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La strategia terapeuticaadiuvante
Giuseppe MalinverniAnnalisa Rossi
S.C. RADIOTERAPIA ONCOLOGICA
A.O “ORDINE MAURIZIANO”TORINO
RadioterapiaRadioterapia AdiuvanteAdiuvante e e TumoriTumori delldell’’EndometrioEndometrioCheChe CosaCosa SappiamoSappiamo
• L’ 80% circa è diagnosticato in stadio I, il 13% in stadio II, e la sopravvivenza globale (OS) a 5 anni è elevata, 88% nella malattia in stadio I
• Un sottogruppo di pazienti con malattia in stadio I ha una riduzione significativa della OS a 5 anni, sulla base di diversi fattori prognostici, come lo stadio IC grado 3 che ha solo il 66% di OS
Uterine Cancer Staging System5562 pts- FIGO 1988 – 5y survival
Stage I: Stage I: 8080--90%90%AA G123, limited to G123, limited to endometriumendometriumBB G123, invasion < 50% G123, invasion < 50% myometriummyometriumCC G123, invasion > 50% G123, invasion > 50% myometriummyometriumStage II: Stage II: 6565--75%75%AA G123, G123, endocervixendocervix glands onlyglands onlyBB G123, G123, endocervixendocervix stromastromaStage III: Stage III: 3030--60%60%AA G123, (+) G123, (+) serosaserosa/ / adnexaadnexa /washings/washingsBB G123, (+) vaginaG123, (+) vaginaCC G123, (+) pelvic, PAN nodesG123, (+) pelvic, PAN nodesStage IV: Stage IV: 1515--25%25%AA G123, (+) GI, GU mucosa G123, (+) GI, GU mucosa BB G123, distant G123, distant metsmets, + groin nodes, + groin nodes
Uterine Cancer Staging System. FIGO 2010FIGO Annual Report on 42.000 pts - 5y survival
Pecorelli S, Int J Gynecol Obstet 2009; 103-104
Stage I: Stage I: 7575--90% 90% (1988 80(1988 80--90%)90%)AA G123, invasion < 50% G123, invasion < 50% myometriummyometrium: : 88% 88% BB G123, invasion > 50% G123, invasion > 50% myometriummyometrium: : 75%75%Stage II: Stage II: 70% 70% (1988 65(1988 65--75%)75%)
G123, G123, endocervixendocervix stromastromaStage III: Stage III: 4545--60% 60% (1988 30(1988 30--60%)60%)AA G123, (+) G123, (+) serosaserosa/ / adnexaadnexa: : 58%58%BB G123, (+) vagina/G123, (+) vagina/parametriumparametrium: : 50%50%CC G123, (+) nodes: G123, (+) nodes: 47%47%
IIIC1: (+) pelvic nodesIIIC1: (+) pelvic nodesIIIC2: (+) PAN nodesIIIC2: (+) PAN nodes
Stage IV: Stage IV: 1515--20% 20% (1988 15(1988 15--25%)25%)AA G123, (+) GI, GU mucosa: G123, (+) GI, GU mucosa: 17%17%BB G123, distant G123, distant metsmets, + groin nodes: , + groin nodes: 15%15%
Radioterapia Adiuvante e Tumori dell’EndometrioChe Cosa Sappiamo
• Fattori prognostici di rischio per recidiva– Età
– LVSI (invasione degli spazi vascolo-linfatici)
– Profondità di invasione miometriale
– Tipo istologico
– Grado 3
– LFN
– Diametro tumorale (< 2 cm vs ≥ 2 cm)
La radioterapia pelvica è indicata negli Stadi I in presenza di almeno 2 o 3 fattori di rischio: invasione miometriale profonda (≥50% dello spessore del miometrio), grado 3, ed età ≥60 anni
712
45
33
1 0,505
101520253035404550
OssBRTVRTERTE+BRTVRTA32 P
Naumann RW et al - Gynecol Oncol 75, 1999
St. I C G3 ESSSt. I C G3 ESS
RT ADIUVANTE NEL CARCINOMA ENDOMETRIALERT ADIUVANTE NEL CARCINOMA ENDOMETRIALEQUESTIONARIO SGO QUESTIONARIO SGO -- 19991999
90 %
CARCINOMA DELLCARCINOMA DELL’’ ENDOMETRIOENDOMETRIO
FREQUENZA PER CLASSE FREQUENZA PER CLASSE DIDI RISCHIO E RISCHIO E
RISCHIO RISCHIO DIDI RECIDIVARECIDIVA
Lukka H et al - Gynecol Oncol 102: 361, 2006 (mod)
Rischio rec loc basso 2- 4%
Rischio rec locoregionale 4-20%
Rischio rec locoregionale +/- a distanza >20%
Key Questions• How to define Risk Groups in EC in order to adequately
tailor therapy?– Low risk
–– Intermediate/Low, Intermediate and Intermediate/Hig hIntermediate/Low, Intermediate and Intermediate/Hig h
– High risk
• What is the Level of evidence regarding Adjuvant Therapy?
