 1' risk'factors'CS' IIB' with' c)' or' d)' but'without'a)'and'b)'
CS' IJII' with' ≥' 1' risk'factors'
CS'IJII'with'≥'1'risk'factors' CS' IJII' with' ≥' 1' risk'factors'
Early'stage'Hodgkin'lymphoma:'risk'factors'
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HD10'Trial'Design'
Engert A et al, N Engl J Med 2010
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ABVD'x'2'plus'IFRT'20'Gy'is'the'golden'standard'for'favorable'HL'
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With'4'cycles'of'BEACOPP,'IFRT'30'Gy'and'IFRT'20'Gy'are'equivalent'
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Pahrik et al, Oral Presentation, ASTRO 2014
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Pahrik et al, Oral Presentation, ASTRO 2014
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Pahrik et al, Oral Presentation, ASTRO 2014
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Chemotherapy'alone'for'early'stage'HL'
• No'randomized'data'comparing'CT'alone'with'modern'CMT'
• Could'the'benefit'for'CMT'be'offset'by'longJterm'mortality'even'with'modern'RT?'
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Extended fields
INRT/ISRT
MOPP
ABVD
DFT≈40 Gy
DFT≈20 Gy
1960
now
Involved fields
DFT≈30 Gy
Timeline of major changes in RT in early stage HL
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The'concepts'of'INRT'and'ISRT'
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INRT'Guidelines'
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GTV'on'preJchemotherapy'CT'
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GTV'on'preJchemotherapy'PET'
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Fusion'between'preJchemotherapy'PET/CT'and'planning'CT''GTVCT'and'GTVPET'import''Modifica0on'according'to'response''INRT*
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“InvolvedJSite”'Radiotherapy'
Specht'et'al,'IJROBP'2013'
• 'The'concept'of'ISRT'was'developed'on'the'basis'of'the'INRT'concept'• 'The'irradiated'volume'is'significantly'smaller'than'with'IFRT'• 'If'prechemotherapy'imaging'is'available,'but'image'fusion'with'the'postchemotherapy'planning'CT'scan'is'not'possible''ISRT*• 'If'no'prechemotherapy'imaging'is'available''IFRT*
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“InvolvedJSite”'Radiotherapy'(ISRT)'
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INRT'vs'ISRT'
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ISRT'is'substan0ally'smaller'than'IFRT!'
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Do'we'have'clinical'data'on'safety'and'efficacy'of'INRT/ISRT?'
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Campbell'et'al,'JCO'2008'
INRT'vs.'IFRT'vs.'EFRT'
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Maraldo'et'al,'IJROBP'2012'
Combined'Modality'Therapy'with'INRT''
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Filippi,'Ciammella'et'al,'IJROBP'2014'
Clinical'data'on'ISRT'with'either'3D'or'IMRT'
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ISRT'with'IMRT'vs.'ISRT'with'3DJCRT'
Filippi,'Ciammella'et'al,'IJROBP'2014'
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Early'Stage'HL'
• Is'Chemotherapy'alone'an'op0on?'• May'PET'findings'aQer'chemotherapy'guide'treatment'strategy?'
• Future?'
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Trials*tesGng*the*capacity*of*FDG4PET*scanning*to*guide*therapy*for*early4stage*Hodgkin*lymphoma.*
Johnson*P*W*M*Hematology*2013;2013:4004405*©2013'by'American'Society'of'Hematology'
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Favorable PET-negative: 85.8% Unfavorable PET-negative: 74.8%
Raemakers et al, JCO 2013
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Early*stage*IA*or*IIA,*no*bulky,*no*B*symptoms*
NCRI'RAPID'–'trial'design'
Ini0al'treatment:'ABVD*x*3*ReJassessment:'if'no'response,'pa0ent'goes'off'study'
'''''''''''''if'remission,'PET'scan'performed'
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2003*–*2010*!*602*paGents*(321*male,*281*female)*
571*paGents*had*a*PET*scan:*
J 'Nega0ve'(Deauville�s'score'1'or'2):'426*paGents*(74.6%)*'420'pa0ents'randomised'RT'vs'observa0on'
J 'Posi0ve'(Deauville�s'score'3'or'4'or'5):'145*paGents*(25.4%)'
Median*follow4up*Gme:'48'months'
34year*PFS:*
J 'IFRT'arm'94.5%*
J 'No'Further'Treatment'arm'90.8%*
J 'non'randomised'PET'+'pa0ents:'86.2%'
NCRI'RAPID'–'results'
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EORTC*H10*A'difference'in'PFS'of'5%'was'considered'unacceptable'(cri0cs'to'the'trial'design?)'
