This is a Multicentre International Study Evaluating CT-based IGABT With / Without Either TRUS During BT/Pre BT MR as Per IBS-GECESTRO-ABS Recommendations for Target contouring-as an Alternative to MRIGABT for Cervical Cancer From Implementation Perspectives Under EMBRACE-III:TRIPLET IMPACT Study.

The study is a multi-centre prospective observational study. Reporting on the key clinical treatment and outcome parameters are mandatory for the individual centre.

The study will evaluate CT-IGABT for cervical cancer in two different CT based clinico- radiological environments.

Cohort A - Advanced CT Environment: \[CT or MR at Diagnosis\] and \[ (Pre BT MR or TRUS) and CT at BT\] Cohort B - Basic CT Environment: \[CT or MR at Diagnosis\] and \[CT at BT\]

After satisfying the inclusion and exclusion criteria, patients will be taken up in the study.

External Beam Radiotherapy:

The primary focus of this protocol is to prospectively validate the target volume concepts and benchmark the clinical outcomes with CT based IGABT for cervical cancer. However, for the overall outcome of the study with regards to secondary endpoints like regional control and survival as well as to morbidity, the contribution from EBRT may have a certain impact. Harmonization of dose and volume components of EBRT for targets (local and regional) as well as organs at risk is mandatory to ensure comparable treatment volumes across treating centres. Nomenclature of targets and organs at risk preferably needs to be uniform and in line with the EBRT protocols of EMBRACE-II study to maintain uniform reporting. Contrast CT scan in supine position with adequate positioning and immobilisation as per institutional protocols is mandatory for planning, with a slice thickness not exceeding 5 mm (preferably 1-3 mm). Oral contrast and vaginal markers are optional, as per institutional protocols. A reproducible protocol for bladder and rectal filling (at the time of simulation as well as treatment delivery) is mandatory and may be adopted as per institutional protocols. Delineation of target volumes and organs at risk should be done on the planning CT scan, taking into consideration all the information obtained from diagnostic and staging investigations including clinical drawings and NMD's. CTV\_T should include the cervix, parametrium, entire uterus (and adnexa), and 2cm of uninvolved vagina as a minimum. Involved lymph nodes should be contoured as GTV\_N and an optional margin of 0 to 3mm may be given to generate CTV\_N. Lymph nodal regions to be included in elective nodal CTV (CTV\_E). ITV and PTV should be generated around the CTV\_T as per institutional practice (population based generic margins, or patient specific margins based on empty and full bladder scans) and should reflect the protocol employed for reproducible bladder and rectal filling. In general, a total safety margin of approximately 1 to 1.5cm is recommended around the CTV\_T (including ITV and PTV). A PTV should be generated around CTV\_E, and CTV\_N as per institutional practice for elective and involved nodal boost volumes, respectively.

For uniform reporting of EBRT dose-volume parameters, the final PTVs should be labelled as PTV\_Prescribed Dose (Eg: PTV\_45, PTV\_55, etc).

The dose contribution from EBRT must be homogenous for patients included in this study, especially in regions corresponding to the small volumes of interest for BT (CTV-THR-CT and adjacent OARs like anterior-lateral walls of rectum and sigmoid, posterior-inferior wall of the bladder, walls of the vagina adjacent to macroscopic disease, etc). Such homogeneity ensures optimal comparison of dose-volume effects of BT on local control and morbidity.

For reporting dose in defined absolute tissue volumes it is necessary to report the dose for EBRT in each OAR. It is assumed that the small volumes of interest for BT will receive the EBRT dose prescribed to PTV. Therefore, no additional dose volume assessment is required for the different organs at risk, apart from the confirmation that the EBRT dose received in the volumes of interest does not exceed the prescribed dose by ± 5%. If nodal boost given by EBRT is contributing to a specific OAR volume adjacent to / overlapping with the target of interest for BT, the total dose including the EBRT boost dose received by that organ must be reported and used for the cumulative EQD2 calculations for that OAR. Dose volume constraints being utilized in the EMBRACE II protocol may be used as a general reference for treatment planning (Annexure-5). Participating institution to evaluate their EBRT plans, especially when IG-IMRT and/or simultaneous integrated boost techniques are used.

Physical dose ranges for EBRT should not be beyond the range of 45 to 50 Gy in conventional fractionation of 1.8 to 2 Gy per fraction and 5 fractions a week. To compensate for unplanned treatment breaks, however, two daily EBRT fractions at least 6 hours apart may be used. To minimize the risk of consequential late damage, dose accumulation of EBRT must, however, not exceed 12 Gy per week. A nodal boost equivalent to a cumulative dose of 55 to 60 Gy (10) (including potential contribution from BT) may be used for node positive disease, as per institutional practice. Nodal boost may be delivered either as simultaneous integrated boost (SIB) or sequential boost (SEB) using IG-IMRT, without compromising on the overall treatment time. Parametrial / nodal EBRT boost through midline shielding or 3D-CRT is not allowed.

Based on the observations from EMBRACE I study, overall treatment time (OTT) has a significant impact on local control probability. Therefore, OTT (including EBRT, BT and concurrent chemotherapy) must be limited to less than 49 days. Any prolongation in OTT beyond 49 days should be documented and reported, along with specific reasons for such prolongation.

