Recent Advances and current status of radiotherapy for cervix cancer

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1 Recent Advances and current status of radiotherapy for cervix cancer Richard Pötter MD Department of Radiation Oncology, Medical University of Vienna, Austria ICARO-2, IAEA, Vienna, June, 24, 2017

2 Recent Advances Outline Radiochemotherapy Image Guided Adaptive Brachytherapy (IGABT) ICRU GEC ESTRO Report 89 Image Guided EBRT (IMRT(IGRT) Current Status Transition from 2D to 3D IGABT 3DCRT and IMRT/IGRT (transition) Conclusions

3 Concomitant Radiochemotherapy No essential advances in general level 1-evidence for stage IIIB RCHT: +6% OS Cis-Platinum 40 mg/m2 weekly x 5-6 plus EBRT 45 Gy in 5 weeks, 1.8 Gy/fract. No multi-center level 1-evidence on value of (neo)-adjuvant chemotherapy (Outback/Interlace trial results pending)

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Primary

(IGABT) External beam radiotherapy: 3D EBRT or IMRT/VMAT

4 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Primary radiochemotherapy and Image guided adaptive brachytherapy (IGABT) External beam radiotherapy: 3D EBRT or IMRT/VMAT Start 45 Gy Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Chemotherapy 1. Cycle 5-6 Cycles Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Cisplatin 40 mg/m² Brachytherapy: IGABT HDR or PDR EQD 2 60 Gy EQD 2 85 Gy

5 Recent developements (since 2000): Brachytherapy: from 2D (to 3) to 4D Image guidance (MRI (CT, US))+rep Gynexam Adaptive target concept: GTV initial +GTV residual High radiation dose in HR CTV (>85-90 Gy) Reduced dose to organs at risk Bladder, rectum, sigmoid, bowel, vagina

6 Imaging technology development integrating US, CT (and MRI) for CTV HR contouring TRUS: target delineation, applicator reconstsruction TRUS/CT registration via applicator + target transfer to CT ienna Group, work in progress: Nesvacil, M Schmid, C Kirisits comparison of CTV HR from MRI, TRUS, CT MRI TRUS TRUS MRI CT CT

7 Overview of the adaptive target concept in cervix cancer stage IB, IIB, IIIB Initial and residual GTV High Risk CTV Intermediate Risk CTV Low Risk CTV 7 GEC ESTRO Recommendat. I, 2005; ICRU/GEC ESTRO report 89, 2016, Fig

EBRT dose 0 Gy Initial GTV Volume 75 ccm

EBRT dose 9 Gy Cisplatin (40 mg/m 2 ) x1 18 Gy

mg/m 2 ) x3 36 Gy Cisplatin (40 mg/m 2 ) x4 45

Gy Cisplatin (40 mg/m 2 ) x5 GTV CTV modified

8 EBRT dose 0 Gy Initial GTV Volume 75 ccm Example: cervical cancer: total dose 90 Gy EQD2 EBRT dose 9 Gy Cisplatin (40 mg/m 2 ) x1 18 Gy Cisplatin (40 mg/m 2 ) x2 27 Gy Cisplatin (40 mg/m 2 ) x3 36 Gy Cisplatin (40 mg/m 2 ) x4 45 Gy Pre-brachytherapy Residual GTV: 8 ccm EBRT45 Gy Cisplatin (40 mg/m 2 ) x5 GTV CTV modified from ICRU 89, 2016 IGABT 45 Gy Brachytherapy HR CTV 30 ccm

Example: cervical cancer, FIGO IIIB (mod.