– Level I: Randomized Control Trials
– Level II evidence: Non-randomized, retrospective data
• What have we learned from 1000’s pts enrolled in clinical trials?
Patient Selection, Type of therapy, Patient Selection, Type of therapy, Outcome, QOL, CostOutcome, QOL, Cost
RT ADIUVANTE NEL CARCINOMA RT ADIUVANTE NEL CARCINOMA ENDOMETRIALEENDOMETRIALE
– Is it there a role for EBRT or VBT in early
stage radically resected endometrial cancer?
– Is it there a role for VBT alone in low
and/or medium risk early stage endometrial cancer?
– Does VBT +/- EBRT play a significant role
in the adjuvant treatment of intermediate
and high risk endometrial cancer
CRTBT
GOG #122 - 2006
NSGO - EORTC - 2007
J - GOG - 2008
IT - CNR - 2006
ASTEC - NCIC - 2009
GOG #99 - 2004
PORTEC-2 - 2008
PORTEC-1 - 2000
Aalders - 1980
CHEB+BTEBNFT
Sorbe - 2009
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:randomized trials - Low - Intermediate Risk
IR
HR
LR
• 645 PTS• TAH+BSO +/- PLND
RANDOM
NFT
BT
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: Sorbe - 2009
• Stage– IA-B – G1-2
• endometrioid
Sorbe B et al. Int J Gynecol Cancer;19:873, 2009
LR 100%median FU 68 months Low Risk100%
n s94.7%95.1%OS
n s2.9%0.9%tox G2
n s0.3%0.9%Pel Rec
n s1.2%3.1%Vag Rec
pVBTNFT• local control improved in
BT arm, not significantly
• OS rate not different
• No G3 toxicity
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: Sorbe - 2009 Sorbe B et al. Int J Gynecol Cancer;19:873, 2009
• Results– LRR, 2.6%; distant mets 2.1%– Vaginal recurrences, 3% vs 1%– 2.8% grade 1-2 toxicity with IVB
• No benefit of adjuvant RT in the low-risk group
CRTBT
GOG #122 - 2006
NSGO - EORTC - 2007
J - GOG - 2008
IT - CNR - 2006
ASTEC - NCIC - 2009
GOG #99 - 2004
PORTEC-2 - 2008
PORTEC-1 - 2000
Aalders - 1980
CHEB+BTEBNFT
Sorbe - 2009
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - Intermediate Risk
IR
HR
LR
PORTEC: Patterns of RecurrenceCreutzberg et al, Lancet 2000; 355: 1404-1411Creutzberg et al. Gynecol Oncol 2003; 89: 201
Site of FailureSite of Failure Surgery Surgery + EBRT+ EBRT NFTNFT
LocoregionalLocoregionalfailure failure 4%4%
15%, 15%, P< 0.0001P< 0.0001
VaginaVagina 2 %2 % 10%10%
PelvisPelvis 2%2% 5%5%
Distant failureDistant failure 10%10% 6%6%
Death from ECDeath from EC
LRRLRRDistant MetsDistant Mets
10%10%
1%1%8%8%
7.5%7.5%
2%2%5%5%
NonNon --EC DeathEC Death
NonNon --ECEC22ndnd cancerscancers
14%14%5%5%
11%11%5%5%
P< 0.0001P< 0.0001
8-year Actuarial Rate
73% of the recurrenceslimited to the vagina
No RT
• 392 PTS• TAH+BSO & PLND
RANDOM
observation
EBR 50.4 Gy
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: GOG #99 - 2004
L I R66%
H I R *34%
Stage IB - IC - II (occult)
Keys HM et al. Gynecol Oncol 92:744,2004
∗ age G2 - G3 LVSI M>50%
0.0010.00114%5.5%tox >G2
0.592%86%OS
0.0010.00198%91%LC
pEBRNFT • adjunctive RT in early stage IR endometrial carcinoma decreases the risk of recurrence
• but should be limited to patients in HIR* group
• 905 PTS• TAH+BSO +/- PLND
RANDOM
NFT +/- BT
40-46 Gy EBR+/- BT
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: ASTEC - NCIC - 2009
L R1%
I R76%
H R23%
• Stage– IB G3 – IC – IIA
• endometrioid • SC/CC
Blake P. et al Lancet 373:137, 2009
over 50% in each group received IVB
Overall SurvivalOverall Survival Disease Disease –– Specific SurvivalSpecific Survival
No difference in OS or DSS with the addition of adjuvant EBRT
3% difference in the cumulative incidence of vaginal relapses –
BUT… over 50% in each group received IVB
MRC, ASTEC and NCIC CTG EN.5 TrialsLancet, 2009; 373: 137
• RTE postoperatoria non è indicata nelle pz a basso rischio
(età < a 60 anni e/o in stadio IB e con tumori G2 con
invasione superficiale)
• RTE postoperatoria riduce le recidive loco-regionali ma
non ha impatto significativo sulla sopravvivenza
• RTE postoperatoria incrementa la morbilità legata al
trattamento (14% vs 6%).
