Image Guided IMRT, Radiochemotherapy and MRI-based IGABT in Locally Advanced Cervical Cancer

Summary

The research group on adaptive image-guided radiotherapy for locally advanced cervical carcinoma completed the protocol for the EMBRACE II study in October 2018. This study will be carried out in the next few years at the University Clinic for Radiotherapy at the Medical University of Vienna and other international partner institutes. EMBRACE II builds on the findings of the current EMBRACE study. These are already implemented in everyday clinical practice in order to further improve the accuracy of the entire therapy of cervical carcinomas, using state-of-the-art techniques of tele- and brachytherapy. The aim of the EMBRACE II study is to maintain and enhance the excellent local tumor control as well as the nodal and systemic control for all tumor stages while minimizing the adverse reaction rates for all affected organs (rectum, sigmoid, urinary bladder, and vagina) to increase the quality of life of patients with cervical carcinomas.

Conditions

• Uterine Cervical Neoplasms

Interventions

RADIATION

Increased use of IC/IS technique in BT

In EMBRACE II, the improved therapeutic window (through increased application of IC/IS) will be exploited for tumour dose-(de-)escalation and/or OAR dose de-escalation. In tumours 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. The strategy of EMBRACEII is to aim for an application of the IC/IS technique in at least 20% of the patients in each institution. The threshold of 20% is relevant for a classical stage distribution of \~20% IB, \~50% IIB, \~20% IIIB and \~10% others. If a given patient population includes significantly higher proportions of limited or extensive disease, the threshold of 20% IC/IS applications must be adapted.

RADIATION

Reduction of vaginal source loading

A multicenter investigation in 50 EMBRACE patients from 3 institutions (Mohamed SM. et al, in submission 2015) shows that reduced loading in ring/ovoids and increased loading in tandem (and needles when available) can be applied without compromising CTVHR and GTVres dose. Decrease of relative vaginal loading from a mean of 50% to 33% had potential to reduce ICRU recto-vaginal dose by a mean of 4±4Gy, and furthermore, bladder and rectum doses could be reduced by 2-3Gy with the same re-arrangement of loading. Similar evidence is available from a study on simulation of different intracavitary standard loading patterns in EMBRACE patients, where it was shown that limited size tumours could often be covered by tandem loading alone (Nkiwane KS. et al. 2013).

RADIATION

Systematic utilisation of IMRT

Many institutions deliver 3D conformal radiotherapy (3D CRT) based on a four-field box technique although IMRT has been available for a number of years. The practice in EMBRACEI has been utilisation of IMRT and 3D CRT in 27% and 73% of the patients, respectively. However, EMBRACE morbidity data as well as data published by Mundt et al (Mundt AJ. et al. 2003) indicate that IMRT significantly reduces the incidence of bowel morbidity, and therefore IMRT is considered as instrumental for reducing the incidence of bowel morbidity and with a potential also to be beneficial for urinary morbidity.

RADIATION

Utilisation of daily IGRT (set-up according to bony structures)

PTV margins of 10 mm to the elective lymph node target are currently applied in many institutions. This margin is related to set-up uncertainties with patient positioning performed based on skin marks. However, currently, most institutions have in-room imaging available which makes it possible to perform daily imaging and couch correction 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 (Laursen LV. et al. 2012). The 5mm margin reduction has potential to decrease the volume irradiated to 43Gy by approximately 500cm, which is expected to decrease bowel morbidity by \~50%.

RADIATION

EBRT target concept related to the primary tumor (CTV-T) and internal motion; concepts for OAR contouring

New target concepts are introduced for EBRT related to primary tumor: initial CTV-T, initial CTV-HR, initial CTV-LR and ITV-LR. Use of this novel contouring approach in conjunction with available MRI allows to target safely the visible tumor (CTV-T) and the high risk region (CTV-HRintitial) while consenting for dose to a low risk region (CTV-LRinitial). Anatomical changes due to organ filling variation and cervix/uterus position are considered. ITV-LR is outlined using planning scan and MR images in patients with MRI in treating position while a fixed margin is added to the CTV-LR initial in patients with only diagnostic MRI. New concepts are introduced for OAR contouring. Bowel loops are outlined in one volume restricted to the outer contour, including the mesenterium, for better approximation of the bowel volume and dose constraints. Rectum/sigmoid structures are contoured distinctly. Vaginal lower border is 2,5cm from the caudal extend of the tumor (2cm ITV-LR initial + 0,5cm PTV).

RADIATION

EBRT dose prescription and reporting

There is currently a significant variation with regard to EBRT dose and fractionation in the EMBRACE study with doses ranging from 45Gy to 50Gy and being delivered in 25-30 fractions. Furthermore, there is a wide variety of lymph node boosting strategies. In EMBRACEII, the EBRT dose and fractionation to the elective lymph node CTV and initial CTV-T is fixed at 45Gy in 25 fractions, and lymph node boosting must be performed as a simultaneous integrated boost. The dose de-escalation from 50Gy to 45Gy has potential to reduce morbidity. A system of reporting dose to targets and OARs is introduced in terms of dose volume parameters and a system of point dose reporting for the vagina.

RADIATION

Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence

EMBRACEII applies a risk adapted target concept for nodal CTV. This target concept is based on pattern of nodal recurrence analysis which shows 50% of recurrences beyond the classical L5/S1 cranial pelvic field border. A target volume "Large Pelvis" is defined for intermediate risk patients and includes internal, external, common iliac, obturator and presacral nodes. For high risk patients, defined as common iliac or \>2 nodes involved, the para-aortic region is included. For low risk patients, defined as stage IA/IB1/IIA1, N0, small cell carcinoma (SCC), no uterine invasion, "Small Pelvis" is defined which is "Large Pelvis" without common iliac nodes. Intermediate risk is defined as not high and not low risk.

DRUG

Systemic application of simultaneous chemotherapy

According to international standard and evidence, simultaneous chemotherapy (CHT) (min. 5x40 mg/m2 cis Platinum) was prescribed in the EMBRACE protocol for all patients, who qualify for its administration. Certain rules were given for adaption according to international guidelines. 90-95% of EMBRACE patients received simultaneous CHT. Most of the EMBRACE cohort is consecutive patients representing the cervix cancer patient population in the respective centers. About 70% of patients received ≥5 cycles, while 30% received 0-4 cycles. CHT has impact on systemic control, which is pronounced in high risk patients (node positive and/or stage III/IV) with a 20% difference in systemic recurrence. A center effect has been found in the ability to administer chemotherapy with 15-85% of the patients receiving ≥5 cycles of CHT. To reach optimal outcome, particularly in the high risk group, the EMBRACEII protocol also focusses on appropriate administration of CHT following international guidelines.

OTHER

Reduction of overall treatment time

Several studies indicate that maintaining an overall treatment time (OTT) of \<=50 days is important for local control. RetroEMBRACE data confirms that OTT remains of importance in the realm of IGABT. As there is significant variation of OTT across patients and institutions in retroEMBRACE, the EMBRACEII study aims to reduce the OTT so that the majority of patients (\>80%) will adhere to the \<=50 day threshold. The measures to reduce OTT in EMBRACE is to systematically apply 25 fractions of EBRT including lymph node boost, and furthermore to carefully plan the BT schedule, so that brachytherapy is delivered towards the end of EBRT and/or directly after EBRT.

Sponsors & Collaborators

• Universitaire Ziekenhuizen KU Leuven

  collaborator OTHER

• Aarhus University Hospital

  collaborator OTHER

• Rigshospitalet, Denmark

  collaborator OTHER

• Odense University Hospital

  collaborator OTHER

• North Estonia Medical Centre

  collaborator OTHER

• Institut Bergonié

  collaborator OTHER

• Gustave Roussy, Cancer Campus, Grand Paris

  collaborator OTHER

• University Hospital Heidelberg

  collaborator OTHER

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  collaborator OTHER

• Oslo University Hospital

  collaborator OTHER

• Institute of Oncology Ljubljana

  collaborator OTHER

• Complejo Hospitalario de Navarra

  collaborator OTHER

• Hospital Clinic of Barcelona

  collaborator OTHER

• Skane University Hospital

  collaborator OTHER

• Region Örebro County

  collaborator OTHER

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  collaborator OTHER

• Radiotherapiegroep

  collaborator OTHER

• Leiden University Medical Center

  collaborator OTHER

• Maastro Clinic, The Netherlands

  collaborator OTHER

• UMC Utrecht

  collaborator OTHER

• The Netherlands Cancer Institute

  collaborator OTHER

• Radboud University Medical Center

  collaborator OTHER

• Catharina Ziekenhuis Eindhoven

  collaborator OTHER

• Erasmus Medical Center

  collaborator OTHER

• Cambridge University Hospitals NHS Foundation Trust

  collaborator OTHER

• The Leeds Teaching Hospitals NHS Trust

  collaborator OTHER

• The Christie NHS Foundation Trust

  collaborator OTHER

• University Hospitals Coventry and Warwickshire NHS Trust

  collaborator OTHER

• University Hospitals Bristol and Weston NHS Foundation Trust

  collaborator OTHER

• Royal Marsden NHS Foundation Trust

  collaborator OTHER

• Cross Cancer Institute

  collaborator OTHER

• McGill University

  collaborator OTHER

• Princess Margaret Hospital, Canada

  collaborator OTHER

• Tom Baker Cancer Centre

  collaborator OTHER

• Loyola University Chicago

  collaborator OTHER

• M.D. Anderson Cancer Center

  collaborator OTHER

• University of Pittsburgh

  collaborator OTHER

• Pamela Youde Nethersole Eastern Hospital

  collaborator OTHER

• Tuen Mun Hospital

  collaborator OTHER_GOV

• Post Graduate Institute of Medical Education and Research, Chandigarh

  collaborator OTHER

• Tata Memorial Centre

  collaborator OTHER

• Chulalongkorn University

  collaborator OTHER

• Siriraj Hospital

  collaborator OTHER

• Liverpool Hospital, Sydney

  collaborator UNKNOWN

• Maisonneuve-Rosemont Hospital

  collaborator OTHER

• National Cancer Institute, Slovakia

  collaborator OTHER_GOV

• Institut Català d'Oncologia

  collaborator OTHER

• Ludwig-Maximilians - University of Munich

  collaborator OTHER

• Mount Vernon Cancer Centre

  collaborator UNKNOWN

• St Thomas' Hospital, London

  collaborator OTHER

• Medical University of Vienna

  lead OTHER

Principal Investigators

• Richard Pötter, MD · Medical University of Vienna

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

99 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-04-30

Primary Completion

2021-12-31

Completion

2031-04-30

Countries

• Austria

Study Locations