Cisplatin (40 mg/m 2 ) x4 45 Gy 45 Gy Cisplatin (40 mg/m 2 ) x5

9 Example: cervical cancer, FIGO IIIB (mod. From ICRU report 89, 2016, Fig. 4.3) EBRT dose EBRT dose 0 Gy 9 Gy Cisplatin (40 mg/m 2 ) x1 18 Gy Cisplatin (40 mg/m 2 ) x2 27 Gy Cisplatin (40 mg/m 2 ) x3 36 Gy Cisplatin (40 mg/m 2 ) x4 45 Gy 45 Gy Cisplatin (40 mg/m 2 ) x5 GTV initial and residual CTV initial and adaptive GTV res total 108 Gy CTV HR total 90 Gy Pre-brachytherapy + 45 Gy Brachytherapy

10 Dose prescription according to risk large variations in initial/adaptive volumes and doses (EMBRACE studies (06/2017)) (n=1416 pats.) EQD2 Initial CTV-T LR 230 cm Gy Initial GTV-T 55 cm Gy Adaptive CTV-T IR 78 cm 3 D90 med. 70 Gy Adaptive CTV-T HR 33 cm 3 D90 med. 89 Gy Residual GTV 9 cm 3 D98 med. 102 Gy

11 ose effect for CTV HR, GTV res and CTV IR Tanderup et al RO, Radiother and Oncol, vol 120,

12 Dose prescription protocol in cervix cancer EMBRACE II ( ) prospective validation of DVH parameters for adaptive BT D90 CTV HR EQD2 10 D98 CTV HR EQD2 10 D98 GTV EQD2 10 D98 CTV IR EQD2 10 Point A EQD2 10 Planning Aims > 90 Gy < 95 Gy > 75 Gy >95 Gy > 60 Gy > 65 Gy Limits for Prescribed Dose > 85 Gy - >90 Gy - -

13 Dose prescription according to risk different volumes receive different doses (EMBRACE studies (06/2017)) (n=1416 pats.) Volumes From 230 cm 3 78 cm 3 55 cm 3 33 cm 3 9 cm 3 LR CTV GGGG dd 89 GGGG dd 102 GGGG EQD2 dd 70 GGGG

Dose prescription protocol in cervix cancer EMBRACE II

validation of DVH parameters for adaptive BT Planning Aims

90 Gy Rectum D 2cm³ EQD2 3 Rectovaginal point EQD2 3

14 Dose prescription protocol in cervix cancer EMBRACE II ( ): OAR dose volume constraints prospective validation of DVH parameters for adaptive BT Planning Aims Limits for Prescribed Dose Bladd er D 2cm³ EQD2 3 < 80 Gy < 90 Gy Rectum D 2cm³ EQD2 3 Rectovaginal point EQD2 3 Sigmoid/ Bowel D 2cm³ EQD2 3 < 65 Gy < 65 Gy < 70 Gy* < 75 Gy < 75 Gy < 75 Gy*

* dose point paramters (2D) ICRU GEC ESTRO 89 (published 062016) Website Oxford University Press: http://jicru.oxfordjournals.

concepts and terms (level 1-3) for cervix cancer brachytherapy for: * volumes, in particular initial/residual GTV initial/adaptive CTV

15 * dose point paramters (2D) ICRU GEC ESTRO 89 (published ) Website Oxford University Press: International Commission for Radiation Units: ICRU (since 1920) European Brachytherapy Group: GEC ESTRO To provide common concepts and terms (level 1-3) for cervix cancer brachytherapy for: * volumes, in particular initial/residual GTV initial/adaptive CTV and OAR (2D/3D/4D) * radiobiological variations (equi-effective dose) * dose volume parameters (3D/4D) * the process from planning aims to prescription

16 Seppenwoolde et al Advances in EBRT: IMRT and IGRT Significant reduction of V43 Gy by ccm achievable (EMBRACE)

17 Clinical Evidence in IGABT Cervix Cancer Upcoming Evidence Mono-institutional cohorts (ongoing, >14 publicat. since 2007) Multi-center cohorts with retrospective evaluation RetroEMBRACE (n=731, first publications in 2016) Prospective Trials STIC: comparative 2D vs. 3D (n=200; published 2012) EMBRACE I: observational, 08/ /2015 (n=1416) EMBRACE II: interventional, start 04/2016

18 Monoinstitutional patient cohorts Table from Mazeron 2015 > patients from 14 centres Castelnau-Marchand et al. Gyn Onc 2015

