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

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Merryl Edwards
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1 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 Remi Nout Radiation Oncology, Leiden University Medical Centre, The Netherlands

2 Endometrial Carcinoma Incidence 22 / Mortality 5.5 / Endometrial Cancer NL 2015 Mortality Incidence Histology other mucinous clear cell serous endometrioid 50 0 Age is a prognostic factor Increasing co-morbidities Obesity epidemic Cijfers over kanker VIKC, 2016

alone in medical non-operable women Systematic review 25 reports 2694 patients, results at 5-years:

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

4 Colombo N. et al Ann of Oncology 2015 ESMO-ESGO-ESTRO consensus: risk groups Risk Group Description (FIGO 2009) Low Stage IA Endometrioid + grade LVSI negative Intermediate Stage IB Endometrioid + grade LVSI negative High Intermediate Stage IA Endometrioid + grade 3, regardless of LVSI status Stage I Endometrioid + grade LVSI unequivocally positive, regardless of depth of invasion Surgery alone Vaginal Brachytherapy Radiotherapy High Stage IB Endometrioid + grade 3, regardless of LVSI status Stage II & stage III with no residual disease 15% Non endometrioid (serous, clear cell, undifferentiated carcinoma, carcinosarcoma, mixed >10%) Radiotherapy? Chemotherapy? Both? Advanced Metastatic Stage III with residual disease & IVA Stage IVB

5 Seccord A.A. Gynecol Oncol 2013; Klopp A.H. Gynecol Oncol 2009 Stage III node positive: retrospective Regional RT N=50 No regional RT N=18

6 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 Stage III vs stage IV Randall, JCO 2006

7 Radiotherapy vs Chemotherapy JGOG pts RT vs chemo* x3 Italian trial pts RT vs chemo* x5 Overall survival Progression-free survival * cyclophosphamide doxorubicin - cisplatin Radiotherapy delays local recurrence, chemotherapy delays distant metastasis Susumu, Gynecol Oncol 2008; Maggi, Br J Cancer 2006

8 Pooled randomised NSGO-EORTC/Iliade trials Radiotherapy vs RT plus platinum-based chemotherapy x4 Progression free survival Overall survival PFS 69 vs 78%, p=0.009 OS 75 vs 82%, p=0.07 Hogberg et al, EJC 2010

9 First GOG-249 results Stage I-II HIR / 20% serous, cc N=601 89% LND, 74% stage I R Pelvic RT 3x carboplatin + paclitaxel + VBT No difference in PFS and OS RT: better pelvic control CT/B: more acute toxicity McMeekin, SGO 2014, Fleming, IGCS 2014, Randall ASTRO 2017

PORTEC-3 trial design 686 stage I High risk, stage II/III

6 Gy + 2x Cisplatin 50mg/m2 4x Carboplatin AUC5 Paclitaxel

6Gy 5 weeks uniform treatment schedule upfront pathology

10 PORTEC-3 trial design 686 stage I High risk, stage II/III Endometrial Cancer Pelvic RT 48.6 Gy + 2x Cisplatin 50mg/m2 4x Carboplatin AUC5 Paclitaxel 175mg/m2 R 5 weeks 2 wks 12 weeks Pelvic RT alone 48.6Gy 5 weeks uniform treatment schedule upfront pathology review quality of life analysis PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology

11 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% 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 % 80%-72% PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology 6/2/2017

12 Survival, median follow-up 60.2 months HR 0.79 [ ], p=0.109 (adjusted) HR 0.77 [ ], p=0.022 (adjusted) 5 yr OS: 82% (CTRT) versus 77% (RT) 5 yr FFS: 76% (CTRT) versus 69% (RT) PORTEC-3 results De Boer et al, ASCO 2017, in press Lancet Oncology 6/2/2017

13 First sites of recurrence 5 years CTRT N % RT N % HR P-value Vaginal recurrence % % 1 1 Pelvic recurrence % 5 1.5% Distant recurrence % % Distant + vaginal 4 1.2% 4 1.2% Distant + pelvic % % Distant only % % - - PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology 6/2/2017

14 Survival results stage III 5-year OS 79% vs 70% [HR 0.69, , p=0.135] 5-year FFS 69% for CTRT vs 58% for RT [HR 0.66, 95% CI , p=0.032] PORTEC-3 results De Boer et al, ASCO 2017; in press Lancet Oncology 6/2/2017

15 Adverse events (CTCAE v3.0) CTRT RT Grade 2 AE Grade 3 AE Grade 4 AE PORTEC-3 results De Boer et al, Lancet Oncology /2/2017

