Title: A phase II randomised feasibility study of Chemoresection and surgicAl management in Low rIsk non muscle invasive Bladder cancER (CALIBER)
Funder: Department of Health and Social Care

Abstract: Background Bladder cancer is the seventh most common UK cancer, with around 10,500 people diagnosed in 20091. Approximately 49% of all patients with bladder cancer have low risk NMIBC3. This recurs frequently and a patient survey indicated that inpatient surgical management of recurrence was the most bothersome aspect of the condition. CALIBER thus investigates using chemotherapy within the bladder (chemoresection) as an outpatient alternative to inpatient surgery for recurrence. Chemotherapy is routinely used following surgery to treat patients with higher risk disease4 and may enable low risk patients to avoid surgical management under general anaesthetic altogether. Primary research question In low risk recurrent NMIBC, is outpatient chemoresection a potential alternative to inpatient surgical management that is worthy of further research? Objectives To demonstrate that chemoresection will enable 60% of participants to avoid surgical intervention for low risk NMIBC recurrence, as assessed by complete response rate at 3 months. To collect further information to support development of a phase III study. Plan of investigation CALIBER is a multicentre feasibility study. 174 patients with recurrent low risk NMIBC will be randomised (2:1) over 27 months to: Chemoresection (116 patients): 4 once weekly intravesical installations of 40mg Mitomycin-C; or Surgical management (58 patients - control): type of surgery according to local practice. Participants will be followed up after treatment according to European Association of Urology guidelines4. Endpoints are: o Feasibility of recruitment o In the chemoresection group: Primary endpoint: complete response (CR) 3 months post-treatment (i.e. absence of any tumour assessed visually by patients urologists) Treatment compliance; o Both groups: Time to recurrence in patients disease free at 3 months; Salvage surgery rate; Progression-free survival; Toxicity; Quality of life; Working days missed; Cost effectiveness The sample size has been determined based on the assessment of CR in the chemoresection group using a Simon s 2 stage phase II design. A control group has been included to provide prospective data about surgical management and outcomes and assess feasibility of recruitment to a randomised study. Following consultation with patient representatives, CALIBER has been designed to exclude a CR rate of less than 45%. A CR rate lower than this would suggest that chemoresection is not an attractive alternative to surgical management as it would delay rather than prevent surgical intervention in the majority of patients and hence would be unlikely to reduce the impact of treatment of recurrence. If 25 or fewer responses are seen in the first 51 chemoresection patients the trial will be stopped for futility. If at least 58/110 chemoresection patients have a CR overall then it would be concluded that the CR rate was at least 60% and thus the strategy of chemoresection would warrant further investigation Progression to phase III randomised controlled trial Should CALIBER demonstrate that response rates associated with chemoresection are at least 60%, and that recruitment is feasible in this setting, a definitive phase III trial will be developed. This will compare the effects of chemoresection versus surgical management on time to subsequent recurrence, with the aim of establishing whether chemoresection can offer patients with recurrent low risk NMIBC the opportunity to avoid surgery. Potential benefits to patients and the NHS CALIBER will identify potential benefits of chemoresection to be further explored in a phase III trial. If chemoresection is ultimately proven to be as effective as surgical management, benefits to patients should include fewer side effects and reduced impact on day to day living. In addition, chemoresection delivered to outpatients will release surgical resources currently utilised in treatment of low risk NMIBC, which could be reassigned elsewhere.

Lay abstract: CALIBER is a randomised feasibility study investigating treatment of low risk non-muscle invasive bladder cancer (NMIBC). This is diagnosed in 5,000 people in the UK each year and frequently comes back following initial treatment (recurs), but rarely progresses to a life threatening condition. European guidelines on NMIBC treatment and monitoring recommend that patients with low risk NMIBC undergo annual outpatient check-ups involving the introduction of a telescope into the bladder (cystoscopy) under local anaesthetic. Should a recurrence be found, an inpatient operation under general anaesthetic is scheduled to surgically remove the tumour. A survey of 100 patients with low risk NMIBC indicated that inpatient surgery for recurrence was the most bothersome aspect of their condition. This led to the development of CALIBER to investigate using chemotherapy delivered into the bladder (chemoresection) as an outpatient alternative to surgery. Chemotherapy is routinely used following surgery to treat patients with higher risk disease and may enable low risk patients to avoid inpatient surgery altogether. Patients with recurrent low risk NMIBC will be invited to join CALIBER. Patients with a first diagnosis of NMIBC will not be included. Participants will be randomly assigned between inpatient surgical management of recurrence and 4 outpatient treatments of chemoresection over 4 weeks. As suggested in the European guidelines for monitoring NMIBC, all participants will have an outpatient cystoscopy 3 months after treatment to visually assess whether any tumour is present. If any tumour is seen participants will return for inpatient surgery. CALIBER aims to demonstrate that chemoresection offers patients the opportunity to avoid inpatient surgery for their recurrent tumours. This would provide support for further investigation into chemoresection as a treatment strategy for recurrent low risk NMIBC patients, with the aim of reducing the impact of treatment of recurrence on patients daily lives.

Research activity codes: 6.4 SURGERY;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS