EMBRACE- Studien Analysen und Perspektiven

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Cynthia Norah Pearson
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1 EMBRACE- Studien Analysen und Perspektiven Alina Sturdza EMBRACE study group

2 Outline Historical development of GEC ESTRO Gyn Group Historical development of the MRI compatible applicators Presentation of RetroEMBRACE with results with the focus on outcome and interstitial data and dose effect

3 EMBRACE: Brief Presentation of the currently published results of EMBRACE Rationale for EMBRACE II Conclusion Outline

4 Cervical cancer is still a challenge!

5 Cervical cancer Historical, definitive role

6 Target Dose: 2D Main limitation of 2D approaches: Absence of visual information on spatial relations between tumour and applicator Clinical findings + Sectional imaging (MRI) A A visualize target organs applicator Asses interrelations

7 ADAPTATION: TRANSLATION FROM 3D TO 4D BRACHYTHERAPY before treatment during EBRT treatment ICRU Report No 89 Van de Bunt et al., IJROBP 2006

8 Historical development of GEC ESTRO Gyn Group

9 The Vienna Congress Gynaecological GEC-ESTRO Group 2000

Gynaecological GEC-ESTRO Group in 2018 24

10 Gynaecological GEC-ESTRO Group in Active Centers Vienna Aarhus Utrecht Leiden Leuven Ljubljana London Arnhem Pamplona Paris Kaposvar Maastricht Trondheim Leeds Oslo Amsterdam Kuopio Cambridge Mumbai Chandigarh Milwaukee Edmonton Iowa BCU

11 Cancer cell density Gyn GEC ESTRO Recommendations Target volumes according to cell density & recurrence risk Potential microscopic Significant microscopic IR CTV Macroscopic cancer cell density HR CTV Significant microscopic Potential IR CTV microscopic LR CTV LR CTV GTV (visible/palpable tumor) Different dose levels required to sterilize the three CTVs Pelvic wall Cervix Pelvic wall Haie Meder C, et al. Radiother Oncol 2005

treatment plan (which is assumed to be delivered to an individual

12 DOSE PRESCRIPTION Planning aim Set of dose and dose/volume constraints for a treatment Prescribed dose Finally accepted treatment plan (which is assumed to be delivered to an individual patient) Delivered dose Actually delivered dose to the individual patient EMBRACE II

13 Historical development of MR compatible interstitial applicators

14 MRI and US guided freehand BT implant - in the MRI suite

15 Utrecht Interstital CT/MR applicator set Vienna Ring = Vienna-I Nucletron s interstitial Ring

16 Physical distance between tandem and needle Rationale for interstitial applications Distal parametria Needle loading In relation to intracavitary Distance: tandem to prescribed isodose line on level of point A Intracavitary only No needles + Parallel needles 20mm + Oblique needles 20 (23-27mm) 0% 20 [15-25] mm 10-20% mm A 5-10% 35-40mm Applicator view Vienna II D.Berger et al.

17 Vienna II applicator D.Berger et A, B, C - diagrammatic representation of needle holes for rings of diameter 34 mm, 30 mm, and 26 mm, respectively D, E - 26 mm ring add on cap, frontal and side view F, G, H - Tandem-ring applicator with add on cap along with parallel and oblique needles A.STURDZA

18 Advanced Gynecological Applicators Venezia - the commercial avaiable product by Elekta Vienna-I needles (parallel to tandem) Vienna-II needle (oblique orientation) Perineal template for further options Vaginal extension

19 D I A G N O S I S Sagittal view Cervical Cancer FIGO IIIB Coronal view Axial view A T I G A B T HRCTV 63Gy 88Gy High Risk CTV = HRCTV IRCTV GTV 60Mts Follow up IGABT = Image Guided Adaptative Brachytherapy

