Device-Assisted Therapy in Non-Muscle-Invasive Bladder Cancer

Challenges

NMIBC represents a noteworthy disease state in the context of drug delivery, as it contains challenges due to the physiologic barriers present in the urothelium and the unique method of intravesical drug delivery. The first barrier to drug or toxin permeation into the urothelium is provided by a robust network of glycosaminoglycans (GAG) [7]. This dense extracellular matrix is comprised of a number of mucopolysaccharides, such as hyaluronic acid and chondroitin sulfate, that formulate a barrier whose integrity is essential to prevent reabsorption of urinary solutes and bacterial adherence to urothelium [8]. Various pharmaceutical agents have been employed in preclinical studies to perturb the GAG barrier function such as intravesical detergents, inhibitors of various GAG constituents, and therapeutic agents that suffuse a drug of interest within the GAG layer [9].

The subsequent barrier present for intravesical drug delivery is provided by the urothelium itself. The apical junctions of the umbrella cells regulate paracellular transport of solutes and materials even when formidable mechanical forces are present during bladder filling [10]. Tight junctions make up part of the apical junction and are crucial for regulating the transport of materials past the umbrella cells. Clinically, the effects of these barriers on drug penetration are apparent in drug diffusion studies. In one such study, intravesical Mitomycin C (MMC) diffusion was assessed by placing 20 mg MMC in 40 mg of water for a two-hour dwell time in 11 patients prior to radical cystectomy for urothelial cell carcinoma or locally invasive colon cancer [11]. Median drug concentration was highest at 5.6μg/ml in the urothelial basement membrane, 2.7μg/ml in the lamina propria, and 0.9μg/ml at the base of the muscularis. No considerable difference in drug penetration between normal tissue and tumor was noted; however, this was only assessed in a small subset of patients on study and was limited by technical difficulties. The same group conducted a similar study assessing drug penetration of 40 mg of doxorubicin diluted in 20 mg of water with a dwell time of 1–2 hours in ten patients undergoing radical cystectomy [12]. Similarly, median drug concentration was highest at 8.6μg/ml in the urothelial basement membrane, 5.3μg/ml in the lamina propria, and 1.1μg/ml at the base of the muscularis. Notable in both studies was the considerable decrease in drug concentrations at increasing tissue depths and an appreciable intersubject variability. These findings highlight the need for mechanisms of drug delivery that facilitate improved concentrations at higher depths of tissue.

Radiofrequency induced thermochemotherapy effect (RITE)

The Synergo system SB-TS 101 (Medical Enterprises, Amsterdam, Netherlands) allows for concomitant hyperthermia to be applied to the bladder with intravesical instillation of either MMC or epirubicin. The system utilizes a specialized disposable 20 Fr 3-way catheter modified with an integrated miniature RF antenna and five thermocouples to assess bladder and urethral temperatures [16]. The RF generator provides 915 MHz of non-ionizing radiation directly to the bladder to raise tissue temperature to 42±2°C. Five total thermocouples monitor both the urethral and bladder temperature while cooled chemotherapy is instilled within a closed circuit for the putative benefits of urethral comfort and drug stability. The treatment is given in an outpatient setting to patients with either no or local anesthetic gel applied to the urethra. Dwell time is planned for 60 minutes and mitomycin is dosed at 20 mg in 50 mL of water and refreshed with another 20 mg MMC in 50 mL of water halfway through the treatment time [17]. Epirubicin was also administered in earlier studies, but contemporary use of the system has replaced it in favor of MMC.