• RTE indicata nelle pazienti con alto rischio di recidiva
locale(LRR ≥ 10-15%)
What have we learned from these randomized trials regarding adjuvant therapy
in Intermediate-Risk EC patients?
Systematic review & Meta-analysisJohnson et Comes BJOG 2007; 114: 1313-20
Total 1864 pts Pelvic Total 1864 pts Pelvic recrec in EBRT 21/868 No EBRT 81/996in EBRT 21/868 No EBRT 81/996•• EBRT reduced LRR, RR 0.34 (p< 0.0001), in intermediate risk EC EBRT reduced LRR, RR 0.34 (p< 0.0001), in intermediate risk EC
with an absolute risk reduction of 5,25%with an absolute risk reduction of 5,25%–– No impact in survival from lower risk cancers or distant failureNo impact in survival from lower risk cancers or distant failuress
–– A potential survival advantage for about 10% with EBRT A potential survival advantage for about 10% with EBRT shuoldshuold be be considered in patients with multiple highconsidered in patients with multiple high--risk features, including risk features, including pStpSt 1C G31C G3
Systematic review & Meta-analysisA. Kong et al, Ann Oncol 2007; 18: 1595-1604
•• Total 1770 pts Pelvic Total 1770 pts Pelvic recrec in RT 21/870in RT 21/870 No RT 80/900No RT 80/900
•• EBRT reduced LRR, RR 0.28 (p< 0.0001), with an absolute EBRT reduced LRR, RR 0.28 (p< 0.0001), with an absolute risk reduction of 6%risk reduction of 6%–– No impact in death from all causes, ECNo impact in death from all causes, EC--deaths or distant failuresdeaths or distant failures
–– EBRT should be considered in patients with multiple highEBRT should be considered in patients with multiple high--risk features, risk features, including G3 and including G3 and pStpSt ICIC
• EBR greatly reduced locoregional recurrence, a RR
reduction of 72% (PORTEC)
• However, there is not a reduction in the risks of distan t
recurrence, death from all causes, and from EC.
• EBR has a trend toward reduction in the risks of death
from all causes and from EC for patients with multiple
high risk factors (G3 and stage Ic).
• EBR increases the risk of toxicity and should be
avoided in stage with low recurrence rate (Ia-b G1- 2 )
Kong A, et al. Cochrane Database 2007,
ADJUVANT TREATMENT OF ENDOMETRIAL CANCERCochrane review stage I - 2007
What is the role of IntracavitaryVaginal Brachytherapy Alone?
