Study of Weekly Radiotherapy for Bladder Cancer (HYBRID)

A Multicentre Randomised Phase II Study of HYpofractionated Bladder Radiotherapy With or Without Image Guided aDaptive Planning

Background Localised muscle invasive bladder cancer (MIBC) is life-threatening and can cause significant symptoms. Around 50% of patients with MIBC who are referred for radiotherapy are unfit for standard radical treatment (surgery or daily radiotherapy with chemotherapy), but would have a normal life expectancy if their cancer were adequately controlled. Retrospective studies suggest that radiotherapy which is given weekly using fewer fractions and higher doses (hypofractionated), may be an alternative where daily radiotherapy is not an option.

Radiotherapy treatment is planned based on information from a CT scan which shows the position and shape of the bladder. This plan needs to take into account the fact that the bladder's shape and position can change, depending on how full it is and because of where it is in relation to the bowel. A safety margin is therefore added around the bladder on the planned treatment, to reduce the risk of missing any of the bladder with the radiotherapy.

It is now possible to take scans of the bladder's position before each treatment and adjust the position of the treatment plan accordingly to ensure the bladder is fully covered by it. In this study we are also looking at whether it is possible to design a series of treatment plans with different size safety margins and then choose one that fits best for each particular day. This is called 'adaptive radiotherapy'. This technique may enable accurate treatment delivery using smaller safety margins and this might help to reduce side effects.

Aims

In patients with MIBC not suitable for cystectomy or daily radiotherapy we aim to assess:

1. whether treatment using adaptive planning can be successfully delivered at multiple sites across the UK and results in acceptable levels of toxicity
2. the local tumour control rate achieved by hypofractionated weekly radiotherapy
3. the requirement to treat with adaptive planning.

How results will be used Results will provide robust evidence for use of hypofractionated radiotherapy and assess whether this is a plausible and worthwhile treatment in this patient population. The randomised element of the trial will support the implementation of image-guided adaptive radiotherapy for bladder cancer in the UK. HYBRID will provide evidence on the benefits or otherwise of this methodology and inform the development of further trials in this and other patient groups.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer
• Intervention / Treatment: Radiation: Standard planning radiotherapy; Radiation: Adaptive planning radiotherapy

Detailed Description

OBJECTIVES:

Primary To assess whether adaptive radiotherapy techniques when delivered at multiple centres can lead to a reduction in the level of acute non-genitourinary (GU) toxicity experienced by patients with muscle invasive bladder cancer unsuitable for daily radical radiotherapy.

Secondary

• Establish the local disease control rates of hypofractionated bladder radiotherapy as measured at 3 months
• Assess time to local disease progression
• Assess the overall survival time of patients who have received hypofractionated radiotherapy.
• Investigate the control rate of presenting symptoms, the effect of hypofractionated treatment on late radiotherapy side effects and patient reported outcomes.
• To establish the proportion of fractions benefiting from adaptive planning.

OUTLINE: This is a multicentre randomised Phase II study in patients with muscle invasive bladder who are not suitable for cystectomy or daily radiotherapy.

All patients will be planned to receive six 6Gray (Gy) fractions of image guided radiotherapy delivered weekly (total dose: 36Gy) and will be randomised to standard or adaptive planning.

Participants allocated to the standard planning group will have one radiotherapy plan generated and this will be used to deliver all 6 treatments, with a cone beam CT scan prior to treatment delivery which can be used by the local investigator to adjust treatment delivery according to local practice.

Participants allocated to adaptive planning will have three radiotherapy plans generated; small, medium and large. A cone beam CT taken prior to each treatment delivery will be used to select the most appropriate plan of the day.

Patients are followed up in terms of the trial up to 24 months, after this time only basic routine follow-up data will be collected.