Initial studies of intermediate- to high-risk NMIBC by van der Heijden et al. utilized two treatments of 20 mg MMC in 40 mL of water and demonstrated favorable outcomes [18]. In 90 patients who underwent an induction course of six to eight weekly sessions and a maintenance course of four to six monthly sessions, one- and two-year rates of recurrence were 14.3% and 24.6%, respectively. The BCG-exposed cohort of patients (n = 41) experienced recurrence rates of 23.1% and 41.2% at one and two years, respectively. Subsequently, a single-center series reported by Moskovitz et al. demonstrated similar responses in intermediate- to high-risk subjects, with 20 patients (91%) experiencing no recurrence at a median follow-up of 10 months [19]. The experience from this institution was later updated with 64 patients, 47 (73%) of whom were high-risk, undergoing adjuvant therapy in a modified protocol where the maintenance course was changed to six sessions at six-week intervals. At a median follow-up of 23 months, the two-year median recurrence-free survival (RFS) was 32.8% [20].

Columbo et al. described the results of a multicenter, randomized controlled trial comparing adjuvant RITE to normothermic MMC in treatment-agnostic NMIBC [21]. Eighty-three patients with intermediate- to high-risk papillary NMIBC with or without carcinoma in situ (CIS) were randomized to receive 20 mg MMC in 50 ml of water with replacement of the solution after 30 minutes for a total dwell time of 1 hour with or without hyperthermia. Approximately 40% of patients in both arms had received prior treatment with either BCG or chemotherapy, and the presence of grade 3 tumors was 26% in the RITE arm and 17% in the MMC arm. At a minimum follow-up of two-years, 75 patients (90%) were evaluated, and recurrence was noted in six (17%) and 23 (58%) patients in the RITE and MMC arms, respectively. The authors reported on long-term outcomes after a median follow-up of 90 months and demonstrated 5- and 10-year median RFS to be 62% and 53% in the RITE arm compared to 21% and 15% in the MMC arm [17]. These results suggest a sustained, durable, and superior response experienced by patients undergoing RITE; however, the bladder preservation rate and overall survival was similar between the two arms.

Similarly, Arends et al. reported on the results of a randomized controlled trial in which 184 patients with intermediate- or high-risk bladder cancer were randomized to RITE or BCG [22]. The majority (69%) of patients had intermediate-risk papillary-only disease. Patients were randomized to six weekly treatments and six maintenance treatments of RITE, or induction intravesical BCG with 1 year of maintenance therapy. The intention-to-treat analysis did not demonstrate a difference in terms of 24-month RFS (78.1% RITE vs. 64.8% BCG, p = 0.08), but the per-protocol analysis did demonstrate a difference in 24-month RFS (81.8% RITE vs. 64.8% BCG, p = 0.02). Unfortunately, the study closed prematurely and therefore was underpowered to assess its endpoints.

Tan et al. reported on the phase 3, multicenter HYMN trial, which randomized patients with BCG-exposed intermediate- to high-risk cancer with either RITE or a choice between a second course of BCG induction with maintenance or institutional standard of care [23]. A total of 104 patients were assessed; however, the trial was closed prematurely due to a higher than expected rate of recurrence of carcinoma in situ (CIS) noted in the RITE arm. With a median follow-up of 36 months, assessment of co-primary endpoints demonstrated no significant differences in either the disease-free survival (DFS) rate of all subjects or the 3-month complete response (CR) rate in CIS patients. Planned sub-group analysis, however, demonstrated a considerably lower DFS in subjects who harbored CIS with or without papillary disease at baseline (HR: 2.1; p = 0.01). Some important considerations in this study were that it was performed prior to the FDA and AUA definitions of BCG-refractory NMIBC, and thus included a heterogeneous group of BCG exposed patients. Therefore, a second round of BCG therapy, utilized in 59% of controls, remained a highly efficacious treatment for this patient population. Similarly, 23% of control patients were given MMC via electromotive therapy, which is a novel mechanism of drug delivery that may not represent a pragmatic standard of care treatment used throughout most institutions. Given these results, a subsequent retrospective study assessing outcomes in 299 patients with intermediate- to high-risk patients, most of whom were BCG-exposed or refractory (85% and 65%, respectively) was conducted [24]. Heterogenous dosing was utilized with 80 mg of MMC or 100 mg of epirubicin utilized in the neoadjuvant/ablative setting and 40 mg of MMC or 60 mg of epirubicin in the adjuvant setting. The 6-month CR rate for those with CIS±papillary disease (n = 128) or neoadjuvant treatment (n = 22) was 56% while 1- and 2-year RFS for all papillary patients were 79% and 60%, respectively. Patients treated with ablative dosing were noted to have improved RFS (HR 0.54) on multivariate analysis; however, it is unclear if this secondary to patient characteristics.

Study design in this space has matured over time, with a focus on specific patient populations, notably patients experiencing T1 high-grade (HG), CIS, or BCG-exposed NMIBC. Halachmi et al. assessed 56 patients with T1 HG disease, 30 (54%) of whom were treatment naïve, who received RITE [25]. At median follow-up of 18 months, 2-year and 4-year estimated RFS were 43% and 51%, respectively. However, it should be noted that five patients (9%) discontinued therapy prior to the first evaluation secondary to adverse events and were not included in the final analysis. Notably, one patient developed a grade 3 urethral stricture, and another required a cystectomy solely due to troublesome lower urinary tract symptoms. Witjes et al. reported on a retrospective dataset of patients with CIS, with or without papillary disease, who underwent RITE [26]. Fifty-one patients were assessed, 34 of whom received prior BCG with 17 deemed BCG-refractory, 15 BCG-relapsing (recurrence after 12 months) and two being BCG-intolerant. The 3-month CR rate was 92%, and after a median follow-up of 27 months, 51% of responders experienced a recurrence.

The safety profile of RITE is similar to that of other intravesical therapeutics. Lower urinary tract symptoms tend to predominate, with the most common being bladder pain and bladder spasms during treatments. Specific adverse events to note with this treatment are bladder pain and sensitivity during treatment, the relatively higher rate of urethral strictures noted in multiple studies, and the presence of posterior wall thermal reactions [19, 22]. Posterior wall thermal reactions are a unique side effect ascribed to RITE. Due to the location of the RF antennae, a small erythematous lesion can develop at the posterior bladder wall during cystoscopy [19]. Due to its appearance, it can be mistaken for CIS; however, these are benign and resolve spontaneously.

When comparing RITE or BCG for intermediate- to high-risk tumors, chemohyperthermia (CHT) resulted in considerably more bladder pain during sessions (OR: 26.3), bladder spasms (OR 15.5), posterior wall thermal reactions (OR: 5.8), and urethral strictures (OR 2.3) compared to BCG. RITE was noted to have a significantly lower rate of urinary frequency (OR: 0.6), incontinence (0.2), hematuria (0.6), and fatigue (0.2) than BCG. Serious adverse event rates were similar between both arms.

The role for RITE therapy in NMIBC is being further clarified as randomized controlled trials help clinicians gain an understanding of its benefits and pitfalls. Data from these trials suggest an improvement in RFS in patients with intermediate- to high-risk disease compared to normothermic MMC; however, benefit over BCG was only seen in the intention-to-treat analysis when compared to a predominantly intermediate-risk, treatment-naive cohort; and no benefit was noted in a BCG-exposed cohort. Future trials assessing patients with BCG-unresponsive disease will help further define the role of this treatment in the salvage setting.

COMBAT Bladder Recirculation System

The COMBAT Bladder Recirculation System (BRS, Combat Medical, Wheathampstead, UK) is a device that utilizes conductive heating via temperature exchange from externally heated chemotherapy to the bladder wall, resulting in an increase in bladder temperature. Unlike the RITE system, which achieves bladder wall hyperthermia by direct bladder wall heating, the BRS utilizes passive heat exchange from instilled agent to achieve mild hyperthermia. This system mirrors the concept seen in the more established method of hyperthermic intraperitoneal chemotherapy (HIPEC) in which chemotherapy is heated and administered intraperitoneally, allowing for conductive heating to occur in the peritoneal cavity. Given its similar mechanism of action, this type of therapy has also been labelled as hyperthermic intravesical chemotherapy (HIVEC).