Advantages• Lower Cost• Lower Morbidity
– Minimal acute and long-term toxicity
• Patient convenience– Outpatient procedure– Limited number of
Treatments
• 95% relative reduction risk of vaginal recurrences
Disadvantages
• Does not address the pelvis
• Post-operative geometrical restrictions
• Vaginal shortening
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: PORTEC-2 - 2008
Nout RA J Clin Oncol, 26, 20S: 5503 2008
• 427 PTS• TAH+BSO no PLND
RANDOM
VBT21 Gy/3 fr
EBR 46 Gy/23 fr
I R100%
Stage • ICG1-2 - IBG3 > 60 y• IIA G1-2-3 M<50%
Primary endpoint: Vaginal Relapse Rate
Secondary: Quality of Life, Survival
PORTEC 2 trial Results
Outcome EBRT IVB P value
Vaginal Vaginal relapsesrelapses
1.9% 0.9% NS
LRRLRR 2.5% 4% NS
Pelvic Pelvic relapsesrelapses
0.6% 3.5% p = 0.03p = 0.03
Distant Distant relapsesrelapses
5.7% 6.3% NS
DFSDFS 89% 89% NS
OSOS 90% 90% NS
• Significantly decreased GI and toxicity with IVB
• Less impairment in daily activities
• Improved social functioning
• Overall, significant improvement in the QOL
QOL: EBRT QOL: EBRT vsvs IVBIVB
PORTEC 2 trial Conclusions
• Results of EBRT very comparable to EBRT in PORTEC-1
• Brachytherapy as effective as EBRT in preventing vaginal relapses and less toxic compared to EBRT
• QOL significantly better with brachytherapy
• More pelvic recurrences after brachytherapy, but mostly in combination with distant relapse (first failure 1.3 vs 0.7%)
• No differences in DFS (89%) and OS (90%)
CRTBT
GOG #122 - 2006
NSGO - EORTC - 2007
J - GOG - 2008
IT - CNR - 2006
ASTEC - NCIC - 2009
GOG #99 - 2006
PORTEC-2 - 2008
PORTEC-1 - 2000
Aalders - 1980
CHEB+BTEBNFT
Sorbe - 2009
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - High Risk
IR
HR
IT - CNR - 2006 Maggi R et al. Br J Cancer 95: 266, 2006
J-GOG - 2008 Susumu N at al. Gynecol Oncol, 108: 226,2008
NSGO - EORTC - 2007 Hogberg T et al, ASCO 2007
GOG #122 - 2006 Randall M et al. JCO 24:36, 2006
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER: randomized trials - High Risk
EBRT vs CT
EBRT vs CT
EBRT vs CRT
Conclusions of the Role of Chemotherapy in HR EC
•• NessunaNessuna conclusioneconclusione definitvadefinitva puòpuò essereessere trovatatrovata in in
considerazioneconsiderazione deidei varivari critericriteri didi inclusioneinclusione neinei trial trial
disponibilidisponibili didi RCT’sRCT’s
•• La La chemoterapiachemoterapia è è efficaceefficace solo solo nell’analisinell’analisi didi alcunialcuni
sottogruppisottogruppi didi pazientipazienti..
•• Il Il tassotasso didi ricadutaricaduta è simile a è simile a quelloquello dell EBRT (~ 15dell EBRT (~ 15--
20%) ed 20%) ed ilil 50% 50% didi questequeste è è confinataconfinata in in ambitoambito pelvicopelvico
•• SonoSono quindiquindi necessarinecessari adeguatiadeguati trial trial cliniciclinici disegnatidisegnati susu
gruppigruppi didi rischiorischio benben definitidefiniti ed ed emogeneiemogenei per per poterpoter
miglioraremigliorare l’outcomel’outcome in in questaquesta popolazionepopolazione didi pazientipazienti
PORTEC-3Concurrent and adjuvant CT vs RT alone
• N= 800 pts
• FIGO IB G3 (+) LVSI, St IC-IIA G3, St IIB, IIIA, II IC any
grade, IB-III UPSC or CCC, after TAH-BSO +/- LND
• Randomization
– Control arm: Pelvic RT
– Experimental arm: [RT+ weekly CDDP] + 4 courses
CDDP+Taxol
– Primary endpoint: OS and DFS Enrollmentongoing
La maggior parte delle recidive locoregionali sono a livello
vaginale, (soprattutto sulla cupola): Il tasso di controllo
nelle pazienti sottoposte a EBRT varia dal 40–80%
ENDOMETRIAL CANCERthe problem of the local control
OS (3yr)
Jhingran A, IJROBP, 56:1366, 2003 (modif)
ENDOMETRIAL CANCERsurvival after vaginal recurrence
La ricaduta locale ed il successivo trattamento con possibili effetti collaterali provocano ansia e elevato stress, enfatizzando la necessità di un massimo controllo locale al primo trattamento
Considerando l’alto rischio per questo tipo dipazienti con recidiva locala e/o regionale, il dato
sul controllo definitivo si attesta sul ~ 50%
Immediate vs Delayed RT?
