Bladder-directed heated chemotherapy of no clear benefit in NMIBC

In patients with intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), intravesical chemohyperthermia (CHT) does not translate to better cancer control than standard room-temperature chemotherapy, according to a recent phase II study HIVEC-II.

At the 24-month follow-up, 32 percent of CHT recipients experienced disease recurrence, while standard chemotherapy comparators saw a rate of 38 percent. The resulting disease-free survival (DFS) rates were 61 percent and 60 percent, which did not qualify for statistical significance (hazard ratio [HR], 0.92, 95 percent confidence interval [CI], 0.62–1.37; log-rank p=0.8). [Eur Urol 2022;doi:10.1016/j.eururo.2022.08.003]

Per-protocol analysis showed similar findings. While 24-month DFS was better in the CHT arm, the test treatment failed to distinguish itself significantly from room-temperature chemotherapy (65 percent vs 59 percent; HR, 0.7, 95 percent CI, 0.46–1.22; p=0.4).

In contrast, CHT patients were more than thrice as likely to experience disease progression than control counterparts (HR, 3.44, 95 percent CI, 1.09–10.8; log-rank p=0.02). This risk estimate remained high in the per-protocol analysis, though significance was attenuated to borderline levels (HR, 2.87, 95 percent CI, 0.83–9.98; log-rank p=0.06).

A similar effect was reported for overall survival (HR, 2.55, 95 percent CI, 0.77–8.40; log-rank p=0.09).

“The HIVEC-II trial was designed to test the hypothesis that CHT is superior to and resulted in better DFS than with standard mitomycin C in patients with intermediate-risk NMIBC,” the researchers said.

“We report no significant difference in DFS between the arms. We also observed that progression was more common among patients treated with CHT in comparison to patients undergoing the control treatment,” they added.

HIVEC-II is an open-label trial that randomly assigned 259 NMIBC patients to receive either adjuvant CHT (n=131) or standard room-temperature chemotherapy (n=128) with mitomycin C. In the CHT arm, the agent was heated to 43 ^oC. Mitomycin C was given at 40-mg doses for six weekly instillations, each lasting for 60 minutes. The primary endpoint was DFS at 24 months, as determined by cystoscopy and urinary cytology.

The researchers also compared both interventions in terms of safety and tolerability. This analysis showed that 89 percent of controls were able to complete their treatment regimens, whereas only 59 percent of CHT recipients did so.

Equipment issues, cited by 19 patients, was the most common reason for terminating CHT treatment early. This was followed by bladder spasms or urgency (n=10) and allergic reactions or rashes (n=9). Allergic reactions were also commonly cited in the control arm (n=5), as were nontreatment-related reasons for discontinuation (n=3) and urgency (n=2).

Overall, 632 cases of adverse events were documented, most of which (n=341) occurred in the CHT arm. Meanwhile, there were 20 cases of major adverse events, 13 of which occurred in 11 CHT patients. There were no reported cases of grade IV or V treatment-related side effects. The most common toxicities included urinary tract pain, urinary frequency, urinary urgency, haematuria, and rashes.  

“The results from HIVEC-II do not support the use of CHT for intermediate-risk NMIBC,” the researchers said. “We recommend that [these patients] who experience disease recurrence following mitomycin C should receive maintenance bacillus Calmette-Guérin for a minimum of 1 year.” [Eur Urol 2013;63:462-472]