The BRS system is composed of a disposable aluminum foil heat exchanger which externally heats the chemotherapeutic agent. A priming solution of approximately 50 mL is utilized, and a 16 Fr modified 3-way foley catheter with temperature and pressure sensors is used to help instill the agent. The BRS employes a relatively isobaric environment within the bladder, with safety sensors identifying elevated pressures during filling. The majority of studies are conducted with a one-hour hyperthermic instillation time of MMC and a temperature of 43±1°C, though the system does allow for some variability in these settings. General treatment schedules consist of weekly treatments for 6 weeks during the induction period, followed by once monthly treatments during the maintenance period.

HIVEC has been utilized in both the neoadjuvant/ablative setting and in the adjuvant setting, with the majority of studies focusing on its role as a form of adjuvant therapy. Plata et al. reported on the experience of nine centers in Spain utilizing HIVEC with MMC in the adjuvant setting in 502 patients from 2012 to 2020 [27]. The patients were of European Association of Urology (EAU) intermediate- (59%) or high-risk (41%), with a majority of patients being BCG-naïve (90%). Patients were treated with adjuvant HIVEC MMC at 40 mg for 1 hour, with a majority of patients receiving both induction and maintenance treatments (n = 402, 80%), and were followed for a median of 24 months. The five-year RFS, progression free survival (PFS), and overall survival (OS) for the overall cohort were 50% (53% for intermediate-risk and 47% for high-risk), 89% (94% for intermediate-risk and 84% for high-risk), 66% (74% for intermediate-risk and 60% for high-risk), respectively.

Multiple smaller, single-institution studies have demonstrated similar therapeutic efficacy. Magalhães et al. reported on 57 patients with EAU intermediate- (IR) or high-risk (HR) disease who underwent a standard six-week induction course of 40 mg of MMC via HIVEC followed by monthly maintenance treatments for 6 months [28]. The median DFS (mDFS) for the overall cohort was 42 months, with the IR cohort experiencing an improved mDFS of 44 months and the HR cohort exhibiting a mDFS of 39 months. When controlled for recurrences during therapy, patients who were able to complete maintenance therapy had considerably improved mDFS and had a significant improvement in OS (HR: 42.8). Similarly, Conroy et al. reported on 57 high-risk NMIBC patients, half of whom had received prior BCG [29]. They detailed a 12-month RFS, PFS, and OS of 68%, 82%, and 95% for patients who were treated with a standard induction course and a maintenance course of two-cycles of three weekly instillations. However, 20% of patients progressed on study, with 7% progressing to muscle-invasive bladder cancer (MIBC).

In order to assess the comparative efficacy of other treatments to HIVEC MMC, three randomized controlled trials were performed in subjects with high-risk and intermediate-risk NMIBC. HIVEC-HR was a multicenter trial randomizing patients with EAU high-risk, papillary-only NMIBC to either BCG or HIVEC MMC [30]. The HIVEC arm was administered 40 mg of MMC distilled in 40 mL of water in a six-week induction course, with six additional weekly instillations as maintenance. A majority (90%) of subjects were treatment-naïve and only 1 patient had prior treatment with BCG. A total of 50 patients were randomized, and 48 patients received treatment. The primary outcome of 24-month RFS was 86.5% in the HIVEC arm and 71.8% in the BCG arm, demonstrating no significant difference (HR: 0.4; p = 0.2). Similarly, the 24-month PFS was 95.7% in the HIVEC arm and 71.8% in the BCG arm (HR: 0.1; p = 0.07).

