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

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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

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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

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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

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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