Remi NoutRadiation Oncology, Leiden University Medical Centre, The Netherlands

Is there any role for external radiotherapy in FIGO stage III endometrial cancer?

2018 Progress and Controversies in Gynecologic Oncology Conference

19 January 2018 Barcelona

Cijfers over kanker VIKC, 2016

serous

mucinous

endometrioid

clear cell

other

Histology

Endometrial Carcinoma

0

50

100

150

200

250

300

350

400

Endometrial Cancer NL 2015

Mortality Incidence

Incidence22 / 100.000

Mortality5.5 / 100.000

• Age is a prognostic factor• Increasing co-morbidities• Obesity epidemic

Endometrial carcinoma is radiosensitive

➢ Radiotherapy alone in medical non-operable women

Systematic review 25 reports 2694 patients, results at 5-years:

• Local Control: 79.9% (95%CI: 75.7%-84.1%)

• Disease Specific Survival: 78.5% (95%CI: 74.5%-82.5%)

• Overall Survival: 53.2% (95%CI: 49.3%-57.1%)

• Grade III morbidity: EBRT+BT 3.7%, BT alone 2.8%

van der Steen-Banasik E. et al EJC 2016; GEC-ESTRO handbook of Brachytherapy

Risk Group Description (FIGO 2009)

Low • Stage IA Endometrioid + grade 1-2 + LVSI negative

Intermediate • Stage IB Endometrioid + grade 1-2 + LVSI negative

HighIntermediate

• Stage IA Endometrioid + grade 3, regardless of LVSI status• Stage I Endometrioid + grade 1-2 + LVSI unequivocally positive,

regardless of depth of invasion

High • Stage IB Endometrioid + grade 3, regardless of LVSI status• Stage II & stage III with no residual disease• Non endometrioid (serous, clear cell, undifferentiated carcinoma,

carcinosarcoma, mixed >10%)

AdvancedMetastatic

• Stage III with residual disease & IVA • Stage IVB

Colombo N. et al Ann of Oncology 2015

ESMO-ESGO-ESTRO consensus: risk groups

➢ Surgery alone

➢ VaginalBrachytherapy

➢Radiotherapy

➢ Radiotherapy?

➢ Chemotherapy ? Both? 15%

Regional RT N=50

No regional RT N=18

Seccord A.A. Gynecol Oncol 2013; Klopp A.H. Gynecol Oncol 2009

Stage III node positive: retrospective

Randall, JCO 2006

Stage III vs stage IV

Adjuvant chemotherpy versus RT

➢ GOG 122: AP (8x) vs WAI

• 396 pts, stage III-IV

• Residual tumor up to 2 cm allowed

• 5-yr OS for AP 53% vs. WAI 42%

• Substantial toxicity

Radiotherapy vs Chemotherapy

Susumu , Gynecol Oncol 2008; Maggi, Br J Cancer 2006

JGOG - 385 ptsRT vs chemo* x3

Italian trial - 345 ptsRT vs chemo* x5

Overall survival Progression-free survival

* cyclophosphamide – doxorubicin - cisplatin

➢ Radiotherapy delays local recurrence, chemotherapy delays distant metastasis

Pooled randomised NSGO-EORTC/Iliade trialsRadiotherapy vs RT plus platinum-based chemotherapy x4

Progression free survival Overall survival

Hogberg et al, EJC 2010

PFS 69 vs 78%, p=0.009 OS 75 vs 82%, p=0.07

• Stage I-II HIR / 20% serous, cc

• N=601

• 89% LND, 74% stage I

RPelvic RT

3x carboplatin+ paclitaxel + VBT

First GOG-249 results

McMeekin, SGO 2014, Fleming, IGCS 2014, Randall ASTRO 2017

➢ No difference in PFS and OS

➢ RT: better pelvic control

➢ CT/B: more acute toxicity

PORTEC-3 trial design

• uniform treatment schedule

• upfront pathology review

• quality of life analysis

➢ 686 stage I High risk, stage II/III Endometrial Cancer

PORTEC-3 results

Pelvic RT 48.6 Gy + 2x Cisplatin 50mg/m2

R5 weeks 2 wks 12 weeks

4x Carboplatin AUC5 Paclitaxel 175mg/m2

5 weeks

Pelvic RT alone 48.6Gy

De Boer et al, ASCO 2017; in press Lancet Oncology

Tumour and treatment characteristics

Tumour characteristics RT alone CTRT

Histology

Endometrioid grade 1-2

Endometrioid grade 3

Serous/ clear cell/ other

39.7%

32.1%

28.2%

38.5%

32.4%

29.1%

LVSI

Yes

No

58.2%

41.8%

59.7%

40.3%

Stage (%)

