A Study of Short-course Hypofractionated Online-adaptive Radiotherapy for the Post-operative Treatment of Endometrial Cancer: Tolerability and Feasibility

Background and Rationale Endometrial cancer treatment often requires a multi-modality approach, with patients usually treated with up-front surgical resection followed by a combination of adjuvant chemotherapy, adjuvant external beam radiotherapy (EBRT), and vaginal vault brachytherapy. During EBRT, the target treatment area includes the mobile vaginal vault, necessitating large clinical target volume (CTV) to planning target volume (PTV) margins (10 to 15 mm) of the vaginal vault to account for daily interfraction motion. These large margins lead to significant radiation dosage to the adjacent bladder, rectum, and bowel, which increases the risk of toxicity.

While hypofractionation offers resource and health-economic advantages, its use in endometrial cancer has historically been limited due to the large fields required and the associated risks of late adverse normal tissue effects. However, Online-Adaptive Radiotherapy (OART) allows for the daily re-definition of targets and surrounding organs, and daily replanning, whilst the patient remains on the treatment couch. By mitigating interfraction motion, CT-based OART (CT-OART) can safely reduce the CTV to PTV margins, making the delivery of a hypofractionated dose feasible. This trial leverages CT-OART to test the safety and feasibility of a shortened, ultra-hypofractionated treatment course for post-operative radiotherapy in endometrial cancer.

Study Aims The primary aim is to determine the safety of a shortened ultra-hypofractionation regimen of 30 Gray in 5 fractions, delivered via a CT-OART approach for the post-operative treatment of endometrial cancer.

Secondary aims include determining the feasibility of this ultrahypofractionated regimen on a CT-online adaptive platform, assessing clinician and patient-reported acute toxicity up to 12 weeks following completion of radiotherapy, and late toxicity up to 2 years following completion of radiotherapy, assessing patient-reported quality-of-life up to 2 years following completion of radiotherapy, and assessing overall survival (OS), disease-free survival (DFS) and pelvic relapse-free survival (PRFS) up to 2 years following completion of radiotherapy.

Study Design The SHORTEN trial is a single-site, single-arm, non-blinded Phase IIA trial (R-IDEAL framework). The study aims to recruit 30 adult participants with fully resected endometrial cancer and an indication for post-operative external beam radiotherapy.

All participants who consent to the trial will receive an experimental ultra-hypofractionation regimen of 30 Gray in 5 fractions. This treatment will be delivered on alternate weekdays utilizing a CT-online adaptive radiotherapy platform. Participants are permitted to receive adjuvant sequential chemotherapy either before or after radiotherapy, and vaginal vault brachytherapy boost if clinically indicated, but concurrent chemoradiotherapy is an exclusion criterion.

Treatment Pathway and Follow-up Eligible participants will have a baseline CT Thorax Abdomen and Pelvis (CT-TAP / CT-CAP) to exclude metastatic disease prior to trial participation, and baseline blood tests. In participants who have undergone chemotherapy prior to planned radiotherapy there will be a repeat blood test planned within 7 days of beginning trial radiotherapy. Clinician-assessed (CTCAE 6.0) and patient-assessed toxicity (PRO-CTCAE), patient-reported quality-of-life (EORTC QLQ-C30 \& EN24 Module, ED-5D-5L) will be recorded at baseline.

Participants will undergo an offline radiotherapy planning CT scan, which will be used to outline and plan radiotherapy. If there is a significant concern from baseline anatomy on the planning CT scan that organ of interest constraints cannot be met, then patients will either be offered a second planning CT scan, or excluded from trial participation at this point. These patients would still endeavour to be offered CT-OART outside of the trial framework with radiotherapy delivered with standard dose-fractionation over 25 sessions. The number of participants excluded at this point in the trial would be retained for reporting.

For CT-OART process, an on-set CT scan obtained at the beginning of each online session will be used for repeat target and organ of interest contouring, online planning and plan approval. A second CT scan will be taken immediately prior to treatment to verify participant positioning and perform any adjustments as necessary. Immediately following completion of treatment, a third CT scan will be performed to assess for possible participant movement during treatment delivery. All timings of the workflow, and any problems or unexpected events during radiotherapy delivery will be recorded. Participants will also complete an OART tolerability questionnaire on the last day of radiotherapy. Clinician-assessed toxicity (CTCAE 6.0) will be recorded at the end of the first week of radiotherapy, and on the last-day of radiotherapy. On the last day of radiotherapy, patient-reported toxicity (PRO-CTCAE), patient-reported quality-of-life (EORTC QLQ-C30 \& EN24, EQ-5D-5L) will also be recorded and a blood test for full blood count (FBC) undertaken.

Follow-up following completion of radiotherapy will be at 2 weeks, 5 weeks, 12 weeks, 6 months, 9 months, 12 months, 16 months, 20 months and 24 months, with visit windows permitted. Emergent toxicity assessed outside of these timepoints will be recorded at the nearest timepoint visit. Clinician-assessed and patient-reported toxicity (PRO-CTCAE) will be assessed at all visits. At the 2, 5 and 12-week visit quality-of-life (EORTC QLQ-C30 \& EN24, EQ-5D-5L) questionnaires will be undertaken alongside repeat blood tests (FBC). A clinical examination for recurrence, and response assessment scan (CT-TAP) will also be undertaken at the 12-week appointment. Thereafter a clinical examination will be completed at the 6-month, 9-month, 12-month, 16-month, 20-month and 24-month visit, with CT-TAP and Quality-of-life questionnaires at the 12-month and 24-month visit.

Diagnosis of recurrence can be made from radiological findings consistent with recurrence, tissue biopsy or cytological specimen, or concerning clinical examination features subsequently confirmed to represent disease recurrence. If a participant experiences disease recurrence during the trial period, they will be managed as per standard management relevant to site and stage of recurrence. As recurrence may necessitate treatment which may impact upon validity of assessment of post-radiotherapy toxicity, then they will not be included within analyses from the point of recurrence, and questionnaire completion will also cease at this time-point.

Participants may withdraw from study participation at any time. If this is due to poor tolerability of CT-OART then aim would be for participant to complete radiotherapy with standard dose-fractionation on conventional linear accelerator. They would continue within trial follow-up population unless they also wish to discontinue trial involvement fully. Participants may be withdrawn by trial investigators due to attributable grade 4 (CTCAE 6.0) toxicity occurring during the radiotherapy course, an inability to safely tolerate CT-OART, or for an unexpected machine breakdown precluding completion of radiotherapy course in a timely manner. These participants would remain within trial analysis population, other than for the primary endpoint (unless radiotherapy was stopped early due to grade 4 toxicity in which case they would be included within the analysis population).

The end of the trial will be the date of the last visit, at 2 years following completion of radiotherapy, of the last trial participant.