RAPID*trial*A'difference'in'PFS'of'7%'was'considered'acceptable'Same'OS'and'most'pa0ents'receiving'standard'salvage'therapy'(no'ASCT):'but'more'events'are'needed'to'fully'confirm'these'data'
NCRI'RAPID'and'EORTCJGELAJFIL'H10'2'trials'with'similar'results'but'different'interpreta0ons''
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Swerdlow et al, J Clin Oncol 2012
AgeJatJtreatment'has'a'strong'impact'on'breast'cancer'risk'in'female'HL'survivors'
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ADCETRIS, Seattle Genetics-Millenium Takeda
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Maximum*percent*reducGon*in*the*sum*of*the*product*of*diameters*in*individual*paGents*(n*=*98)*per*Cheson*et*al.12*Tumor*size*reducGons*were*observed*in*96*(94%)*of*102*paGents.**
Younes*A*et*al.*JCO*2012;30:218342189*
©2012'by'American'Society'of'Clinical'Oncology'
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BREACH'STUDY'
Allocation 2:1
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PotenGal*Phase*III*trial**for*early4stage*favorable*HL'
cHL*in*CS*I/II*without*RF*
Age*18*4*75*
2*x*ABVD* 4*x*1.8*mg*BV*
20*Gy*IS4RT* 20*Gy*IS4RT*
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HighlyJConformal'Techniques'for'early'stage'HL?'
The fear for low doses….
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Maraldo MV et al, Ann Oncol 2013
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Maraldo'MV'et'al,'ILROG'Centers,'ASTRO'2014''
What are we thinking about when we think IMRT in HL?
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Fiandra et al, Rad Oncol 2012
Different planning solutions for mediastinal HL, including optimzed VMAT
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Op0mized'(burerfly)'VMAT'
vs.'3DJCRT'
Fillippi AR et al, submitted
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PaGents’*characterisGcs*Characteristic n % No. of patients 38 Age (y)
Range Mean
15 – 43
30
Sex Male Female
13 25
34.2 65.8
Ann Arbor Stage I II
8
30
21.1 78.9
Bulky 8 21.1 EORTC prognostic groups
Favorable Unfavorable
21 17
55.3 44.7
Involved sites Mediastinum alone Mediastinum and unilateral neck Mediastinum and bilateral neck
8
19 11
21.1 50
28.9
Fillippi AR et al, submitted
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Fillippi AR et al, submitted
Absolute Excess Risk of Heart Diseases
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Fillippi AR et al, submitted
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Fillippi AR et al, submitted
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Brodin'P'et'al,'IJROBP'2013'
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From Specht & ILROG Steering Committee , ASTRO 2014
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Radia0on'Therapy'in'early'stage'DLBCL?'
'• “Classic”'trials'inves0ga0ng'the'role'of'CMT'in'DLBCL'(some'of'
them'with'risk'stra0fica0on)'
• Trials'inves0ga0ng'the'role'of'CMT'in'DLBCL'in'the'Rituximab'era'
• Data'on'the'role'of'RT'from'systema0c'reviews,'retrospec0ve'analysis'and'epidemiologic'registry''
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UNIVERSITA� DEGLI STUDI DI TORINO
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UNIVERSITA� DEGLI STUDI DI TORINO
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UNIVERSITA� DEGLI STUDI DI TORINO
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UNIVERSITA� DEGLI STUDI DI TORINO
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3 R-CHOP + RT compared with an historical group of 3 CHOP + RT
Persky et all, J Clin Oncol 2008
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Modern,'berer'targeted,'safer'and'lowerJdosage'consolida0ve'RT'
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Lowry et al, Radiother Oncol 2011
40-45 Gy vs 30 Gy
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Leukemia&Lymphoma*2013*
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Why'Radia0on'Therapy'for'Early'Stage'FL?''