PROJECTED ACCURAL: The aim is to recruit 62 participants, 31 to each treatment allocation.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
  • Cardiff, United Kingdom
    • Velindre Cancer Centre
  • Ipswich, United Kingdom
    • Ipswich Hospital
  • Leeds, United Kingdom
    • St James's University Hospital
  • London, United Kingdom
    • University College London
  • London, United Kingdom
    • Royal Marsden NHSFT
  • London, United Kingdom
    • Guy's & St Thomas's Hospital
  • Metropolitan Borough of Wirral, United Kingdom
    • Clatterbridge Cancer Centre
  • Norwich, United Kingdom
    • Norfolk & Norwich University Hospitals NHS Foundation Trust
  • Preston, United Kingdom
    • Royal Preston Hospital
  • Romford, United Kingdom
    • Queens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• Age ≥18 years
• Histologically confirmed invasive bladder carcinoma (T2-T4a N0 M0; any histological sub-type)
• Unsuitable for radical cystectomy or daily fractionated radiotherapy for any reason (including performance status, co-morbidity, patient refusal)
• Expected survival >6 months
• WHO performance status 0-3
• Willing to undergo post treatment cystoscopy

Exclusion Criteria:

• Nodal or metastatic disease
• Concurrent malignancy
• Previous pelvic radiotherapy
• Urinary catheter in-situ
• Any other contra-indication to radiotherapy (e.g. inflammatory bowel disease)
• Unable to attend for post treatment follow up

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard planning; Standard planning radiotherapy	Radiation: Standard planning radiotherapy; 36 Gray dose given in 6 fractions of 6 Grays over 6 weeks, using one plan per patient.
Experimental: Adaptive planning; Adaptive planning radiotherapy	Radiation: Adaptive planning radiotherapy; 36 Gray dose given in 6 fractions of 6 Grays over 6 weeks, selecting the best fit from three plans per patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Experiencing Severe Acute Non-genitourinary Side Effects Following Radiotherapy.	Non-GU CTCAE G3+ treatment-related toxicity occurring within the first 3 months of radiotherapy completing	12 weeks from completion of radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Disease Control Rate	Presence of cancer in the bladder 3 months after treatment. Presented as the proportion of all patients regardless of treatment allocation (standard and adaptive combined) having evidence of residual tumour.	3 months
Time to Local Disease Progression	From randomisation to a maximum follow-up of 30 months. It was pre-planned in the SAP to combine the two treatment arms together because there is insufficient statistical power to detect clinically meaningful differences.	Event-free survival estimates at 12 months and 24 months are reported.
Overall Survival	From randomisation to maximum follow-up of 56 months. It was pre-planned in the SAP to combine the two treatment arms together because there is insufficient statistical power to detect clinically meaningful differences.	Event-free survival estimates at 12 months and 24months are reported.
The Control Rate of Presenting Symptoms	Assessed by looking at change in symptom scores from pre to post radiotherapy. The number of patients with post-radiotherapy scores lower than their baseline score have been used to calculate the control rate of presenting symptoms and is presented separately for the two randomisation groups.	3 months from the completion of radiotherapy
The Proportion of Fractions Benefiting From Adaptive Planning	Assessed by the number of small or large plans being selected rather than the medium plan for patients in the adaptive planning group. The denominator will be the total number of fractions received in the adaptive planning group.	End of treatment, treatment is given over 6 weeks

Collaborators and Investigators

• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: Cancer Research UK
• Investigators: Principal Investigator: Robert Huddart, Institute of Cancer Research/RMNHSFT

Publications and helpful links

General Publications

• Hafeez S, Patel E, Webster A, Warren-Oseni K, Hansen V, McNair H, Miles E, Lewis R, Hall E, Huddart R. Protocol for hypofractionated adaptive radiotherapy to the bladder within a multicentre phase II randomised trial: radiotherapy planning and delivery guidance. BMJ Open. 2020 May 26;10(5):e037134. doi: 10.1136/bmjopen-2020-037134.
• Farbiszewski R, Ustymowicz J, Dudek H. [Participation of free radicals in the mechanism of brain tissue damage]. Neurol Neurochir Pol. 1993 Sep-Oct;27(5):729-37. Polish.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: March 8, 2013
• First Submitted That Met QC Criteria: March 12, 2013
• First Posted (Estimated): March 14, 2013

Study Record Updates

• Last Update Posted (Estimated): January 15, 2026
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: CCR3973; CRUK/12/055 (Other Grant/Funding Number: CRUK); ICR-CTSU/2013/10039 (Other Identifier: ICR-CTSU Protocol Number)