Radiofrequency induced hyperthermia in non-muscle invasive bladder cancer: Oncologic outcomes in a real-world scenario

Abstract

Objectives

Patients with non-muscle invasive bladder cancer (NMIBC) face a high risk of recurrence and progression after transurethral resection, making adjuvant therapies necessary. Intravesical device-assisted therapies, such as radiofrequency-induced thermochemotherapy (RITE), have shown promise in enhancing the effectiveness of intravesical chemotherapies. This study aimed to evaluate oncological outcomes in patients with NMIBC treated with RITE in a real-world setting, encompassing those unresponsive to prior Bacillus Calmette-Guérin (BCG) or intravesical chemotherapy, as well as those who declined or were ineligible for BCG or radical cystectomy (RC).

Methods

A retrospective multicenter analysis of patients treated with RITE for NMIBC between 2015 and 2024 was performed. Co-primary endpoints of the study were intravesical recurrence free survival (RFS) and high-grade intravesical recurrence free survival (HG-RFS). Secondary endpoints included radical cystectomy-free survival (RC-FS), overall survival (OS), cancer-specific survival (CSS), and adverse events (AEs).

Results

Fifty-nine consecutive patients were included in the final analyses. Overall, 12 (20%) and 45 (76%) patients failed previous intravesical chemotherapy, and immunotherapy with BCG, respectively. The 24-months RFS and HG-RFS following RITE were 68.6% (95% CI: 0.568, 0.828) and 74.8% (95% CI: 0.632, 0.885). RC-FS at 24 months was 93.8% (95% CI: 0.872, 1.000). The OS probability at 24 months was 91%, with a CSS of 97.8%. Most common AEs were dysuria and urgency in 27 (45.7%) patients, treatment limiting bladder spasms in 11 (19%) patients, low bladder compliance in 11 (19%) patients and urethral strictures in 5 (8%) patients.

Conclusion

In our analyses, RITE resulted in notable antitumor activity and allows for the avoidance of more aggressive and quality-of-life-limiting therapies, such as radical cystectomy. RITE might be considered as a second-line bladder-sparing option in patients failing previous intravesical therapies. Long-term follow-up and larger-scale data are required to validate our findings.

Resumen

Objetivos

Los pacientes con cáncer de vejiga no músculo invasor (CVNMI) presentan un alto riesgo de recidiva y progresión tras la resección transuretral, lo que hace necesarias las terapias adyuvantes. Las terapias intravesicales asistidas por dispositivos, como la termoquimioterapia inducida por radiofrecuencia (RITE, por sus siglas en inglés), han mostrado resultados prometedores en la mejora de la eficacia de la quimioterapia intravesical. El objetivo de este estudio fue evaluar los resultados oncológicos en pacientes con CVNMI tratados con RITE en un entorno real, incluyendo a pacientes que no respondieron a quimioterapia previa con bacilo de Calmette-Guérin (BCG) o quimioterapia intravesical, así como a los que rechazaron o no fueron elegibles para BCG o cistectomía radical (CR).

Métodos

Se realizó un análisis multicéntrico retrospectivo de los pacientes con CVNMI tratados con RITE entre 2015 y 2024. Los criterios principales de valoración fueron la supervivencia libre de recidiva intravesical (SLR) y la supervivencia libre de recidiva intravesical de alto grado (SLR-AG). Los criterios de valoración secundarios fueron la supervivencia libre de cistectomía radical (SL-CR), la supervivencia global (SG), la supervivencia cáncer específica (SCE) y los eventos adversos (EA).

Resultados

Se incluyeron 59 pacientes consecutivos en los análisis finales. En total, 12 (20%) y 45 (76%) pacientes no habían sido sometidos a quimioterapia intravesical previa ni a inmunoterapia con BCG, respectivamente. La SLR y la SLR-AG a los 24 meses tras el tratamiento con RITE fueron del 68,6% (IC 95%: 0,568, 0,828) y del 74,8% (IC 95%: 0,632, 0,885). La RC-FS a los 24 meses fue del 93,8% (IC del 95%: 0,872, 1,000). La probabilidad de SG a los 24 meses fue del 91%, con una SCE del 97,8%. Los EA más frecuentes fueron disuria y tenesmo en 27 (45,7%) pacientes, espasmos vesicales limitantes del tratamiento en 11 (19%) pacientes, baja acomodación vesical en 11 (19%) pacientes y estenosis uretral en 5 (8%) pacientes.

Conclusiones

En nuestros análisis, el tratamiento con RITE demostró una actividad antitumoral significativa lo que permite evitar terapias más agresivas y limitantes de la calidad de vida, como la cistectomía radical. RITE podría considerarse como una opción de tratamiento conservador de segunda línea en pacientes en los que hayan fracasado terapias intravesicales previas. Se requiere un seguimiento a largo plazo y datos a mayor escala para validar nuestros hallazgos.

Introduction

The standard treatment of non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of bladder (TURB) followed by adjuvant intravesical therapy based on patient's risk for recurrence and progression.¹ In intermediate-risk patients, intravesical chemotherapy with Mitomycin-C (MMC), and in high-risk disease, immunotherapy with Bacillus Calmette-Guérin (BCG) are recommended by international guidelines.^2–5 Despite optimal treatment, patients with NMIBC will experience disease recurrence in up to 70% of the cases, and progress to muscle-invasive bladder cancer, eventually (MIBC).^6–8 In these patients the treatment option recommended by current guidelines is radical cystectomy (RC). However, this surgery can be associated with major complication and changes in quality of life.^1,9

Radiofrequency-induced thermochemotherapy (RITE), which enhances the efficacy of the intravesical chemotherapy agent MMC through microwave-induced hyperthermia, has shown promising antitumor efficacy in patients failing previous intravesical therapies.¹⁰ Local hyperthermia enhances the cytotoxic effect of chemotherapy for various solid tumors.¹¹ When the temperature exceeds 40.5 °C, the production of RNA and DNA decreases, and the process of DNA repair is disrupted.¹² When 43 °C is exceeded vasodilatation occurs, which has an enhancing effect on distribution of chemotherapeutic drugs.¹³ This study shows oncologic outcomes of radiofrequency induced hyperthermia with MMC in NMIBC in a real-world scenario from two university hospitals.

Methods

Study population

We performed a retrospective analysis of consecutive patients treated with RITE for NMIBC between 2015 and 2024 at two European academic centers. The data were extracted from medical records, pseudonymized, and subsequently used as the foundation for the statistical analysis.

Indications for RITE were NMIBC unresponsive to prior BCG (n = 45, 76%) or intravesical chemotherapy (n = 12, 20%), refusal or ineligibility to BCG or RC (n = 9, 15%).

Treatment

RITE was administered at both centers using the Synergo® SB-TS 101.3 (Medical Enterprises LTD) device. Treatment was administered in accordance with the manufacturer’s guidance. Patients received two treatment cycles per session, each 30 min in length, with 40 mg of MMC diluted in 50 mL distilled water with a temperature aim of 42 ± 2 °C.

The treatment protocol included an induction phase of eight weekly sessions, followed by three maintenance sessions at 3, 6, 9 and 12 months. In 2023 the treatment protocol at the department of urology of the Medical University of Vienna was adapted to six weekly induction cycles, followed by one instillation of RITE every 6 weeks for the 1st year and one instillation every 8 weeks for the 2nd year. The number of patients receiving eight versus six cycles of Synergo® is too small to allow for a subgroup analysis. Regular follow-up appointments after RITE treatment were conducted according to the patients’ risk category and individual clinical needs, which varied among patients. These follow-ups included comprehensive clinical assessments, cystoscopy, and imaging to monitor for recurrence and assess treatment efficacy.

Endpoints

Primary endpoints of the study were intravesical recurrence-free survival (RFS) and high-grade intravesical recurrence-free survival (HG-RFS). Secondary endpoints included radical cystectomy-free survival (RC-FS), overall survival (OS), cancer-specific survival (CSS), adverse events (AEs) associated with the therapy. Due to the retrospective nature of the study, AEs assessment was not standardised but extracted from clinical records.

