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Summary of embrace protocol
- 1. Summary of EMBRACEprotocol Ankita Pandey 1
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- 3. HOW EMBRACE CAMETO PICTURE? • The GEC ESTRO gyn network has designed and initiated the EMBRACE studies which develop, perform and evaluate image guided radiotherapy in cervix cancer with a special focus on improving clinical outcome. • The original focus of EMBRACE studies was MRI based adaptive brachytherapy (EMBRACE I). • It was initiated in 2008 with the aim of evaluating and benchmarking image guided brachytherapy in a prospective multicentre study 3
- 4. Prospective study (EMBRACE protocol) retroEMB RACE study technicaland clinical experience of some European institutions the concepts of the Gyn GEC ESTRO working group 4 On what basis this prospective study was conducted?
- 5. • The RetroEMBRACEstudy was initiated in parallel to the EMBRACE I study. A retrospective data collection was carried out in 12 institutions that had built up clinical experience before the EMBRACE I study, applying the Gyn GEC ESTRO Recommendations for target delineation and dose volume reporting • The EMBRACE II study defines a number of interventions which address local, nodal and systemic treatment as well as exposure of organs at risk. 5
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- 7. SUMMARY OF EMBRACE1 • Retrospective study by GEC ESTRO (MRI based BT). • The major advantage of this technique is the possibility to conform the dose given by BT with regard to both volume (3D) and time (4D). • Thus, by repetitive imaging performed before each BT implant it is possible adapt the dose given by BT to the anatomy of each individual patient taking into account not only the position of OAR but also the tumour regression which often is obtained by preceding EBRT and chemotherapy. 7
- 8. CHARACTERISTICS • Total numberof patients = 1416 • Number of centres = 23 • Accrual time = 2008-2015 • EBRT dose = 45-50Gy in 25-30# • Chemotherapy = concurrent cisplatin (5-6 cycles) • imaging = done after EBRT to assess residual disease • Imaging technique= MRI • BT technique = HDR / PDR • BT fractions = 3-4# of HDR BT or 1-2# of PDR brachy • Type of BT= ICR, interstitial
- 9. EBRT TECHNIQUE • Iso-centrictechnique with more than two opposed fields • No midline block is allowed • 3D image-based conformal radiotherapy or IMRT. • Individualized beam shaping according to target definitions by use of MLC or blocks. • For boost volumes treated by EBRT (60-65Gy) the volume encompassed by the D95 isodose curve of the boost dose should not be larger than 300 cm3 • 2D or 3D verification of patient position at least for the first fraction of EBRT
- 10. DOSE PRESCRIPTION FOREBRT • The following physical dose ranges should be applied for EBRT: PTV-E: 45-50 Gy PTV-P: 60-65 Gy PTV-N: 60-65 Gy • Dose per fraction is 1.5-2.0 Gy for PTV-E, 2.0-2.4 Gy for PTV-P and 2.0 to 2.2 for PTV-N.
- 11. CONTOURING IN BRACHYTHERAPY •Contouring for both tumour and OAR is performed for each insertion/implant of BT applicators by contouring on T2 weighted (para)-transversal MRI sequences in a dedicated 3D brachytherapy dose-planning system according to the GEC ESTRO Recommendations • no safety margins are needed
- 12. Recommended Dose Prescription OAR D2cc bladder ≤90 Gy EQD2 D2cc rectum ≤70-75Gy EQD2 D2cc sigmoid ≤70-75Gy EQD2 TARGET For HDR: cumulative dose from EBRT +BT HR-CTV dose: EQD2=85-90Gy The IR-CTV dose: EQD2=60 Gy. Target coverage D90 should be equal to 100 % prescribed dose
- 13. AIM OF STUDY •To introduce MRI based 3D-4D BT in locally advanced cervical cancer in a multicenter setting within the frame of a prospective observational study. • To establish a bench-mark for clinical outcome with image based BT in a large patient population with respect to local control, survival, morbidity and QoL • To establish a reference material with regard to image based DVH parameters according to the guidelines from the GEC ESTRO working group. • To correlate image based DVH parameters for CTV and for OAR with outcome • To develop prognostic and predictive statistical models for clinical outcome including volumetric, dosimetric, clinical and biological risk factors • To establish radiobiological parameter estimates that will allow a precise risk estimation in individual patients and aid in the development of new treatment protocols
- 14. ENDPOINTS Primary endpoint • Localcontrol within the specific BT targets (HR- CTV and IR-CTV) and morbidity related to OAR in the pelvis. Secondary endpoint • regional control, disease free survival and overall survival.
