Dataset Information

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.

ABSTRACT:

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.

SUBMITTER: Hafeez S

PROVIDER: S-EPMC7780718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionPatients 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 analysisPatients 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, β=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 disseminationThe 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 numberNCT01810757.

Project description:BackgroundNeo-adjuvant chemotherapy followed by radical cystectomy with extended pelvic lymph node dissection is considered to be the treatment of choice for patients with muscle invasive bladder cancer (MIBC). Despite this aggressive treatment the outcome is poor and ultimately, 30% of the patients with ≥pT3 tumors develop a pelvic recurrence. We hypothesize that postoperative adjuvant external beam radiotherapy (EBRT) might prevent local and lymph node recurrence and improve disease free- and overall survival as loco-regional recurrence is linked to the development of distant metastasis.MethodsWe plan to perform a multicentric prospective phase two study including 76 patients. Eligible patients are patients with MIBC, treated with radical cystectomy and presenting with ≥1 of the following characteristics: Pathological (p)T3 stage + presence of lymphovascular invasion on pathological examination pT4 stage <10 lymph nodes removed positive lymph nodes positive surgical margins Patients will have a 18F-FDG PET-CT to rule out the presence of distant metastasis prior to EBRT. A median dose of 50 Gy in 25 fractions is prescribed to the pelvic lymph node regions with inclusion of the operative bladder bed in case of a positive surgical margin. Patients with suspected lymph nodes on PET- CT can still be included in the trial, but a simultaneous integrated boost to 74Gy to the positive lymph nodes will be delivered. Blood and urine samples will be collected on day-1 and last day of EBRT for evaluation of biomarkers. The primary endpoint is evaluation of acute ≥Grade 3 intestinal or grade 4 urinary toxicity, in case of a neo-bladder reconstruction, within 12 weeks after EBRT. Secondary endpoints are: assessment of QOL, late RTOG toxicity, local control, disease free survival and overall survival. Biomarkers in urine and blood will be correlated with secondary survival endpoints.DiscussionThis is a prospective phase 2 trial re-assessing the feasibility of adjuvant radiotherapy in high-risk MIBC.Trial registrationThe Ethics committee of the Ghent University Hospital (EC2014/0630) approved this study on 31/07/2014. Trial registration on Clinicaltrials.gov ( NCT02397434 ) on November 19, 2014.