Study of Tumour Focused Radiotherapy for Bladder Cancer

Study Overview
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Brief Summary
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Bladder cancer is the seventh most common cancer in the UK, with 10,399 new cases diagnosed in 2011. In a quarter of these cases the cancer has infiltrated the muscular wall of the bladder (muscle invasive) and is life threatening. This type of bladder cancer is usually treated either with surgical removal of the bladder, or daily radiotherapy treatment (high strength xrays which kill cells), given every day for 4 or 7 weeks. RAIDER will investigate methods which have the potential to improve how well this radiotherapy works. RAIDER is based on a study of novel radiotherapy techniques which was conducted at a single UK NHS Trust. Bladder radiotherapy is normally delivered using a single plan throughout treatment and treats the whole bladder with the same radiotherapy dose. In adaptive radiotherapy the delivery plan is chosen from 3 possible plans. In cancer (tumour) focused radiotherapy, the highest dose of the radiotherapy is aimed at the tumour within the bladder. In RAIDER, at least 240 participants with muscle invasive bladder cancer will be in one of 3 treatment groups: standard whole bladder radiotherapy standard dose tumour focused adaptive radiotherapy dose escalated tumour boost adaptive radiotherapy Participants will visit the hospital 4 weeks, 3, 6, 9, 12, 18 and 24 months after radiotherapy and annually thereafter to check whether the cancer has returned and to receive treatment for any symptoms they may be experiencing. RAIDER aims to confirm in a multicentre setting that novel techniques allow a higher radiotherapy dose than standard to be reliably targeted at the tumour within the bladder and to check that the long term side effects of the treatment are acceptable. If this is the case, results of RAIDER will be used to develop a study to establish whether dose escalated radiotherapy is better at treating bladder cancer than standard dose.

Detailed Description
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RAIDER has a two stage design. Stage 1 will establish the feasibility of delivering DART in a multi-centre setting, and stage 2 will establish the toxicity of DART. 72 patients will be recruited in stage 1, with at least an additional 168 patients in stage 2 (sufficient to recruit 57 evaluable participants to the DART group in each fractionation cohort). Both fractionation regimens in standard use in UK are included - 32f and 20f. Participants will be permitted to receive concomitant chemotherapy. Primary endpoints will be assessed in each fractionation cohort separately with the flexibility to drop either a fractionation cohort or an experimental treatment group (on advice of Independent Data Monitoring Committee) following completion of stage 1.

Official Title
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A Randomised Phase II Trial of Adaptive Image Guided Standard or Dose Escalated Tumour Boost Radiotherapy in the Treatment of Transitional Cell Carcinoma of the Bladder

Conditions
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Bladder Cancer

Intervention / Treatment
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* Radiation: WBRT
* Radiation: SART
* Radiation: DART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥16 years Histologically or cytologically confirmed transitional cell carcinoma (TCC) of the bladder Unifocal bladder TCC staged T2-T4a N0 M0* Fit to receive a radical course of radiotherapy WHO performance status 0-2 Willing and able to comply with study procedures and follow up schedule *Tumour location must be clearly visible on imagine or recorded on a surgical bladder map Exclusion Criteria: Nodal or metastatic disease Multifocal invasive disease Simultaneous TCC in upper tract or urethra Pregnancy Active malignancy within 2 years of randomisation (not including non melanomatous skin carcinoma, previous non muscle invasive bladder tumours, NCCN low risk prostate cancer (T1/T2a, Gleason 6 PSA <10), in situ carcinoma of any site) Bilateral hip replacements Any other conditions that in the Principal Investigator's opinion would be a contra-indication to radiotherapy (e.g. previous pelvic radiotherapy / inflammatory bowel disease)

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: WBRT<br>Standard dose whole bladder radiotherapy | Radiation: WBRT<br>* One RT plan with whole bladder treated to standard dose.<br>|
| Experimental: SART<br>Standard dose Adaptive tumour focused radiotherapy (SART) | Radiation: SART<br>* Three plans (small, medium & large) generated with the standard dose of RT focused on the tumour, sparing the normal bladder from full dose radiation. Pretreatment cone beam CTs will be used to select the best fitting of the three plans prior to treatment.<br>|
| Experimental: DART<br>Dose escalated Adaptive tumour boost radiotherapy (DART) | Radiation: DART<br>* Three plans (small, medium & large) generated with a higher dose than standard focused on the tumour and the remainder of the bladder treated to the same dose as in the SART group. Pretreatment cone beam CTs will be used to select the best fitting of the three plans prior to treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants meeting predefined radiotherapy dose constraints in DART group | Primary outcome of stage 1 of study, predefined radiotherapy dose constraints for bladder, bowel and rectum met for medium plan in DART group. | 4-6 weeks from randomisation | 
| Proportion of patients experiencing severe late side effects following radiotherapy. | Primary outcome of stage 2 of study, late CTC toxicity grade 3 or higher. | 6-18 months post radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinician reported acute toxicity | CTCAE v4 | 0-6 months post radiotherapy | 
| Patient reported outcomes- symptomatic toxicity | Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire | 0-24 months post radiotherapy | 
| Patient reported outcomes- urinary side effects | King's Health Questionnaire (KHQ) | 0-24 months post radiotherapy | 
| Patient reported outcomes- sexual function | excerpt of the EORTC QLQ-BLM30 questionnaire | 0-24 months post radiotherapy | 
| Patient reported outcomes- chronic gastrointestinal symptoms | Assessment of Late Effects of RadioTherapy - Bowel (ALERT-B) questionnaire | 0-24 months post radiotherapy | 
| Patient reported outcomes- health status | EQ-5D questionnaire | 0-24 months post radiotherapy | 
| Loco-regional MIBC control | Control of existing MIBC | 0-5 years post radiotherapy | 
| Progression free survival | Freedom from progressive disease | 0-5 years post radiotherapy | 
| Overall survival | Death from any cause | 0-5 years post radiotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IMRT, IGRT, Muscle invasive, Adaptive Radiotherapy