19 Sturdza et al. R&O 2016 RETRO EMBRACE Vienna (2011) 3y: Loc failure 5% Pelv failure 9% Syst failure 18% 731 patients 12 institutions Loc fail 9-11% Pelv fail 13-16% Syst fail 23-27% Vienna: mean D90 HR CTV 92 Gy Mean D90 HR CTV 84 Gy

20 Sturdza et al. R&O 2016 Pötter et al. R&O 2011 Clinical Results for adaptive RT/BT Local control and FIGO stage RetroEMBRACE (n=731), Vienna (n=158) Local failure RetroEMBRACE 3y Total: 9% IB 2%* IIB 7% IIIB 21% IVA 24% *2 events in IB2 Months Local failure Vienna (2011) 3y Total: 5% IB 0% IIB 4% IIIB 14% IVA 2/6 (n)

adaptive brachytherapy: 10 events P-value= 0.02 P-value= 0.

21 Improved local control with IC/IS in large tumours (retroembrace) Large tumours ( 30 ccm) Small tumours (<30 ccm) ~10% Advanced adaptive brachytherapy: 17 events Limited adaptive brachytherapy: 24 events Advanced adaptive brachytherapy: 4 events Limited adaptive brachytherapy: 10 events P-value= 0.02 P-value= 0.50 Numbers at risk Numbers at risk Fokdal et al RO, Radiotherapy and Oncology 2016 Fortin et al, World Conference Brachytherapy 2016

22 Results on morbidity, PRO, QoL DVH based predictive dose factors Rectum proctitis, bleeding (G1-2), fistula rare Bowel Bladder diarrhea, flatulence (G1-2), anal incontinence (low), stenosis and fistula rare frequency/urgency, incontinence (G1-2), cystitis, bleeding, fistula, ureter strict. (low) Vagina (G 2) stenosis/shorten, dryness, bleeding, mucos. PRO shows significantly more burden Dynamic field with multiple publications coming up, from G2 symptoms for patients Descriptive and analytical evaluations Work in progress, much to learn in near future (EMBRACE)

23 Dose effect relation Vaginal stenosis and ICRU recto-vaginal point (ICRU 89) N=630 multi-centre, prospective EMBRACE patients Kirchheiner et al. Radiotherapy and Oncology 2016

24 Rectal dose volume effects 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., RO P. Georg et al., IJROBP 2011

25 Status Radiotherapy in LACC (062017) Radiochemotherapy with concomitant cis-platin CCRT as 3D CRT or IMRT (favourably as IGRT) Para-aortic RT (risk adapted) (IMRT), SIB (IMRT) Transition from 2D to 3D adaptive Brachytherapy (IGABT) preferably based on MRI (US, CT), rep. gyn exam adpative target concept, adapted application: IC/IS high radiation doses to CTV HR >85-90 Gy EQD2 moderate doses to adjacent OARs Patterns of events and understanding dose/volume effects Adjuvant treatment no standard at present

Hands-on workshops (Vienna, Aarhus >25) International hands-on

technology transfer grants (since 2008) web based contouring

(2017-2019) Cambridge CCMO: web based e-learning program cervix

26 I. Aalderwegen BT acad. C. Verfaillie ESTRO School Ongoing Activities Education & Training Hands-on workshops (Vienna, Aarhus >25) International hands-on workshops (~10) ESTRO School (international programmes): ESTRO School technology transfer grants (since 2008) web based contouring workshops (3 so far) AROI ESTRO Teaching and Training Programme ( ) Cambridge CCMO: web based e-learning program cervix cancer (EMBRACE II) LT Tan, Cambridge IAEA programmes E. Fidarova et al. Umesh Mahantshetty, AROI J. Swamidas, AROI Linking research and education

27 Outlook More evidence from EMBRACE studies (I and II) volume and dose modelling multi-parametric prescription protocols Spread of image guided BT and EBRT using different workflows/technologies CT, US, MRI Prognostic and predictive parameters More patient and treatment selection Development of efficient adjuvant therapy in risk groups

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