Mitomycin-C before the resection, for the patient who cannot have it after

Design

Single-centre, open-label, randomised phase 2 trial with about five years of follow-up and exploratory RNA sequencing

Population

71 patients with non-muscle-invasive bladder cancer: 33 given pre-resection mitomycin-C, 38 resection alone

Primary outcome

Three-year recurrence-free survival

Effect

90.7% vs 78.6%; multivariable HR 0.266 (p = 0.044); progression-free survival HR 0.078 (p = 0.014)

An immediate post-resection instillation of intravesical chemotherapy is standard in non-muscle-invasive bladder cancer, and is often not given — because of perforation, extensive resection, bleeding, or simply theatre logistics. This single-centre open-label phase 2 trial reversed the timing: 33 patients received two split doses of mitomycin-C 40 mg in 20 mL immediately before transurethral resection, and 38 had resection alone. At a median follow-up of about 60 months in both arms, three-year recurrence-free survival was 90.7% against 78.6%, with a multivariable hazard ratio of 0.266 (p = 0.044). Progression-free survival at three and five years was 100% against 92.1% and 85.8% (HR 0.078, p = 0.014). Exploratory RNA sequencing on 28 treated patients found low GSTM1 expression most strongly associated with recurrence.

The idea is mechanically sensible. Chemotherapy instilled before the tumour is cut sits on an intact urothelium, so systemic absorption through a raw resection bed is avoided — which is exactly the safety concern that stops the standard instillation being given. It is also the argument for why this timing might work where the conventional one cannot be used.

The size governs everything. Seventy-one patients randomised, at one centre, open-label, with the progression hazard ratio of 0.078 resting on a handful of events — that number should be read as 'very few progressions in either arm' rather than as a 92% risk reduction. Treat this as a reasonable option for the patient in whom immediate post-resection instillation is contraindicated or impractical, which is how the authors frame it, and not as a replacement for a standard supported by far larger trials. The GSTM1 finding is hypothesis-generating and should not be tested outside research.

• Consider pre-resection instillation only where the standard immediate post-resection dose cannot be given.
• The regimen studied was two split doses of mitomycin-C 40 mg in 20 mL immediately before resection.
• Do not quote the progression hazard ratio to patients; it rests on very few events.
• This does not displace immediate post-resection instillation where that is feasible and safe.
• GSTM1 expression is exploratory — there is no role for testing it in practice.

The statistics, in plain English

A hazard ratio of 0.266 for recurrence looks decisive until you count the patients generating it: 33 against 38, with recurrence-free survival differing by 12 percentage points at three years. That is roughly a handful of events either way, and small trials systematically overstate effect sizes because only the larger observed differences reach significance. The progression result, HR 0.078 with p = 0.014, is the clearest example — a 92% relative reduction is not a plausible effect size for a single pre-operative instillation, and the figure is being driven by near-zero events in one arm. The design is sound; the precision is not there, and a phase 3 trial would be expected to report something much closer to null.

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