Study: NCT03617133

Intervention type: RADIATION
Group type: OTHER
Intervention: Systematic utilisation of IMRT
Description: 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.

Intervention type: RADIATION
Group type: OTHER
Intervention: Utilisation of daily IGRT (set-up according to bony structures)
Description: 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%.

Intervention type: RADIATION
Group type: OTHER
Intervention: EBRT target concept related to the primary tumor (CTV-T) and internal motion; concepts for OAR contouring
Description: 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).

Intervention type: RADIATION
Group type: OTHER
Intervention: EBRT dose prescription and reporting
Description: 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.

Intervention type: RADIATION
Group type: OTHER
Intervention: Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence
Description: 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.

Intervention type: DRUG
Group type: OTHER
Intervention: Systemic application of simultaneous chemotherapy
Description: 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.

Intervention type: OTHER
Group type: OTHER
Intervention: Reduction of overall treatment time
Description: 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.