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Adjuvant Radiotherapy in Endometrial cancer
February 27th, 2016
FERAH YILDIZ
What we have known in theadjuvant setting
Uterine confined disease:
• EPRT improves LCRs in patients withintermediate risk EC
• No OS benefitPORTEC I, GOG 99
What we have known in theadjuvant setting-II
For patients with dx outside the uterus
• ERT improves pelvic control
• CT improves systemic and abdominalcontrol
Cochrane metaanalysis, 2012
What has changed in Uterusconfined dx?
– Long term results of PORTEC 1 published
– GOG 99 supported the PORTEC results
– Mature results of PORTEC-II changed thetx policy
• 1990-1997, 714 pts• Int risk or HIR• HIR: 2/3 risk factor
– Gr3, ≥60y, >%50 MITAH+BSO , then NFT or EPRTHIR %51 %52
70% recurrence when NFT located in vaginaNSD in secondary cancer risk
EBRT after TAH-BSO-LND
GOG 99• 448 pts: Int risk or HIR• Fup: 69 m• TAH/BSO+LND
EPRT vs NFTRR 3% 12%OS NSD
Keys HM et al, Gynecol Oncol, 2004
YUN5
Slayt 7
YUN5 Burada özl le HIR de pelvik ve vajinal nuls izlem kolunda fazla ama bu GS a yansımıyor. Yazarlar sadece HIR de EPRT juygulanmalı diyorYour User Name; 29.01.2016
EPRT in Int risk EC
– İmproves LC– NSD in OS
– Why?• 70-75% of recurrences are located in vagina
and salvage rates are high
No need for EBRT
YUN6
Slayt 8
YUN6 Özellikle HIR de LOk kontrol avantajı belirginYour User Name; 29.01.2016
ERT vs BRT
Can we use vaginal BRT instead of EBRT?
• Phase III trialsPORTEC2, 2010Sorbe B et al, 2012
PORTEC 2
• 427 pts, HIR
gr 1-2, ≥ 50% MI, age>60ygr 3Cervical glandulary inv
Nout RA ve ark, Lancet 2010
YUN8
Slayt 11
YUN8 Merkezi Pat değerlendirmesi yapılan 316 hastada ise LBRR %2,4 vs %4.8 ve p:0.42
Pelvik nüks : %0.6 vs %3.3 ve p: 0.06
Your User Name; 30.01.2016
PORTEC 2
TAH+BSO then EPRT vs BRTfup 45 m
4y LRR: %2.1 vs %5.1 p: 0.17Pelvic rec %0.5 vs %3.8 p: 0.02
Nout RA ve ark, Lancet 2010
YUN7
Slayt 12
YUN7 Merkezi Pat değerlendirmesi yapılan 316 hastada ise LBRR %2,4 vs %4.8 ve p:0.42
Pelvik nüks : %0.6 vs %3.3 ve p: 0.06
Your User Name; 30.01.2016
• Surgery then BRT vs EPRT+BRT• fup: 62 m
• 5yLRR %5 vs %1.5• OS NSD• İncrease in toxicity with EBRT
Recent developments in EC
Risk groups
• Low risk
• Intermediate risk
• High-Intermediate risk: HIR
• High risk
Low risk
• USAStg I +Grade1-2<%50 MIendometrioidno LVSINo cervical inv
No residual dx after D&C<60y
• EuropeStgI +Grade 1-2<%50 MIendometrioidNo LVSI
Low risk EC
SurgeryTAH+BSO
Recurrence Risk <%5No need for adjuvant treatment
ESMO-ESGO-ESTRO, 2016ASTRO 2014ASCO 2015
Ingtermediate Risk/HIR
• ASTRO-ASCO
Limited to uterus+ risk factor
≥%50 MIhigh grade>60yLVSICervical inv.
ESMO-ESGO-ESTRO
• Orta Risk • HIR
Stg IA+grad 3Stg I gr1-2+LVSI
• IntermediateStg I +grade1-2≥%50 MIendometrioidno LVSI
Intermediate Risk EC
Is there a need foradjuvant RT?
If so, How?EPRT?BRT?