- 15. 15 AIM 1 AND2 1. To introduce MRI based 3D-4D BT in locally advanced cervical cancer in a multicenter setting within the frame of a prospective observational study. 2. To establish a bench-mark for clinical outcome with image based BT in a large patient population with respect to local control, survival, morbidity and QoL
- 16. 16 Retrospective study thatshowed importance of MRI based contouring and treatment planning in brachytherapy Also established guideline about what parameters to use for effective MRI image that is helpful in tumor delineation and catheter reconstruction
- 17. AIM 3 AND4 • To establish a reference material with regard to image based DVH parameters according to the guidelines from the GEC ESTRO working group. • To correlate image based DVH parameters for CTV and for OAR with outcome 17
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- 19. Findings in EMBRACE Istudy 19
- 20. ARTICLE 1 concept ofisodose surface volumes (ISVs) as the volumes encompassed by clinically relevant equi-effective dose (EQD2) levels (e.g., 60 Gy, 75 Gy and 85 Gy). 20
- 21. 21 With the IGABTand individualized dose prescription practiced in EMBRACE, the median V85 Gy was 72 cm3 which represents a 23% reduction in volume compared to the average standard loading volume with Point A dose
- 22. • Volume de-escalationneeds to be performed with great care as contouring uncertainties can have a significant impact on target dose. Under-contouring can lead to unnecessary dose and volume de-escalation and unwanted increased risk for local recurrence. • CT based IGABT is associated with larger contouring uncertainties than MR based IGABT. • The local control in the retro EMBRACE study was excellent and preliminary results from the EMBRACE I study also indicate high level of local control with the overall volume de-escalation 22
- 23. ARTICLE 2 The response-adaptedtarget volume concept developed by GEC-ESTRO has been validated by analyzing the patterns of local failure in the EMBRACE I study, which found that 98% of local failures were located within the CTV HR and the CTV IR. Reference - (Schmid M, Haie-Meder C, Mahanshetty U, Jürgenliemk-Schulz IM, Segedin B,Hoskin P, et al. Local failures after radiochemotherapy and MR-image-guided brachytherapy in cervical cancer patients. Radiother Oncol 2017;123:S26.)
- 24. ARTICLE 3 In EMBRACEI, early results suggest that the use of combined IC/IS brachytherapy results in less OAR morbidity compared to IC brachytherapy alone in patients with parametrial infiltration Reference- Fortin I, Tanderup K, Haie-Meder C, Lindegaard JC, Mahantshetty U, Segedin B, et al. Image guided brachytherapy in cervical cancer: a comparison between intracavitary and combined intracavitary/interstitial brachytherapy in regard to doses to HR CTV, OARs and late morbidity – early results from the embrace study in 999 patients. Brachytherapy 2016;15:S21.
- 25. The overall rateof EMBRACE I patients developing nodal failure was low (crude 11%) with significantly less failures in patients without pathologic nodes at diagnosis compared to the node positive ones (7% versus 16%, respectively) (data under evaluation). Reference- Berger T, Assenholt M, Seppenwoolde Y, Mahantshetty UM, Jürgenliemk- Schulz IM, Hoskin P, et al. Importance of technique, dose prescription, and contouring in cervix external beam radiation therapy: current and future practice in a large multicenter study (EMBRACE). Int J Radiat Oncol Biol Phys 2016;96:E292. ARTICLE 4
- 26. Summary of retro EMBRACEstudy 26
- 27. 27 histologically confirmed cervicalcancer, treatment with curative intent by definitive EBRT ±concomitant chemotherapy followed by IGBT with MRI/CT guidance para-aortic nodal disease as the exclusive site of extra-pelvic disease at the time of diagnosis were also eligible Patients treated between January 1998 and August 2012 were included Median follow up of the entire cohort - 43 months (mean 47 months, range 2– 169 months).
- 28. 28 Overall 3/5 yearLC was 91% and 89% In the 581 patients treated with MRI- based IGBT, 3-year LC – 95% for tumours <5 cm 85% for tumours >/= 5 cm Three year and Five-year OS of 74% and 65%. OS : ( 3 year/ 5 year) IB : 88%/83% (21/123), IIB : 78%/70% (114/368), IIIB : 56%/42% (75/145),
- 29. Summary of EMBRACEII protocol 29
- 30. The aims ofthe EMBRACE II study are to prospectively validate the findings of the Retro EMBRACE and EMBRACE I studies and to benchmark an excellent overall survival, based on improved local, nodal and systemic control, as well as reduction of morbidity and improvement of quality of life. 30
- 31. AIM OF STUDY 1.IMRT with daily IGRT as well as advanced image guided adaptive BT in a prospective multi-centre setting 2. dose prescription protocol for IGABT 3. contouring, prescription and reporting for EBRT CTV and OARs. 4. to improve para-aortic and systemic control in high risk patients and not to decrease lymph node control in low risk and intermediate risk patients 5. To benchmark an outstanding high level of local, nodal and systemic control as well as survival with application of advanced EBRT, BT and chemotherapy within limited overall treatment time 6. To benchmark a low incidence of intermediate and major morbidity as well as a high level of quality of life with application of advanced EBRT, BT and chemotherapy 31
- 32. EBRT= 45Gy/ 25#/5weeks IMRT / VMAT MRI based contouring CTV to ITV margin of 5mm Involved nodes are boosted preferably based on PET CT with 10-15 Gy and treated as simultaneous integrated boost within 5 weeks (2.2-2.4 Gy per fraction) OTT= 50 days TREATMENT PROTOCOL
- 33. Based on theevidence from EMBRACE, Retro EMBRACE and literature findings, three categories will be defined according to the risk of nodal and systemic recurrence: 1. low risk 2. intermediate risk 3. high risk
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- 35. • Total doseto PTV-Ns of about 60 Gy EQD2 can be achieved with the following fractionation schedules: • Inside true pelvis: EBRT with SIB 25x2.2Gy= 55Gy physical dose. This schedule is equivalent to 56 Gy EQD2 EBRT + 3-4 Gy EQD2 from BT which results in a total dose of ~60 Gy EQD2. • Outside true pelvis: EBRT with SIB 25x2.3Gy =57.5 Gy physical dose. This schedule is equivalent to ~59 Gy EQD2 and BT dose contribution is negligible.