• Probabilmente il tasso di controllocomplessivo (overall control rate) è inferiore a quello stimato [>70%]
• Le recidive con il solo solo coinvolgimentocoinvolgimento delladellamucosa mucosa vaginalevaginale, possono essere guarite nel70% dei casi con EBRT+/-IVB con unatossicità di grado 3-4 del of 5-10%
Cost-effectiveness of adjuvant RT in Intermediate Risk Endometrial cancer
N.C. Rankins et al. Gynecol Oncol, 2007; 106: 388-393
Costi ragionevoli nelle pazienti a rischio intermedio e intermedio-alto
• RTE postoperatoria incrementa la morbilitàlegata al trattamento
• Complicanze: 25% RT vs 6% no RT
– 66 % di grado 1; 2% di grado 3-4,
June 1990 Dec 1997
RT Technique
• AP-PA: 101 pts
• 3 fields: 61 pts
• Box: 176 pts
PORTEC: MorbilityCreutzberg et al, Lancet 2000; 355: 1404-1411Creutzberg et al. Gynecol Oncol 2003; 89: 201
162
EBRT in GINECOLOGIA
OTTIMIZZAZIONE DELLA RADIOTERAPIA
POSTOPERATORIA
2D ���� 3D
Vecchia Radioterapia Basata su reperi ossei
Da dimenticare !!
IJROBP 1999
Uso dell’imaging x ottimizzazione della RT
PTV
Ginecologia: planning 2D
■ 30% omissione geografica (“tecnica box”)
Kim, IJROBP, 31, 1995
■ 10% omissione geografica LL e CranialePendlebury IJROBP 1993 – Zunino IJROBP 1992
� 32 % sottodosaggio regionale
Russell IJROBP, 23, 1992
■ 45% sottodosaggio LN iliaci esterni
Bonin IJROBP, 34, 1996
A margini inadeguati
corrisponde un mancato
controllo locale
PTVPTV
Contouring su immagini TC e/o RM per evitare ….Imaging TC e RMTarget Missing !!
EBRTproblematiche
Sistemi di immobilizzazione
Quale tecnica?
R&O 2001
Supino
PronoBellyboard
Dislocazione delle anse intestinali
CARCINOMA CARCINOMA
ENDOMETRIALEENDOMETRIALE
RT PELVICA RT PELVICA
ADIUVANTE ADIUVANTE
bellybelly boardboard
Vescica Piena
Vescica Vuota
Vescica Vuota
Rischio di spostamento dell’intestino all’interno del campo di trattamento
Riduzione dei margini Riduzione dei margini
IMRT = Quale obiettivo?IMRT = Quale obiettivo?
Riduzione Volume di Riduzione Volume di
trattamentotrattamento
Risparmio OARRisparmio OAR
Modern treatment techniques IMRT
Dose escalationDose escalation
Perché IMRT in Ginecologia?
• Copertura omogenea del Target• Riduzione del volume irradiato di ileo di un
fattore 2• Riduzione del volume di retto e vescica irradiati
del 23%• Riduzione della tossicità enterica• Riduzione della tossicità midollare
Roeske: IJROBP 49, 2000Mundt: Med Dosim 27, 2002Lujan: IJROBP 57, 2003 Brixey: IJROBP 52, 2002
V95
IMRTBOX
↓ tossicità enterica
Roeske: IJROBP 49, 2000 - IJROBP 56, 2003
• ↓↓↓↓ dell’uso della richiesta di farmaci dal 75 % nel gr uppo
RT convenzionale al 34 % con IMRT (p= 0.001)
↓ Tossicità midollare
• ↓ midollo osseo irradiato (- 40%)• ↑ tolleranza ematologica CT concomitante
Lujan AE et al.: IJROBP 57, 2003 Brixey IJROBP 52, 2002
SIB ipofrazionato
adjuvant RT improves the LC in IR with toxicity
EBRT is better than BT in IR but the benefit is
small and the morbidity is higher
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:
Take home messages
No benefit of adjuvant RT in the low-risk group
the association RT + CHT might be superior to RT in HIR and HR, but is more toxic
no prospectic studies of concurrent chemo-RT closed at present
chemotherapy is better than a suboptimal RT in HR pts
� Use Modern Radiotherapy !!!
ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:ADJUVANT TREATMENT OF ENDOMETRIAL CANCER:
Take home messages
Grazie per l’attenzione
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