ASTRO-ASCO recommendation
• ≥50% MI+g1-2• < 50% MI+g3
After surgical stagingBRT alone is an effective adjuvant Tx.
ESMO-ESGO-ESTRO
• Stg IB, g1-2, no LVSI
– Adjuvant BRT is recommended todecrease vaginal recurrence
(Level of evidence I)
– No adjuvant tx is an option for pts aged<60y
(Level of evidence II)
HIR Endometrial cancerBRT?
EBRT?NFT?
HIR: g3, LVSI
– PORTEC 15y LRR : 20% vs 5%
– GOG 995y LRR: 26 % vs 6%
HIR: ASTRO recommendation
• ≥ 50% MI+ g3 or cervical stromal inv. EPRT is recommended to reduce pelvic
recurrence
However: ≥ 50% MI, g1-2 + >60y or LVSI…may alsobenefit from EBRT
ESMO-ESO-ESTRO
• Stg IA + gr 3• Stg IB, gr1-2 +LVSI
No LN met after surgical stagingAdj BRT (LOE III, Strength of Rec B)
NFT (LOE III, Strength of Rec C)
ESMO-ESO-ESTRO
• Stg IA + gr 3• Stg IB, gr1-2 and LVSI
No surgical nodal stagingEPRT to decrease PRR when LVSI (+)BRT alone for gr 3 and LVSI(-)Sys CT is of uncertain benefit
High Risk EC
High Risk EC
• ≥50% MI+g3………..stgIII
• Stg IVA?
ESMO-ESGO-ESTRO
High Risk• Stg IB-g3• Stg II• Nonendometrioid• Stg III, RO
resection
Advanced• Stg III, R1 res.
• Stg IVA
Stg III, RO resection
TAH,BSO, Surgical staging5y DFS: %58, OS: %64RR: %41
pelvic: %32DM: %46 LRR: %54pelvic+DM: %22
Ayhan A et al, Eur J Gynecol Oncol, 2002
Prognostic factor- Recurrence pattern
• >50%MIgrade 3
• Cervical stromal invLN met
• (+)cytologySPK, Clear cell hist
• Hematogen
• Lymphatic
Pelvic side wall
• Whole abdominalcavity
Mariani et al, 2004, Randal et al, 1994, Greven et al1993
Adjuvan RT how?
• Whole abdominal RT(TART)?
• Tumor directed RT : EPRT, PART?
• BRT only with CT?
WART
• Whole peritonealcavity: 30 Gy/20f
• +15 Gy pelvic ± PA RT
WART vs CTGOG 122• 388 stg III-IV patients• WART vs 8 cycles CDDP-ADR• fup: 74 m
– PFS: %38 vs %42– OS: %42 vs %53– % recurrence: %54 vs %50
Randall ME ve ark, JCO 2006.
GOG 122
• RecurrencePelvik(%) Abd(%) DM(%)
WART 13 16 22CT 18 14 18
GOG 122
• No optimal surgery<2 cm rezidue !!!!!!, LND optional
• RT inadequate and toxic30 Gy WART+15 Gy pelvic RTPART when there is no PALND.
Can we limit RT todisease spesific sites?
CT vs EPRT/phase III trials
– İtalian GICOG: stg ICG3-III• 5 cyles CA vs 45-50 Gy EPRT
– JGOG 2033: EICG3-III• 3CAP vs 45-50 Gy EPRT
GICOG
J GOG 2033
• 385 pts, stgIC-III+>50 % MI• TAH+BSO+LND--- RO resection• 45-50 Gy EPRT vs ≥3 cycles CAP• fup: 60 m
PFS: %83.5 vs %81.8 NSDOS: %83.5 vs %86.7 NSD
Susumu N ve ark, Gynecol Oncol , 2008
Cochrane Metaanalysis 2012• After optimal surgery• CT vs RT
– Risk of death (HR): 0.86 NSD– CT decreases systemic and abdominal RR– RT decreases PRR
Can we use both CT and RT?
• Purpose: – Efficient control in reducing recurrence
inside and outside the pelvis
• BUT WITHOUT : – İncreasing the toxicity…..
How to combine CT and RT?