- 37. • dose escalationfor advanced disease with large adaptive CTV-T HR including IC/IS techniques and dose de-escalation for limited size CTV-T HR to spare organs at risk and in particular the upper vagina. • imaging method is MRI • The applicator and the reference points are reconstructed in the same image series. • All treatment plans have to be optimized to achieve defined planning aims for dose and volume parameters for tumor (D98 for GTVres) and target volumes (e.g. D90-95 Gy for adaptive CTV-T HR) and for 2cm3 reference volumes for OARs (e.g. <80 Gy for bladder, <65 Gy for rectum) and for vaginal reference points (recto-vaginal point < 65 Gy, PIBS). Brachytherapy
- 38. • All treatmentplans have to be optimized to achieve defined planning aims for dose and volume parameters for tumor 1. D98 for GTVres 2. D90-95 Gy for adaptive CTV-T HR 3. 2cm3 reference volumes for OARs (e.g. <80 Gy for bladder, <65 Gy for rectum) and for vaginal reference points (recto-vaginal point < 65 Gy, PIBS).
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- 40. RATIONALE OF DOSEESCALATION • suboptimal local control is predicted for the patients not achieving the 85 Gy constraint. • The ability to reach dose constraints for both targets and OARs relies on a change of practice, which mainly involves increased use of IC/IS brachytherapy. • patients with small tumors at the time of brachytherapy and small CTVHR (<30 cm3), were treated to high doses which did not translate to higher local control. There is therefore potential to de-escalate the dose in these patients to reduce OAR dose. 40
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- 42. • In EMBRACEII, the improved therapeutic window (through increased application of IC/ IS) will be exploited for tumour dose- escalation and/or OAR dose de-escalation. • In tumors with large residual CTVHR volumes at time of brachytherapy, dose-escalation has the potential to improve local control significantly. • In limited size CTVHR volumes dose-de-escalation will be performed since dose de-escalation has minor impact on local control while it has potential to reduce morbidity. 42
- 43. OUTCOME HYPOTHESIS OFEMBRACE II 43
- 44. REASON FOR BETTEROUTCOME • Increased use of IC/IS brachytherapy • Protocol for target and OAR contouring for EBRT and BT • Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence • Use of IMRT/VMAT and daily IGRT for EBRT delivery (45 Gy in 25 fractions to elective target volume) • Use of simultaneous integrated boost for pathological lymph nodes • Systematic application of concomitant chemotherapy • Reduction of overall treatment time 44
- 45. in-room imaging daily imaging couchcorrection according to fusion on bony anatomy With daily imaging, bony image fusion, and couch correction, a margin reduction from 10mm to 5mm can be performed without compromising target coverage. The 5mm margin reduction has potential to decrease the volume irradiated to 43Gy by approximately 500 cm3, which is expected to decrease bowel morbidity by ~50%
- 46. • Some newconcepts will be introduced for OAR contouring. Instead of contouring the abdominal cavity, the bowel loops will be outlined in one volume restricted to the outer contour of bowel loops including the mesenterium. • This will allow for a better approximation of the bowel loops volume and optimization of the dose constraints. • Rectum and sigmoid structures will be contoured as distinct structures. Vaginal lower border will be not more than 2.5cm from the caudal extend of the tumor (2cm in the ITV-LR initial + 0.5cm PTV).
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- 48. • The majorcurrent challenges in treatment of locally advanced cervical cancer are (1) local control in advanced tumours (2) treatment-related morbidity and quality of life (3) distant metastatic spread with the para-aortic region being one of the most common sites of distant failure (4) selection of patients for additional systemic treatment. • EMBRACE II will address these challenges through state of the art brachytherapy applicators, advanced EBRT, increased administration of para-aortic irradiation and systematic use of chemotherapy (5 cycles) in an international multicentre setting. • The EMBRACE II study is expected to further improve disease control, morbidity and QoL compared to EMBRACE I and retroEMBRACE. 48
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