Reporting EBRT parameters:

* Dose per fraction, number of fractions, total prescription for each target * Overall treatment time of whole EBRT * Dose Volume parameters for EBRT as per CRF

* Body Absolute volume (in cc) receiving atleast 43 Gy dose (V43Gy ) * Volume (in cc) of PTV-E

Concomitant chemotherapy:

Cisplatin is to be given intravenously at a dose 40 mg/m2 once a week for a total of preferably 5-6 cycles during the entire course of radiotherapy including BT, according to institutional practice. Patients not suitable for cisplatin chemotherapy are to be excluded from the IMPACT study. Cisplatin dosing may be adjusted / withheld at the discretion of the treating physician, based on tolerance and hematological / renal parametres.

Response to EBRT + Concomitant Chemotherapy:

The categorical classification system is based on the disease extent of the cervix, parametria, vagina, uterine corpus, bladder and rectum at diagnosis and at BT as per IBS-GEC ESTRO - ABS Guidelines.

Brachytherapy:

Treatment planning and performance of BT is based on the recommendations of the "ICRU 89/GEC ESTRO Report" on "Prescribing, Recording and Reporting Brachytherapy for Cancer of the Cervix" (ICRU Report 89, 2013/2016) where the concepts and parameters for image guided adaptive brachytherapy are systematically described.

Overall Schedule for EBRT and BT and chemotherapy:

The overall treatment time (OTT), defined from the first external beam fraction to the end of brachytherapy fraction dose delivered should be \< 49 days. This is based on the Retroembrace and Embrace I clinical outcome studies.

To obtain maximal tumour regression the treatment should always be initiated with EBRT and concomitant chemotherapy for 4-5 weeks before BT is applied in weeks 5-7. For a small and/or well responding tumour BT may be initiated already during EBRT to shorten the overall treatment to 5-6 weeks. In any case every effort should be made to keep the overall treatment time \< 49 days.

Concomitant chemotherapy given on the first 2-3 days of the week also theoretically paves the way for sensitizing more fractions of EBRT in that week, rather than giving chemotherapy towards the weekend where the sensitizing effect is expected to vanish during the weekend. There is limited data on the optimal timing of EBRT and concomitant chemotherapy on the actual day where it is given. Centres can use their own schedule. Minimum of 5 cycles of cisplatin should be delivered throughout the radiation therapy including BT to ensure optimal outcome from concomitant chemotherapy effect.

Pre-Brachytherapy Planning:

For an ideal brachytherapy application for cervix cancer, a pre-planning procedure is essential which allows tailoring the BT application based on tumour topography and patient anatomy at the time of brachytherapy. This requires a comprehensive clinical gynaecologic examination assessing utero-vaginal topography, tumour response at the primary, parametria and vagina after external beam therapy. Precise documentation on the standard gynaecologic template in three orientations including the speculum view is mandatory. These findings can be supported by volumetric imaging like pre-BT MRI, TRUS imaging during BT application to efficiently define the NMD's on CT with BT applicator in situ. An individual adaptive CTV-THR is defined with a certain width, thickness and height based on the above information. Essential are the correlation of these CTV dimensions to cervical canal, later location of tandem, in particular, distances to outer borders of the contemplated CTV-THR and if symmetrical or not. A calculated decision is taken regarding type of application, in particular, if it can be only intracavitary or a combination of intracavitary and interstitial application. The most precise pre-treatment planning is with a tandem and vaginal applicators in place, and position of needles decided on the image taken according to extent of high- risk CTV. The type of BT application, use of interstitial tubes /needles, pre-BT MR protocol with/without tandem/vaginal applicator for each case is at the discretion of the treating physician and Institutional practice.

Based on the Imaging Environment during BT, two clinical scenarios for CT based BT planning can be utilized. BT treatment with more than 1 BT fraction for every BT application is allowed for either environment.

A. Advanced CT Environment: Pre BT MR to assess the regression of primary tumour after EBRT +/- CT, defining target and pre-planning of BT implantation followed by CT Imaging with BT applicator in place. Alternatively, if Pre-BT MR is not feasible, use of TRUS imaging information during BT application to define the target on CT Imaging with BT applicator in situ.

B. Basic CT Environment: CT Imaging with BT Applicator in place-based treatment planning for each BT application.

Patient preparation for BT Application:

Detailed counselling helps in patient acceptance and compliance to application and treatment. Fitness for anaesthesia will be obtained. In case of co-morbidities, adequate time for optimization of drug regimens is provided without compromise in overall treatment time. The practice of ward admission 1 day prior to BT application is encouraged. Bowel preparation is always to be used to ensure relatively empty recto-sigmoid and small bowel, which is of particular importance when interstitial needles in addition to intracavitary treatment are used and if more than one fraction of BT treatment is planned with same application. This would help to prevent major variations in OAR volumes and subsequently the DVH parameters. Supportive treatment such as DVT prophylaxis (lower limb stockings / low molecular weight heparin), antibiotics and analgesics may be given according to individual patient needs and institutional practice.

BT Applicator Implantation:

The procedure should be performed under anaesthesia (General /spinal) with /without sedation. Strict asepsis throughout the BT procedure has to be maintained. Bladder catheterization with 7 ml of normal saline/ distilled water (high density contrast should be avoided) to inflate the foley's balloon and maintaining the tip end towards base of bladder and a mild negative suction using asepto syringe is recommended.

A thorough clinical assessment under anaesthesia with description of primary tumoral extension, and in

• Regional control [Срок оценки: 6, 9, 12, 18, 24, 30 and 36 months]
• Progression free survival [Срок оценки: 6, 9, 12, 18, 24, 30 and 36 months]
• Overall survival [Срок оценки: 6, 9, 12, 18, 24, 30 and 36 months]
• Morbidity [Срок оценки: 6, 9, 12, 18, 24, 30 and 36 months]