Statistical analyses

Follow-up was calculated from the date of last TURB to the date of last visit or patient death. Time to RC was calculated from the date of last TURB to the date of RC. Survival probability was graphically plotted using the Kaplan-Meier method. Difference in survival was estimated using the log-rank test. Pre-planned subgroup analyses were performed according to previous intravesical treatment, tumor stage, or whether patients received maintenance therapy or not. Cox-regression models were fitted to evaluate the association between recurrence and covariates, including prior intravesical therapy, tumor grade, CIS status or whether patients underwent maintenance therapy.

Statistical analyses were performed using R (The R Foundation for Statistical Computing, Vienna, Austria). All tests were two sided. Statistical significance was set at p < 0.05.

Results

A total of 60 patients were treated with RITE for NMIBC. After exclusion of patients with incomplete clinical data for the primary endpoint (n = 1), 59 patients were included in final analyses. Patient characteristics are shown in (Table 1). A detailed summary of treatment-related data is shown in (Table 2).

Table 1.

Characteristics of patients treated with radiofrequency-induced thermochemotherapy for non-muscle invasive bladder cancer.

Variable N = 59^a
Age	74 (63, 78)
Gender
Female	9 (15%)
Male	50 (85%)
Prior UTUC	4 (6.9%)
Smoking status
Smoker	32 (74%)
No smoker	11 (26%)
Unknown	16
Previous recurrences
0	9 (15%)
1	9 (15%)
2	15 (25%)
3	9 (15%)
≥4	17 (29%)
Pathologic Stage
T0	1 (1.7%)
T1	9 (15%)
Ta	30 (51%)
Tis	15 (25%)
Grade
High Grade	40 (70%)
Low Grade	17 (30%)
Tumor size (cm)	2.00 (1.00, 2.50)
Tumor number
1	14 (30%)
2−5	27 (59%)
>5	5 (11%)
Cis
Yes	17 (32%)
No	36 (68%)
Detrusor in TURB specimen	47 (94%)
Second look TURB	9 (18%)
Second look pathologic stage
not reported	1 (8.3%)
T0	10 (83%)
Tis	1 (8.3%)
Previous intravesical chemotherapy therapy^b	12 (20%)
Prior BCG therapy	45 (76%)

UTUC = upper tract urothelial carcinoma; TURB = transurethral resection of bladder tumor; BCG = Bacillus Calmette–Guérin.

a

Median (IQR); n (%).

b

Excluding single shot chemotherapy after TURB.

Table 2.

Treatment characteristics of patients treated with radiofrequency-induced thermochemotherapy for non-muscle invasive bladder cancer.

Variable N = 59^a
Induction cycles (n)
≤7	24 (41%)
8	34 (58%)
9	1 (1.7%)
Maintenance cycles (n)
0	27 (46%)
1−8	23 (39%)
9−14	9 (15%)
Induction
Average Radiofrequency power during induction (W)	16.6 (9.4–19.7)
Average temperature during induction (°C)	39.9 (37.4–41.6)
Radiofrequency on time during induction (min)	50.6 (27.0–60.8)
Time above 40.5 °C during induction (min)	34.0 (0.0–49.7)
Time above 41.5 °C during induction (min)	19.2 (0.0–42.5)
Maintenance
Average Radiofrequency power during maintenance (W)	16.9 (11.8–22.1)
Average temperature during maintenance (°C)	39.6 (30.3–40.8)
Radiofrequency on time during maintenance (min)	57.4 (43.3–63.0)
Time above 40.5 °C during maintenance (min)	42.9 (35.3–59.0)
Time above 41.5 °C during maintenance (min)	29.5 (15.3–54.0)

a

n (%); Average (Range).

Within a median follow-up of 38.47 (IQR 21.2–56.7) months, a total of 23 (39%) patients experienced an intravesical recurrence, 16 (27%) patients experienced a HG-recurrence and 3 (5%) progressed to MIBC. Median RFS in the overall cohort was 95.1 (95% CI: 29.3, not reached) months (Fig. 1A). The median HG-RFS was 95.1 (95% CI: 56.7, not reached) months (Fig. 1B). A total of 40 (89%) patients failing previous BCG therapy had a sustainable response to RITE and could therefore preserve their bladder. Median OS was not reached during the study period, as fewer than 50% of the patients died. Therefore, a median OS could not be calculated (Fig. 1C). During the follow-up period, six patients underwent RC at 12, 14, 14, 24, 25, and 38 months after, respectively. Additionally, one patient was treated with RC after 9.5 years, after failing previous BCG therapy. Median time to RC was 114 months (Fig. 1D).

Figure 1.

Kaplan-Meier survival curves for recurrence-free survival, high-grade recurrence-free survival, overall survival and radical cystectomy free survival for 59 patients treated with radiofrequency induced chemohyperthermia for non-muscle invasive bladder cancer.

In the pre-planned comparative analyses, subgroups were defined based on clinical parameters: 45 (76%) patients had previously undergone BCG therapy, 17 (29%) patients were identified with CIS, 40 (68%) patients presented with high-grade disease, and 32 (54%) patients received maintenance cycles, ranging from 1 to 14 cycles (median: 6, mean: 6). Patients previously treated with BCG exhibited a lower recurrence-free survival (RFS), although this difference was not statistically significant (p = 0.217). Similarly, patients with CIS showed a slightly reduced risk of recurrence, which also did not reach statistical significance (p = 0.755). Patients with high-grade disease had a modestly increased risk of recurrence; however, this difference was not statistically significant (p = 0.71) (Fig. 2A–C). Patients treated with a maintenance cycle experienced a slightly reduced risk of recurrence; however, this reduction was also not statistically significant (p = 0.72) (Fig. 3). Consequently, it is crucial to recognize that non-significant HRs, such as observed here, do not represent independent predictors of recurrence.

Figure 2.

Kaplan-Meier survival curves for recurrence-free survival of 59 patients treated with radiofrequency induced chemohyperthermia for non-muscle invasive bladder cancer, subanalysed by previous BCG treatment, incidence of CIS, and tumor grade.

Figure 3.

Kaplan-Meier survival curves for recurrence-free survival of 59 patients treated with radiofrequency induced chemohyperthermia for non-muscle invasive bladder cancer, subanalysed by maintenance treatment.

At Cox-regression analyses, prior BCG therapy was associated with an increased risk of recurrence, reflected by a hazard ratio (HR) of 2.16 (95% CI: 0.64, 7.35); however, this increase did not reach statistical significance (p = 0.217). Similarly, patients with CIS exhibited a slightly reduced risk of recurrence with an HR of 0.86 (95% CI: 0.33, 2.24), though this difference was also not statistically significant (p = 0.755). Patients with high-grade disease showed a modestly increased risk of recurrence, with an HR of 1.20 (95% CI: 0.47, 3.07), but this difference likewise did not achieve statistical significance (p = 0.71). It is crucial to recognize that non-significant HRs do not represent independent predictors of recurrence.

Cox-regression analysis of maintenance therapy indicated a slightly reduced risk of recurrence HR 0.86 (95% CI: 0.37, 1.98) associated with maintenance treatment. However, this reduction was not statistically significant (p = 0.72). Consequently, it is crucial to recognize that non-significant HRs, such as observed here, do not represent independent predictors of recurrence.

Adverse events

A total of 59 patients were included in the safety analyses. The most reported AE was dysuria or urgency, occurring in 27 patients (45.7%). Bladder spasms were observed in 11 patients (18.6%), necessitating treatment interruption in 2 cases. Additionally, low bladder compliance was identified in 11 patients (18.6%), with associated complaints of increased urinary frequency and urgency. Urethral stricture was reported in 5 patients (8.5%). One patient developed a skin rash after the third induction cycle, leading to discontinuation of treatment. A summary of adverse events classified according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0)¹⁴ is shown in (Table 3).

Table 3.

Adverse events associated with radiofrequency induced chemohyperthermia, classified according to CTCAE.

