Immediate post-TURBT mitomycin instillation reduces recurrence risk

“Journal Article of the Month” is a new Urology Times section in which Badar M. Mian, MD (left), offers perspective on noteworthy research in the peer-reviewed literature.  Dr. Mian is associate professor of surgery in the division of urology at Albany Medical College, Albany, NY.

Mitomycin C (MMC) instillation within 24 hours after transurethral resection (TURBT) of non-muscle invasive bladder cancer (NMIBC) significantly reduces the risk of recurrence and delays the time to recurrence.

According to a prospective multicenter randomized phase III trial conducted in the Netherlands, this benefit was noted even in those patients who subsequently received adjuvant MMC based on risk category. The findings were published online in European Urology (July 10, 2017).

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In this report by Bosschieter et al, patients were preoperatively randomized to receive 40 mg MMC in 50 mL saline, either immediately (within 24 hours after TURBT) or in a delayed fashion (2 weeks after TURBT). The efficacy endpoints were defined as recurrence risk, time to recurrence, and progression risk, while safety endpoints measured were incidence and severity of adverse effects.

Of the 2,844 patients, 1,384 (49%) were assigned to an immediate instillation and 1,460 (51%) to a delayed instillation group. A total of 601 patients were excluded due to not meeting the study criteria, thus leaving 2,243 patients eligible for intention-to-treat analysis. After TURBT, patients were categorized as low risk (LR): primary, solitary pTa/pT1 grade 1–2 tumor; intermediate risk (IR): primary, solitary pTa/pT1 grade 3 tumor or recurrent, solitary pTa/pT1 grade 1–3 tumor; or high risk (HR): all multiple tumors and/or carcinoma in situ, independent of stage or grade. The LR group received no further adjuvant MMC, the IR group received three weekly and five monthly instillations, and the HR group received three weekly and 11 monthly instillations. Cystoscopy was performed every 3 months for 1 year and then every 6 months.

Next: Significantly lower recurrence risk seen

Significantly lower recurrence risk seen

The recurrence risk in the entire cohort was significantly lower at 27% in the immediate instillation group compared to 36% in the delayed instillation group (p<.001). Further, the difference in time to recurrence after 3 years of follow-up significantly favored an immediate instillation, with 34% reduction in the relative risk of recurrence (hazard ratio: 0.66) compared to delayed instillation. The 3-year cancer progression rate was lower with immediate instillation (2.7%) compared to delayed instillation (5.5%). However, the trial was not powered or designed to evaluate the risk of progression.

When analyzing each risk group separately, no difference was noted in the risk of recurrence in the LR group from immediate versus delayed instillation (43% vs. 46%). However, immediate instillation significantly reduced the risk of recurrence in both the IR (20% vs. 32%) and HR group (28% vs. 35%).

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Adverse effects were recorded in 258 of 1,048 patients (25%) in the immediate instillation group and 257 of 1,195 patients (22%) in the delayed instillation group (p=.08). Most common adverse effects were skin rash (5.4%) and irritative voiding symptoms (5.0%). In six patients (0.57%) in the immediate instillation group, MMC extravasation was reported, which was managed conservatively.

For the entire study population, MMC instillation appears to be more effective when given immediately post-TURBT and appears to have a relatively favorable side effect profile. Because the protocol was devised in 1998, the risk categorization used in this report are somewhat different than the contemporary risk categories and the results of sub-group analysis may not be translatable. Also, a second TURBT or reporting muscle in the specimen (which are now quite standard) for high-risk cases was not required in this trial.

It is postulated that the beneficial effect of post-TURBT MMC may be due to eradicating floating tumor cells, overlooked small tumors, or residual tumor at the resection site. Our clinical paradigm has shifted to bacillus Calmette-Guérin (not used in this trial) as the primary adjuvant therapy, and the increasing use of enhanced visualization technology (blue light cystoscopy, narrow band imaging) to allow more complete resection. One must question whether the benefits of MMC instillation will still be maintained in patients managed using these modalities.

It appears that for all NMIBC patients, an immediate single instillation of MMC within 24 hours after TURBT reduces the recurrence rate and prolongs time to recurrence, regardless of whether adjuvant MMC instillations were given.

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