Recognising the challenges of implementing multi-centre adaptive plan of the day radiotherapy.

Two multicentre adaptive radiotherapy trials utilising Plan of the Day (PoD) with a library of plans were introduced in 35 centres. The common issues that arose from all centres when introducing PoD were collated retrospectively, through reviewing the data pertaining to the pre-trial and on-trial quality assurance programme. It was found that 1,295 issues arose when introducing PoD in outlining, planning, treatment delivery i.e., PoD selection, and in the overall process of delivering PoD. There was no difference in the number of issues that arose from pre-trial to on-trial. Thus, it is recommended that the implementation of PoD is supported by guidance, reviews, and continuous monitoring.

Clinical Outcomes of a Randomized Trial of Adaptive Plan-of-the-Day Treatment in Patients Receiving Ultra-hypofractionated Weekly Radiation Therapy for Bladder Cancer.

PURPOSE: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy. METHODS: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint. RESULTS: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%). CONCLUSIONS: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.

Protocol for hypofractionated adaptive radiotherapy to the bladder within a multicentre phase II randomised trial: radiotherapy planning and delivery guidance.

INTRODUCTION: Patients with muscle invasive bladder cancer (MIBC) who are unfit and unsuitable for standard radical treatment with cystectomy or daily radiotherapy present a large unmet clinical need. Untreated, they suffer high cancer specific mortality and risk significant disease-related local symptoms. Hypofractionated radiotherapy (delivering higher doses in fewer fractions/visits) is a potential treatment solution but could be compromised by the mobile nature of the bladder, resulting in target misses in a significant proportion of fractions. Adaptive 'plan of the day' image-guided radiotherapy delivery may improve the precision and accuracy of treatment. We aim to demonstrate within a randomised multicentre phase II trial feasibility of plan of the day hypofractionated bladder radiotherapy delivery with acceptable rates of toxicity. METHODS AND ANALYSIS: Patients with T2-T4aN0M0 MIBC receiving 36 Gy in 6-weekly fractions are randomised (1:1) between treatment delivered using a single-standard plan or adaptive radiotherapy using a library of three plans (small, medium and large). A cone beam CT taken prior to each treatment is used to visualise the anatomy and select the most appropriate plan depending on the bladder shape and size. A comprehensive radiotherapy quality assurance programme has been instituted to ensure standardisation of radiotherapy planning and delivery. The primary endpoint is to exclude >30% acute grade >3 non-genitourinary toxicity at 3 months for adaptive radiotherapy in patients who received >1 fraction (p0=0.7, p1=0.9, α=0.05, ß=0.2). Secondary endpoints include local disease control, symptom control, late toxicity, overall survival, patient-reported outcomes and proportion of fractions benefiting from adaptive planning. Target recruitment is 62 patients. ETHICS AND DISSEMINATION: The trial is approved by the London-Surrey Borders Research Ethics Committee (13/LO/1350). The results will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities. TRIAL REGISTRATION NUMBER: NCT01810757.

Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance.

INTRODUCTION: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. METHODS AND ANALYSIS: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes. ETHICS AND DISSEMINATION: This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities. TRIAL REGISTRATION NUMBER: NCT02447549; Pre-results.

Quality assuring "Plan of the day" selection in a multicentre adaptive bladder trial: Implementation of a pre-accrual IGRT guidance and assessment module.

BACKGROUND AND PURPOSE: Hypofractionated bladder RT with or without image guided adaptive planning (HYBRID) is a multicentre clinical trial investigating "Plan of the Day" (PoD) adaptive radiotherapy for bladder cancer. To ensure correct PoD selection a pre-accrual guidance and assessment module was developed as part of an image guided radiotherapy quality assurance (IGRT QA) credentialing programme. This study aimed to evaluate its feasibility and effectiveness across multiple recruiting centres. MATERIALS AND METHODS: Individuals from participating centres remotely accessed an image database in order to complete the PoD module. An assessment score of ≥83% was required in order to receive QA approval. A questionnaire was used to gather user feedback on the module. PoD decisions for the first patient at each recruiting centre were retrospectively reviewed for protocol adherence. RESULTS: 71 radiation therapists (RTTs) from 10 centres completed the PoD module. The median assessment score was 92% (Range: 58-100%) with 79% of RTTs passing the assessment on first attempt. All questionnaire respondents reported that the PoD module prepared them for plan selection. In 51/60 of on-trial treatments reviewed, the PoD selected by the centre agreed with QA reviewers. CONCLUSIONS: The PoD QA module was successfully implemented in a multicentre trial and enabled pre-accrual assessment of protocol understanding. This increased operator confidence and resulted in appropriate PoD selection on-trial.

A new era for clinical trial quality assurance: A credentialing programme for RTT led adaptive radiotherapy.

•A multi-centre QA programme incorporating adaptive plan selection has been developed.•This novel QA approach has been validated by 71 RTTs from ten UK centres.•A multidisciplinary approach is essential in the development of a credentialing programme.