I

II

III

29.4%

27.3%

43.3%

29.7%

24.2%

46.1%

6/2/2017PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology

Treatment characteristics RT alone CTRT

Type of surgery (%)

TAH or TLH / BSO

TH/BSO plus LND

41.8%

58.2%

42.4%

57.6%

RT completion(%)

EBRT

BT boost (cervical invasion)

98.5%

47.8%

99.7%

45.8%

CT completion (%)

2 cisplatin

4 carboplatin-paclitaxel

-

-

93%

80%-72%

6/2/2017

Survival, median follow-up 60.2 months

5 yr OS: 82% (CTRT) versus 77% (RT)

HR 0.79 [0.57-1.12], p=0.109 (adjusted)

5 yr FFS: 76% (CTRT) versus 69% (RT)

HR 0.77 [0.58-1.03], p=0.022 (adjusted)

PORTEC-3 results De Boer et al, ASCO 2017, in press Lancet Oncology

6/2/2017

First sites of recurrence

5 years CTRT

N %

RT

N %

HR P-value

Vaginal recurrence 1 0.30% 1 0.30% 1 1

Pelvic recurrence 3 0.95% 5 1.5% 0.60 0.478

Distant recurrence 76 22.4% 93 28.3% 0.78 0.108

- Distant + vaginal 4 1.2% 4 1.2% - -

- Distant + pelvic 11 3.2% 20 6.1% - -

- Distant only 61 18.0% 69 21.0% - -

PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology

6/2/2017

Survival results stage III

• 5-year FFS 69% for CTRT vs 58% for RT

[HR 0.66, 95% CI 0.45-0.97, p=0.032]PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology

• 5-year OS 79% vs 70%

[HR 0.69, 0.44-1.09, p=0.135]

6/2/2017

CTRT RT

Adverse events (CTCAE v3.0)

De Boer et al, Lancet Oncology 2016

Grade 2 AE Grade 3 AE Grade 4 AE

PORTEC-3 results

Quality of life

De Boer et al, Lancet Oncology 2016PORTEC-3 results

Quality of life

De Boer et al, Lancet Oncology 2016

Very much

Quite a bit

A little

Not at all

PORTEC-3 results

Sensory neuropathy (“quite a bit” or “very much”): 25% vs 6%

Data cut off 3/9/2017Median FU 47 months

813 patients were enrolledand randomized (2009-2014

407 assigned to C-RT 406 assigned to CT

37 ineligible14 wrong stage16 inadequate path2 wrong cell type2 second primary3 other

24 did not receive study Tx

40 ineligible13 wrong stage24 inadequate path0 wrong cell type2 second primary1 other

5 did not receive study Tx

370 included in efficacy analysis346 included in safety analysis

366 included in efficacy analysis361 included in safety analysis

139 disease recurrence or death

79 died

131 disease recurrence or death

84 died

GOG-258 trial – stages III-IV

Matei et al; presented at ASCO 2017

➢ 95% stage III, 18% serous, 3% clear cell

Events Total HR 90% CI132 370 0.90 (.74, 1.10)139 366

Matei et al; presented at ASCO 2017

First GOG-258 results

Events Total 86 37079 366

5 year OS estimatesC-RT: 70%CT: 73%

Data cut-off 03/09/2017 Data not mature for final analysis

Vaginal Recurrence Pelvic and PA Recurrence

C-RT vs. CT : HR=0.36 (CI: 0.16-0.82) HR=0.43 (CI: 0.28-0.66)

Pelvic/PA recurrence 10% 19%

Incidence at 5 years

Matei et al; presented at ASCO 2017

First GOG-258 results

Distant Recurrence

HR=1.36 (CI: 1.00-1.86)

Conclusion PORTEC-3, GOG 249 & 258 results

Early stage with HR factors:

• Question if FFS benefit outweighs the toxicity of added chemotherapy

• Across trials: good pelvic control with RT alone

➢ Pelvic RT remains standard for stage I-II with risk factors

Stage III:

• Combined CT/RT schedule provides 11% FFS improvement

➢ Combined CT/RT vs CT alone: better pelvic and para-aortic control

• Translational studies to determine who benefit

Stelloo et al, Clinical Cancer Research 2016

Molecular integrated risk profile PORTEC-1/2 cohort

Creutzberg IJROBP 2001; Nout et al, JCO 2011

A. B.

PORTEC-1: 30% AP-PA70% 3-4 fields with shielding

Intensity ModulatedRadiation Therapy

Improvement of EBRT techniques

➢ Entering era of daily online image guided (MRI) adaptive RT

Klopp et al, ASTRO 2016

Reduction of RT toxicity: IMRT

➢ NRG – RTOG Time C trial Randomised trial of• IMRT vs 4-field pelvic radiotherapy • IMRT reduces acute GI and GU toxicity at 5 wks• IMRT improved QOL with regard to physical functioning

<60 yrs by treatmentSecond cancers by age

Wiltink et al, JCO 2015

No. at risk

No RT 1008 708 496 84 2

EBRT 1332 862 482 83 1

VBT 214 157 8 - -

No RTEBRTVBT

PORTEC&TMEN>2500Competing riskanalysis

No increased risk of second cancers

Salvage radiotherapy for local recurrence

Aarhus 2006-2013 N=43; PDR; median follow-up 30 months

24 interstitial – 19 intracavitary

Late grade 3 morbidity 12%

Brachytherapy 2013

Brachytherapy 2013

Conclusion – Radiotherapy for stage III EC: PRO

• Majority are elderly; frequent co-morbidities and obesity

• Endometrial carcinoma is radiosensitive

• Good pelvic control with RT alone (PORTEC-3 and GOG-249)

• Reduced morbidity with IMRT (TIME-C)

• Salvage RT for symptomatic recurrence: effective but intensive and more side effects

Conclusion – Radiotherapy for stage III EC: PRO

➢ Stage III disease improved FFS with both CT+RT and CT

• PORTEC-3 significant 11% FFS benefit with CT+RT

• GOG-258 better pelvic and para-aortic control with CT+RT

➢ Shared decision making

➢ Future:

• Integrated molecular risk profile

• Targeted therapies

• Daily adaptive image guided (MRI) radiotherapy

Marnix Lybeert Catharina Hospital Eindhoven

Jan Jobsen Medisch Spectrum Twente Enschede

Ina Jürgenliemk-Schulz University Medical Center Utrecht

Jan Willem Mens Daniel den Hoed Cancer Centre Rotterdam

Karin De Winter Bernard Verbeeten Institute Tilburg

Ludy Lutgens MAASTRO clinic Maastricht

Betty Pras UMC Groningen

Elzbieta vd Steen-Banasik Radiotherapy Institute Arnhem

Marika Stenfert Kroese Radiotherapy Institute Deventer

Annerie Slot Radiotherapy Institute Leeuwarden

Jan Willem Leer RadboudMC Nijmegen

Lon Uitterhoeve Academic Medical Center Amsterdam

Baukelien van Triest NKI/vLeeuwenhoekhuis Amsterdam

Tanja Stam Westeinde Hospital Den Haag

Peter Koper Leyenburg Hospital Den Haag

Otto Meijer VUMC Amsterdam

Veronique Coen Radiotherapy Institute Vlissingen

Remi Nout Leiden University Medical Center

Utrecht

Ijsselmeer

Groningen

DrentheNoord

Holland

Gelderland

Limburg

Flevoland

Zuid Holland

Noord Brabant

Zeeland

Overijssel

Friesland

Waddenzee

Acknowledgments

Hein Putter, Wim van Putten PORTEC statisticians

Karen Adema, Philine van den Tol PORTEC datamanagers

Vincent Smit, Harry Hollema, Henk Beerman PORTEC pathologists

Carien Creutzberg

Stephanie de Boer

Vincent Smit

Tjalling Bosse

Ellen Stelloo

Inge van Gool

PORTEC study group

PORTEC - 3International Intergroup Trial