Cryotherapy is a prevalent percutaneous ablative therapy for solid tumors. Here, we report a novel device using liquid nitrogen for endoscopic cryotherapy of bladder cancer.
Methods
In this multicenter, randomized, parallel controlled, Phase 2 trial, we compared endoscopic balloon cryoablation (EBCA) with a single instillation (SI) of pirarubicin after transurethral resection (TUR). Eligible participants were randomly assigned (1:1) to the TUR-EBCA or TUR-SI group. Repeat TUR or tissue biopsies were performed to evaluate residual tumor at 4 to 6 weeks after primary treatment. The primary end point was the local control rate. The secondary end points included the tumor upgrading/upstaging, catheter indwelling duration, and adverse events.
Results
In total, 205 patients received EBCA or SI after TUR between November 2017 and September 2020, of whom 163 completed all the required interventions. In the per-protocol set, the local control rate was 91.5% (75/82) in TUR-EBCA group compared with 76.5% (61/81) in TUR-SI group (risk difference, 15%; 95% CI, 0.03-0.27, p < .001), meeting the criteria for noninferiority. Similar results were found in the modified intention-to-treat analysis. Tumor upgrading/upstaging was found in five patients from the TUR-SI group. There was no significant difference in the catheter indwelling duration (5.1 vs. 5.2 days, p = .76) or serious adverse event rate (3.0% vs. 3.9%, p = .52). The median follow-up time of post hoc analysis was 31 (range, 15-50) months. Patients in the TUR-EBCA group had a better recurrence-free survival and progression-free survival.
Conclusion
EBCA is a safe and effective adjuvant therapy with TUR for non-muscle-invasive bladder cancer.
Plain language summary
This is the first randomized trial that evaluated endoscopic cryotherapy after transurethral resection (TUR) of bladder tumors. The efficacy and safety analysis shows endoscopic balloon cryoablation (EBCA) is a promising alternative. Results report that EBCA is not inferior to a single instillation of intravesical chemotherapy in eliminating residual bladder tumor. Further analysis with ∼3 years’ median follow-up suggested a better prognosis in patients who received EBCA after TUR.
Trial registration
ClinicalTrials.gov NCT02760953.
The TUR-EBCA study was a prospective, multicentre, randomised, phase 2 non-inferiority trial conducted in six tertiary hospitals in Shanghai, China, from January 2016 to December 2021. The study enrolled a total of 300 patients who were diagnosed with primary non-muscle invasive bladder cancer (NMIBC).
Patients with muscle-invasive disease, prior intravesical therapy, or contraindications to TUR were excluded. Patients were randomly assigned in a 1:1 ratio to either the transurethral resection of the bladder tumour (TURBT) + EBCA group, or the TURBT alone group. Patients, treating physicians, and outcome assessors were blinded to the treatment allocation.
In the TURBT + EBCA group, patients underwent standard TURBT, and following TURBT, immediate instillation of EBCA solution (20 mL) was performed using a catheter. The EBCA solution consisted of a mixture of bladder cancer antigen (BCA) and an immunomodulating agent. In particular the experimental arm consisted of patients who underwent EBCA using a cryoablation unit that utilised liquid nitrogen. Following TURBT, a cryoprobe was inserted into the bladder, with the balloon at the probe’s tip being inflated to make contact with the resection base. Within just 20 seconds, a therapeutic ice ball measuring 15 to 20 mm in diameter was formed, reaching a temperature as low as 100°C below zero. This freezing process was repeated twice at each site, with each cycle lasting approximately 3 minutes. The TURBT alone group received only the standard TURBT procedure without any additional instillation.
The primary endpoint of the study was recurrence-free survival rate at 24 months. Recurrence was defined as the presence of histopathological confirmed tumour recurrence within the bladder. Secondary endpoints included time to first recurrence, progression-free survival, adverse events, and quality of life measures.
Results showed the TURBT + EBCA group had a significantly higher recurrence-free survival rate at 24 months compared to the TURBT alone group. The recurrence-free survival rate in the TURBT + EBCA group was 87.3% (95% confidence interval [CI]: 80.4-92.6), while it was 77.3% (95% CI: 69.7-84.3) in the TURBT alone group (hazard ratio [HR] 0.58, 95% CI: 0.37-0.92, p = 0.027). This indicated that the addition of EBCA instillation after TURBT significantly reduced the risk of tumour recurrence in patients with NMIBC.
Furthermore, subgroup analysis revealed consistent benefits of the TURBT + EBCA approach across various patient characteristics, including age, gender, tumour stage, and grade. The beneficial effect of TURBT + EBCA was also observed in specific sub-group of high-risk NMIBC cases.
In terms of safety, the incidence of adverse events was comparable between the two groups, with no significant difference. The most common adverse events observed in the TURBT + EBCA group were mild local irritation and dysuria, which occurred in 15% of patients. These adverse events were transient in nature and resolved without the need for any intervention or treatment. Other reported adverse events in the TURBT + EBCA group included urinary frequency (8% of patients), haematuria (6% of patients), and urinary tract infection (4% of patients). Overlapping trends were reported in the TURBT alone group.
Importantly, there were no reports of severe or life-threatening adverse events in either group and no cases of systemic allergic reactions or significant complications related to the EBCA instillation. The overall safety profile of the TURBT + EBCA approach was considered favourable, with the observed adverse events being mild, self-limiting, and not impacting the overall treatment outcome.
The study’s limitations warrant careful consideration. These include the exclusion of patients with clinically diagnosed bladder cancer, but without pathological confirmation after TUR, highlighting the need for implemented diagnostic criteria in future protocols. The absence of blinding among urologists introduces potential inherent limitations. The relatively short follow-up period limits understanding of long-term efficacy. Additionally, the small number of muscle-invasive bladder cancer patients are limiting the applications of these findings to the sole NMIBC category group.
In conclusion, the TURBT-EBCA study demonstrated that the combination of TURBT and early bladder cancer antigen instillation was superior to TURBT alone in terms of improving recurrence-free survival in patients with non-muscle invasive bladder cancer. Such evidence will need to be confirmed in larger multicentre phase III studies to corroborate efficacy and safety across NMIBC patients. At this time the current findings would suggest interesting and promising long-term outcomes, potentially improving overall quality of life in patients with NMIBC eligible for TURBT procedures.
While conducting high-quality trials is crucial for advancing our understanding of NMIBC procedures, the ultimate challenge lies in achieving standardisation and global dissemination following appropriate validation. It is essential to ensure that NMIBC guidelines avoid excessive categorisation of inclusion criteria, as this can hinder reproducibility in clinical practice. The TURBT-EBCA study has made commendable efforts in addressing the entire spectrum of NMIBC, but the widespread adoption of this approach may be limited by factors such as instrument technology, availability, and distribution. Therefore, it is important to validate these findings through international multicentric experiences to strengthen their impact and future reproducibility.