In the UK 20,000 people develop urothelial bladder cancer each year with 75-80% having Non-Muscle Invasive Bladder Cancer (NMIBC). The current standard of care for patients with High Risk-NMIBC (HR-NMIBC) is either surgery to remove the tumour (transurethral resection of bladder tumour; TURBT) followed by BCG (Bacillus Calmette Guérin, an immunotherapy drug) given directly into the bladder, or surgery to remove the bladder (cystectomy). BCG is given weekly for six weeks followed by maintenance treatment up to 3 years. However, in up to 50% of patients their cancer returns (recurrence) or gets worse (progression) after BCG and 25% stop treatment due to side effects. Globally BCG supply has been restricted in recent years has increased HR-NMIBC recurrence rates and costs. Improved treatments are required, to prevent recurrence, progression and cystectomy, and mitigate the effects of unpredictable supply.
Trimodality treatment (TMT) is maximal TURBT + radiotherapy + a radiosensitiser (gemcitabine, mitomycin C/fluorouracil or carbogen/nicotinamide) and is an equivalent alternative treatment to cystectomy for muscle-invasive bladder cancer (MIBC). TMT is not routinely used for HR-NMIBC. A study found that 54% of HR-NMIBC patients who received TMT did not have recurrence within 5 years. Modern radiotherapy is expected to further improve outcomes and minimise side-effects.
Patients will be randomised 1:1 to BCG or radiotherapy with radiosensitisation. Patients randomised to the experimental arm will receive 55Gy in 20 fractions. Investigators can then choose from three different options for the radiosensitiser. TRAIN will test if radiotherapy with radiosensitisation improves outcomes for people with HR-NMIBC compared to BCG.
TRAIN will recruit 328 patients with HR-NMIBC following maximal TURBT. All patients will be followed up for a minimum of two years to record their response to treatment.
Diagnosed with histologically confirmed grade 3 T1 N0 M0 transitional cell carcinoma, OR carcinoma in situ of the bladder (and N0 M0), OR both, with detrusor muscle present in the biopsy specimen if T1 disease (or a repeat resection that does contain muscle that is clear)
Suitable for BCG treatment
Suitable for radiotherapy and radiosensitisation according to the schedule of administration outlined in the Radiotherapy Planning Guidance document.
Life expectancy over 12 months
MDT selected patients with HR-NMIBC who are deemed best suited for primary cystectomy (patients that have had this treatment recommendation but then decline cystectomy remain eligible for TRAIN)
Previous radiotherapy to the pelvis
Previous intravesical therapy
Poor bladder function (IPSS >16)
Parallel
radiotherapy
RadiationRadiotherapy - 55Gy in 20 fractions treating once daily Monday to Friday over 4 weeks.
BCG
Other interventionBCG protocol of 6 weekly intravesical instillations, followed by 3 weekly instillations at 3, 6, 12, 18, 24, 30, 36 months.
To compare event-free survival between BCG and radiotherapy with radiosensitisation.
Event-free survival is defined as recurrence of CIS or high-risk non-muscle invasive papillary tumour, continued presence of HR NMIBC even after treatment completion, progression to muscle-invasive disease, distant metastatic bladder cancer, cystectomy (for any reason) or death from any cause.
To determine the difference between BCG and radiotherapy in terms of patient-reported symptoms.
Patient-reported outcomes will be assessed via questionnaires, including the RTOG (late bladder and intestinal toxicity) questionnaire.
To evaluate each component of the primary outcome comparing between BCG and radiotherapy with radiosensitisation.
The following event outcomes will be analyzed using the Cox proportional hazards model to estimate hazard ratios, and Kaplan-Meier analysis will be used to estimate event rates. * Recurrence-free survival (RFS) defined as time from randomisation to recurrence of non-muscle invasive papillary tumour. Patients are censored at the last follow-up if event free. * Progression-free survival (PFS) defined as time from randomisation to progression to muscle-invasive disease. Patients are censored at the last follow-up if event free. * Metastasis-free survival (MFS) defined as time from randomisation to progression to distant metastatic bladder cancer. Patients are censored at the last follow-up if event free. * Cystectomy-free survival (CFS) defined as time from randomisation to cystectomy. Patients are censored at the last follow-up if event free * Overall survival (OS) defined as time from randomisation to death due to any cause. Patients are censored at the last follow-up if event free
To establish the tolerability and safety of radiotherapy.
MedDRA coded adverse events graded using CTCAE v5.0.
To determine the difference in cancer specific survival between groups.
Cancer specific survival defined as time from randomisation to death from cancer. Patients who die of a cause other than the cancer under study or who are lost to follow-up are censored at death or the last date on which they were known to be alive.
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