20 Gyn GEC ESTRO First multi-institutional results September 2016

21 RetroEMBRACE: Local, Pelvic, Distant Control, Cancer Specific Survival, Overall Survival Actuarial probability 11% events 3y 5y N Local control 69 91% 89% 731 Pelvic control 96 87% 84% 731 Distant control % 73% 731 Cancer specific survival % 73% 731 Overall survival % 65% % 16% Months LC PC DC CSS OS Sturdza et al. 2016, Rad Onc

22 Local control by FIGO stages Local event control s 3y 5y N 1B 2 98% 98% 123 2A 3 97% 94% 42 2B 28 93% 91% 368 3A 5 71% 71% 23 3B 28 79% 75% 145 4A 3 76% 76% 23 months between date of diagnosis and local control / local failure Sturdza et al. 2016, Rad Onc

23 Outcome of adaptation In small tumors (<5cm), 319 patients In big tumors (>5cm), 262 patients Local control events 3y 5y N Limited adaptation 8 % % 165 Advanced adaptation 9 94 % HRCTV D90 95 ± 1Gy vs 85 ± 3 Gy 94 % Local control events 3y 5y N Limited adaptation 26 % % 138 Advanced adaptation % 86 % 124 HRCTV D90 89 ± 2Gy vs 80 ± 5 Gy Log Rank test p=0.652 Log Rank test p=0.071 Fokdal et.al 2016 Rad Onc

24 CTC v3.0 BL and GI morbidity Grade 1-5 morbidity: 279 events Grade 2-5 morbidity: 151 events Grade 3-5 morbidity: 53 events 53% 45% 25% 31% 9% 11% Fokdal et.al 2016 Rad Onc Numbers at risk

25 Fokdal et.al 2016 Rad Onc Interstitial implants DO NOT increase morbidity!

26 RetroEMBRACE results (IGABT compared to large population based cohorts 2D BT) Pelvic failure (crude) retroembrace (n=731) Concomitant chemo IB IIB IIIB 77% 4% 11% 25% Perez % 12% 21% 41% Barillot % 13% 24% 49% Improvement Δ8-9% Δ10-13% Δ16-24% Overall Survival Radiochemo retroembrace Consecutive 3D/4D IGABT UK Survey Vale D BT US SEER D BT US NCDBA D BT No of pts y OS 67% 55% 55% 54% Improvement Reference Δ12% Δ12% Δ13%

27 Overall Survival benefit in locally advanced cervical cancer Total: 25% increase in Overall Survival from no brachy to 2D brachy (Han) to 3D/4D brachy (RetroEMBRACE) 13% 12% Han et al Int J Radiation Oncol Biol Phys 2013;87: Sturdza et al. Improved local control and survival in LACC through 3D/4D BT R&O 2016

28 Dose volume response Local control at 3 years - Cox regression - Dose and volume continous co-variates - Significance: - Hazard ratios: p=0.07 for CTV HR D90 p=0.01 for CTV HR volume for CTV HR D90 (per Gy) for CTV HR volume (per cm 3 ) Reduction of OTT by one week is equivalent to a dose escalation of 5Gy (CTV HR ) 3% 5% 7% Tanderup et al., Rad Onc, 2016

29 Organs at risk

30 Fokdal et al 2015 Bladder D2cc (EMBRACE) EMBRACE CTCAE All endpoints except ureter stenosis G 2 QOL EORTC 18 months follow up >80Gy: 30-40% <80Gy: 15-30%

31 Ureter: EMBRACE and RetroEMBRACE Fokdal et al, Int Jour Rad Phys, 2018

32 Rectal dose volume effects (2cm 3 ) G2 rectal morbidity (EMBRACE cohort, n=960) <65Gy: 5-10% G2 rectal morbidity (bleeding) (Vienna cohort, n=145) 60Gy 75Gy <2% 12% >65Gy: 15-25% Mazeron et al., RadOnc 2016 P. Georg et al., IJROBP 2011

33 P=0.032 P=0.001 dose effects for different endpoints for rectal morbidity EMBRACE (n=960) < 55 Gy Gy P< Mazeron et al, RadiothOncol

34 Bowel toxicity EMBRACE G3,4 at 3/5 years: 5%/5.9% Jensen et al, Radiotherapy & Oncology, 2018

35 Bowel toxicity EMBRACE Jensen et al, Radiotherapy & Oncology, 2018

36 Lymphoedema EMBRACE Najari et al, Radiotherapy & Oncology, 2018

37 Fatigue EMBRACE Smet et al, Radiotherapy & Oncology, 2018

38 Vaginal Dose Points Westerveld et al. 2013

Vaginal morbidity and radiation doses at 5 mm 60-115 Gy 65 Gy ICRU rectovag.

39 Vaginal morbidity and radiation doses at 5 mm Gy 65 Gy ICRU rectovag. P 50 Gy 37 Gy 4 Gy (Westerveld et al. Vienna 2013) ICRU/GEC ESTRO Report 89 Fig. 6.1/Fig. 8.11

40 Vaginal stenosis (EMBRACE) ICRU recto-vaginal point (630 pts) Cox-regression, 2 year actuarial risk of G2 stenosis - Significant impact of EBRT dose (45Gy versus 50Gy) - Significant impact of BT ICRU recto-vaginal dose 100% 90% 80% 70% Prevalence vaginal stenosis G0 G1 G2 G3 60% 50% 40% 30% 20% 10% 0% 3M 6M 9M 12M 18M 24M 30M 36M Kirchheiner K et al.manifestation pattern of early-late vaginal morbidity. IJROBP 2014 May 1;89(1):88-95 K Kirchheiner et al, MUW/AUH 2016

41 EMBRACE II (2016) cervix cancer: D2cm 3 for OARs protocol for planning aims and dose prescription Bladder D 2cm³ EQD2 3 Rectum D 2cm³ EQD2 3 Rectovaginal point Sigmoid/ Bowel D 2cm³ EQD2 3 Planning Aims Limits for Prescribed Dose EQD2 3 < 80 Gy < 65 Gy < 65 Gy < 70 Gy* < 90 Gy < 75 Gy < 75 Gy < 75 Gy*

42 EMBRACE II (2016) cervix cancer: D2cm 3 for OARs protocol for planning aims and dose prescription Bladder D 2cm³ EQD2 3 Rectum D 2cm³ EQD2 3 Rectovaginal point Sigmoid/ Bowel D 2cm³ EQD2 3 Planning Aims Limits for Prescribed Dose EQD2 3 < 80 Gy < 65 Gy < 65 Gy < 70 Gy* < 90 Gy < 75 Gy < 75 Gy < 75 Gy*

RChTh + BT in < 50 days EBRT Chemotherapy Brachy EMBRACE II Start 1/2016; 255 patients week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 1 week 2 week 3 week 4

43 RChTh + BT in < 50 days EBRT Chemotherapy Brachy EMBRACE II Start 1/2016; 255 patients week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 1 week 2 week 3 week 4 week 5 week 6 Initial GTV Initial GTV Initial GTV GTV res CTV HR CTV IR CTV LR Residual GTV-T, Adaptive HR CTV-T, IR CTV-T

44 Conclusion IGABT results in excellent local control and limited side efects The EMBRACE I and RetroEMBRACE established a bench mark for dosis prescription for the target and constraints for OARs EMBRACE II will respond remaining questions regarding dose to LN, side effects when EBRT is done by IMRT and combined with IGABT and further outcome

45 Gustav Klimt: Life and death

Image guided brachytherapy in cervical cancer Clinical Aspects

Image guided brachytherapy in cervical cancer Clinical Aspects Richard Pötter MD Department of Radiation Oncology, Medical University of Vienna, Austria ICARO-2, IAEA, Vienna, June, 22, 2017 Outline Tumor