16 Quality of life PORTEC-3 results De Boer et al, Lancet Oncology 2016

17 Quality of life Very much Quite a bit A little Not at all Sensory neuropathy ( quite a bit or very much ): 25% vs 6% PORTEC-3 results De Boer et al, Lancet Oncology 2016

18 GOG-258 trial stages III-IV 37 ineligible 14 wrong stage 16 inadequate path 2 wrong cell type 2 second primary 3 other 813 patients were enrolled and randomized ( assigned to C-RT 406 assigned to CT 40 ineligible 13 wrong stage 24 inadequate path 0 wrong cell type 2 second primary 1 other 24 did not receive study Tx 5 did not receive study Tx 370 included in efficacy analysis 346 included in safety analysis 139 disease recurrence or death 79 died 366 included in efficacy analysis 361 included in safety analysis 131 disease recurrence or death 84 died Data cut off 3/9/2017 Median FU 47 months 95% stage III, 18% serous, 3% clear cell Matei et al; presented at ASCO 2017

19 First GOG-258 results 5 year OS estimates C-RT: 70% CT: 73% Events Total HR 90% CI (.74, 1.10) Events Total Data cut-off 03/09/2017 Data not mature for final analysis Matei et al; presented at ASCO 2017

20 First GOG-258 results Vaginal Recurrence Pelvic and PA Recurrence Distant Recurrence Pelvic/PA recurrence 10% 19% Incidence at 5 years C-RT vs. CT : HR=0.36 (CI: ) HR=0.43 (CI: ) HR=1.36 (CI: ) Matei et al; presented at ASCO 2017

21 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

22 Molecular integrated risk profile PORTEC-1/2 cohort Stelloo et al, Clinical Cancer Research 2016

with shielding Intensity Modulated Radiation Therapy A. B.

23 Improvement of EBRT techniques Creutzberg IJROBP 2001; Nout et al, JCO 2011 PORTEC-1: 30% AP-PA 70% 3-4 fields with shielding Intensity Modulated Radiation Therapy A. B. Entering era of daily online image guided (MRI) adaptive RT

24 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

25 No increased risk of second cancers PORTEC&TM E N>2500 Competing risk analysis No RT EBRT VBT Second cancers by age <60 yrs by treatment No. at risk No RT EBRT VBT Wiltink et al, JCO 2015

Salvage radiotherapy for local recurrence Brachytherapy 2013 Aarhus 2006-2013 N=43; PDR; median

26 Salvage radiotherapy for local recurrence Brachytherapy 2013 Aarhus N=43; PDR; median follow-up 30 months 24 interstitial 19 intracavitary Late grade 3 morbidity 12% Brachytherapy 2013

27 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

28 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

29 Acknowledgments Carien Hein Creutzberg Putter, Wim van Putten Stephanie Karen de Adema, Boer Philine van den Tol Vincent Vincent SmitSmit, Harry Hollema, Henk Beerman Tjalling Bosse Ellen Stelloo Inge van Gool Marnix Lybeert Jan Jobsen Ina Jürgenliemk-Schulz Jan Willem Mens Karin De Winter Ludy Lutgens Betty Pras Elzbieta vd Steen-Banasik Marika Stenfert Kroese Annerie Slot Jan Willem Leer Lon Uitterhoeve Baukelien van Triest Tanja Stam Zeeland Peter Koper Otto Meijer Veronique Coen Remi Nout PORTEC study group Zuid Holland PORTEC statisticians PORTEC datamanagers PORTEC pathologists Groningen Waddenzee Catharina Hospital Eindhoven Friesland Medisch Spectrum Twente Enschede University Medical Center Utrecht Ijsselmeer Drenthe Noord Daniel den Hoed Cancer Centre Rotterdam Holland Bernard Verbeeten Institute Tilburg MAASTRO clinic Maastricht Flevoland Overijssel UMC Groningen Radiotherapy Institute Arnhem Gelderland Radiotherapy UtrechtInstitute Deventer Radiotherapy Institute Leeuwarden RadboudMC Nijmegen Noord Brabant Academic Medical Center Amsterdam NKI/vLeeuwenhoekhuis Amsterdam Westeinde Hospital Den Haag Limburg Leyenburg Hospital Den Haag VUMC Amsterdam Radiotherapy Institute Vlissingen Leiden University Medical Center PORTEC - 3 International Intergroup Trial

GCIG updates PORTEC-3 and PORTEC-4a

GCIG updates PORTEC-3 and PORTEC-4a Lisbon, October 2016 Carien Creutzberg Leiden University Medical Centre, The Netherlands The PORTEC-3 trial High risk Endometrial Cancer R Pelvic RT (48.6 Gy) 686 Pelvic