GICOG, J GOGRT vs CT
• Compliance to tx– RT: 88-98% KT: 75-97%
• Complication type– RT: bowel– CT: bone marrow
EPRT vs EPRT+CT• NSGO ve EORTC 55991
– 382 pts %81-90 Stg I– EPRT±BRT vs EPRT+4 cycles CT
• MaNGO- ILIADE III – 157 pts, Stg II-III, fav histology– EPRT±BRT vs RT+3 cycles CT
• Finland– 156 pts, Stg IG3-III– EPRT vs RT+3 cycles CT
• GOG 34– 181 pts, Stg IC-III– ERT vs ERT+ADR
Metaanaliz 2012
Cochrane Collaboration, 2012
The absolute difference with CT: %6 in OS
RT katkısı ne?>%50 MI+G3
ERT offers 10% survivaladvantage
RT vs CT-RT
RTOG 9708phase II, 46 ptsStg IC-II, g2-3, Stg IIIA-C145 Gy EPRT+BRT, CDDP in 1.-28. days
+ 4 cycles CDDP-Paclitaxel
Greven K ve ark, Gynecol Oncol, 2006
RTOG 9708
• fup: 4.3 y– 4y OS: 85 %– Stg III : 77%
• Tx compliance >90%• G3-4 compl: 16%-5%
What we are waiting for?
• PORTEC 3Conc CRT vs EBRT
• GOG 258CRT vs CT
• EORTC 55102CT vs izlem
YUN4
Slayt 49
YUN4 PORTEC 3 ve GOG 258 sonlandı. EORTC devam ediyor. Burada LN negatif, Yüksek riskli hastalar alındıYour User Name; 30.01.2016
EPRT vs CT + BRT
• GOG 0249• phase III, 601 high risk pts• EPRT vs 3 T/KP+BRT
2y OS : NSDSignificant increase in hem toxicity with CT
Mc Meekin et al, SGO annualmeeting, 2014, Abst LBA1
ASTRO recommendation• High risk EC
– EBRT standard of care
– EBRT +BRT when there is high risk of vaginal recurrence
ESMO-ESGO-ESTRO
• After surgical stg, stg IB g3
EPRT to decrease LRR (LOE I)
BRT may be considered as an alternative todecrease vaginal RR (LOE III)
Systemic CT: under investigation
ESMO-ESGO-ESTRO• No surg staging, Stg IB g3
EPRT generally recommended for pelviccontrol and RFS (LOE III)
seq CT-RT may be considered in to improvePFS and CSS (LOE II)
There is more evidence to support giving CT and EBRT in combination rather than either txalone (LOE II)
ESMO-ESGO-ESTROStg II dx
Surgical Stg
g1-2, LVSI(-)BRT (LOE III)
g3, LVSI (+)EPRT (LOE III)
+BRT: (LOE IV)
CT: under investigation
No surgical Stg
EPRT standard of care
Consider BRT boost
G3, LVSI(+): Seq adj CT
ESMO-ESGO-ESTROStg III - RO resection
EBRT to decrease PRR (LOE I) to increase PFS (LOE I) to increase OS (LOE IV)
CT to increase PFS and CSS (LOE II)
ESMO-ESGO-ESTRONonendometrioid
Serous, clear cell
CTLOE III
Stg IA, LVSI (-)Only BRT : LOE IV
≥Stg IB, esp in LN + dxEBRT+CT: LOE III
Carcinosarcoma, Undiff
CT LOE II
EPRTLOE III
Optimal Timing of CT-RT
RTOG 9708, phase II trial• Stg I, >50% MI+ g3- stg III• EPRT+conc CDDP—4 cycles of adj
Taxane-Platin
• 4y OS: 85%• 4y DFS: 81%• 4y PRR: 2 %
Greven K et al, 2004
ASTRO recommendation
• Concomittant CRT-----adj CT
• However sequential combinations arealso welcome.
In conclusion…..• Uterine confined EC
– Low risk: No role of adj RT
– Intermediate risk: Vaginal BRT only
– HIR: EBRT, BRT only in certain pts
• High Risk, advanced EC: EBRT
Recommended