Adverse Event Frequency n (%) CTCAE Grade Comments
Dysuria or urgency	27 (45.7%)	Grade 1−2	Managed symptomatically
Bladder spasms	11 (18.6%)	Grade 2−3	Treatment interruption in 2 cases
Low bladder compliance	11 (18.6)	Grade 2	–
Urethral stricture	5 (8.5%)	Grade 3	–
Skin rash	1 (1.7%)	Grade 3	Discontinuation of therapy

Discussion

We conducted a retrospective analysis of patients treated with RITE for NMIBC and observed a 50.2% response rate at 5 years. The findings of our study are in line with those of Brummelhuis et al., who reported a 5-year durable response rate of 40.3% in patients with CIS treated with RF-CHT, and a RFS rate of 37.2% in patients with papillary tumors.¹⁵ We observed an overall bladder preservation rate of 88% in patients treated with RITE, with a rate of 89% in those who had previously undergone BCG therapy. We observed a slightly better RFS compared to those observed in a recent randomised-controlled trial.¹⁶ This might be attributed to differences in patient selection, previous therapies and tumor biology itself. These results are particularly noteworthy when compared to recent phase II trials of alternative bladder-sparing therapies. For instance, the phase II KEYNOTE-057 trial of pembrolizumab in patients with BCG-unresponsive NMIBC demonstrated a durable complete response (CR) rate of 41% at 3 months. However, the efficacy of pembrolizumab declined over time, highlighting the challenges associated with achieving long-term bladder preservation using immune checkpoint inhibitors.¹⁷ When compared to the 5-year follow-up results from the phase 3 trial of nadofaragene firadenovec which reported a bladder preservation rate of approximately 53% in patients with BCG-unresponsive NMIBC,¹⁸ our findings suggest that RITE may provide a promising long-term bladder preservation outcome. While nadofaragene firadenovec has shown effectiveness, particularly in patients unresponsive to BCG, the preservation rates observed with RITE, especially in those previously treated with BCG, highlight its potential as an alternative approach for maintaining bladder integrity over time. Further research would be valuable to better understand the relative benefits of each treatment option. When compared to the IL-15 superagonist NAI (Nogapendekin alfa inbakicept), combined with BCG in patients with BCG-unresponsive NMIBC, our results show strong parallels. In patients with CIS treated with NAI plus BCG, a CR was achieved in 71%, with a median duration of response of 26.6 months. Additionally, at 24 months, the Kaplan-Meier estimated probability of avoiding cystectomy was 89.2%, with a 100% disease-specific survival rate.¹⁹ Our study included patients unresponsive to initial chemotherapy, many of whom also underwent BCG therapy, reflecting complex clinical histories. While EAU guidelines recommend BCG re-challenge for chemotherapy-failed patients,²⁰ deviations are often required due to individual factors such as patient preference and treatment tolerance. This highlights the need for adaptable treatment strategies in real-world settings. Our analysis is not devoid of limitations, which are mainly inherent to its retrospective design. Variation in treatment schedules and follow-up protocols might overestimate therapy efficacy. We did not perform a comparative analysis against a control group or other treatment modalities such as BCG or conventional intravesical chemotherapy, which limits the ability to definitively attribute the observed 50% 5-year response rate solely to RITE. Our cohort size, while reflective of a real-world scenario, may also limit the generalizability of our findings compared to larger, prospective trials. The limited number of patients receiving eight versus six cycles of Synergo® precludes a viable subgroup analysis. Additionally, the wide confidence interval observed in our subgroup analysis underscores the considerable uncertainty in the HR estimate, likely due to the relatively small sample size. Despite these limitations, our analyses provide relevant clinical data that might be used for patient counselling regarding bladder sparing therapies after BCG-failure.

Conclusion

This study evaluated the oncological outcomes of RITE in patients with NMIBC in a real-world setting, including those unresponsive to prior BCG and intravesical chemotherapy, as well as those who declined or were ineligible for BCG or RC. Our findings demonstrate that RITE exhibits notable antitumor efficacy, offering favorable survival outcomes and high bladder preservation rates. Importantly, RITE allows for the avoidance of more invasive, quality-of-life-limiting treatments, such as RC, positioning it as a viable bladder-sparing option for patients failing prior intravesical therapies. While these results underscore the potential of RITE as a second-line therapeutic strategy, validation through long-term follow-up and larger-scale RCTS is essential to optimize its clinical application and establish its role in treatment paradigms.