• 'Indolent'BJcells'lymphomas'are'highly'radiosensi0ve'
• 'Local'recurrences'are'unusual'• 'Low'toxicity,'high'feasibility'• 'Possibility'to'cure'a'significant'propor0on'of'pa0ents'
'
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Historical'data'
Hoppe'RT,'Best'Pract'Res'Clin'Hematol'2011'
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LongJterm'outcome:'SEER'data'
• '6568'pts'with'stage'IJII'follicular'lymphoma'diagnosed'between'1973'and'2004'
• '2222'pts'(34%)'treated'with'upfront''RT'
Pugh'et'al,'Cancer,'2010'
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Pugh'et'al,'Cancer,'2010'
LongJterm'outcome:'SEER'data'
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Lymphocare'study'
Friedberg'et'al,'JCO,'2012'
• '471'pts'with'stage'I'follicular'lymphoma'
• '206'pts'rigorously'staged'(bone'marrow'aspirate'and'biopsy'and'an'imaging'study'–'CT,'PET'or'both)''
• 'Treatment:*
'RJchemo'28%'
'RT'27%' 'observa0on'17%' 'systemic'therapy'+'RT'13%'
'rituximab'monotherapy'12%'
'other'3%'
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Friedberg'et'al,'JCO,'2012'
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Median'followJup'0me:'5.6'years'
Lowry'L,'Radiother'Oncol'2011'
Reduced'RT'dose'40'Gy'vs'24'Gy':'a'phase'III'randomized'trial'
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Hoskin'et'al,'Lancet'Oncol,'2014'
614*sites*in*548*pts*with*FL*and*some*with*MZL*
Random'to'24'Gy'(299'sites)'and'4'Gy'(315'sites)'
Median'followJup'0me:'26'months'
Reduced'RT'dose'in'NHL'FORT'trial:'4'Gy'vs.'24'Gy'
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Hoskin'et'al,'Lancet'Oncol,'2014'
Reduced'RT'dose'in'NHL'FORT'trial:'4'Gy'vs'24'Gy'
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Campbell'et'al,'Cancer,'2010'
Median'followJup'0me:'7.5'years'
“Regional”'RT'vs'Involved'Nodal'RT≤5cm'
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“Regional”'RT'vs'INRT≤5cm'
Campbell'et'al,'Cancer,'2010'
PFS*
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Illidge'et'al,'IJROBP,'2014'
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UNIVERSITA’'DEGLI'STUDI'DI'TORINO'
• M.'L.,'43'years'old,'follicular'NHL'IA'
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How'to'improve'results?''
Pugh'et'al,'Cancer'2010'
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Guckenberger'et'al,'Radiat'Oncol,'2012'
EFRT/TNI'does'not'protect'from'relapses'
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RituximabJRadiotherapy'Combina0on'
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Ruella'M,'Fillippi'AR'et'al,'under'submission'
RituximabJRT:'caseJcontrol'study'(PI:'C.'Tarella,'L.'Devizzi,'A.M.'Gianni)'
Weekly*Rituximab*X*4*followed*by*IFRT*
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RITUXIMAB 375 mg/sm i.v. IF-RT
Follow Up
1 8 15
stage I-II non
bulky FL 22 day 50-57
BM PCR
BM PCR
BM PCR
Ruella'M,'Fillippi'AR'et'al,'under'submission'
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A B
Y e a r s
Pe
rce
nt
su
rviv
al
0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0P F S R T
P F S R i t - R T
p<0.05
Ruella'M,'Fillippi'AR'et'al,'under'submission'
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12
43
5
76
89
10 11 12 13 14 15 16 17 18 19 20 21 22
23 24 25 26 27 28 29 30 31 32 33
34 35 36 37
39 40 41 42 43
= bcl-2/IgH negative
= bcl-2/IgH positive
= IgH negative = IgH positive
N/A = not available probe
Diagnosis Post RIT-RT
Last FU Diagnosis Post RIT-RT
Last FU
N/A
N/A
N/A N/A N/A N/A
N/A N/A N/A N/A
N/A N/A N/A
N/A N/A N/A
N/A N/A N/A N/A N/A N/A N/A
= Relapse
N/A
N/A N/A N/A N/A N/A N/A
N/A N/A N/A
N/A
N/A
N/A N/A N/A N/A N/A
N/A
N/A N/A N/A
N/A N/A N/A
N/A N/A
N/A N/A
N/A N/A
N/A N/A N/A N/A
N/A N/A
UPN#
UPN#
38
A 3
Ruella'M,'Fillippi'AR'et'al,'under'submission'
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B
Y e a r s
Pe
rce
nt
su
rviv
al
0 5 1 0 1 5
0
2 0
4 0
6 0
8 0
1 0 0P C R -
P C R +
Ruella'M,'Fillippi'AR'et'al,'under'submission'
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WitzensJHarig'et'al,'BMC'Cancer,'2011''
Rituximab'and'RT:'Phase'II'MIR'trial'
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FLOW CHART
FLStageI / II
Bcl-2 local Bcl-2 Bcl-2PB-BM radiotherapy PB-BM PB-BM
30Gy q 6 months
stopneg
pos
neg
pos anti-CD20(ofatumumab)
x 8
*
*
* In case of conversion from neg to pos anti-CD20 (ofatumumab) x 8
�MIRO’�'study'(Molecularly'ImmunoJRadiotherapy'Oriented)'
INRT'24'Gy'
Courtesy'A.'Pulsoni,'FIL'Follicular'Lymphoma'Group'
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• RT'may'cure'a'propor0on'of'pa0ents,'however'prospec0ve'data'are'lacking'on'its'role'vs.'other'op0ons'
• Discrepancy'between'guidelines'and'“real'life”'• LowJdose/smaller'fields'are'now'widely'accepted'as'the'
standard'• The'addi0on'of'Rituximab'may'prolong'PFS'and'probably'
increase'curability'rate'• Treatment'choice'should'be'individualized'
Considera0ons'on'the'role'of'RT'in'FL'