The HIVEC-I was a phase 3 trial randomizing patients with intermediate-risk NMIBC in a 1 : 1:1 fashion to four weekly then three monthly instillations of 40 mg of MMC in normothermic conditions (n = 106), 43°C for 30 minutes (n = 107), or 43°C for 60 minutes (n = 106) [31]. The primary outcome of 24-month RFS was 77% for normothermia, 82% for the 30-minute HIVEC arm, and 80% for the 60-minute HIVEC arm (p = 0.6). Pooled assessment of all HIVEC-treated subjects compared to normothermic subjects also demonstrated no difference in RFS at 24 months. Health related quality of life was assessed and demonstrated no considerable difference between the three arms. One of the issues the authors noted was a lower rate of events than was expected at 24 months. A rate of approximately 30–40% was hypothesized; however, the outcomes showed only 20–25% rate of recurrence, leading to a sample size that was underpowered to detect the anticipated magnitude of change. The subsequent HIVEC-II trial randomized patients in a 1 : 1 fashion with EAU defined intermediate-risk NMIBC to induction therapy of six weekly instillations of 40 mg of MMC in either normothermia (n = 128) or 43°C for 60 minutes [32]. At a median follow-up of 24 months, the 24-month DFS was 61% in the HIVEC arm and 60% in the normothermic arm. PFS was noted to be higher in the normothermic arm (HR: 3.44, p = 0.02) in the intention to treat analysis, but was found to not be significant in the per protocol analysis (HR: 2.55; p = 0.06). Notably, patients undergoing HIVEC therapy were less likely to complete their treatment when compared to the normothermic arm (59% vs 89%, respectively). Final takeaways from the authors were that hyperthermic MMC cannot be recommended over standard normothermic MMC in intermediate-risk patients.

Multiple studies have assessed HIVEC with variations in dosing and timing. In the neoadjuvant ablative setting, doses of 80 mg were generally employed for the purposes of chemoablating tumors prior to resection. Sousa et al. described their results of a pilot study in which 15 patients with intermediate- to predominantly high-risk NMIBC were treated with 80 mg MMC in 50 mL of distilled water for six sessions prior to planned TURBT and random bladder biopsies [33]. Partial response (PR) was defined as >50% tumor reduction. The investigators reported a visual PR rate of 40%, a visual CR rate of 60%, and a pathologic CR rate of 53%. Patients who experienced a PR went on to receive normothermic monthly maintenance for 1 year. The responses of an expanded cohort of 24 total patients, 60% of whom had prior BCG exposure, was later described by the same group [34]. Visual PR was noted in 33% of subjects while a histologic CR was observed in 62.5%. The overall four-year incidence of recurrence was 21%. The increased dosage was well tolerated, with 96% of planned instillations being administered. The most common adverse events were irritative voiding (42%), bladder spasms (33%), and pain (30%), which were consistent across studies incorporating different dosages.

Higher doses have also been utilized to treat higher-risk patients, including those who are BCG-unresponsive. Grimberg et al. reported on the use of adjuvant HIVEC with 120 mg MMC diluted in 60 ml of water [35]. The analysis cohort included 14 intermediate- to predominantly high-risk patients, a majority of whom had prior BCG exposure (79%). DFS was 85% at a median follow-up of 11 months, and both recurrences were noted in patients who had discontinued therapy after two doses due to adverse events. Adverse events in this group were all grade 1 and 2, and included lower urinary tract symptoms as noted in other studies. Unique to this group was the presence of rash in four patients (29%), which was thought to be related to an MMC allergy, and a grade 2 leukopenia. Further assessment of hematologic parameters did not show concerns for myelosuppression with the 120 mg in 60 mL dose.

Promising outcomes in treating BCG-unresponsive patients with 80 mg of MMC via HIVEC have subsequently led to larger retrospective series assessing this very high-risk patient cohort. Pijpers et al. assessed 56 BCG-unresponsive patients treated at multiple centers who were planned to receive a six-week induction followed by a monthly maintenance regimen for six months [36]. CIS was present in 32 patients (57%). After a median follow-up of 32.2 months, the 1- and 2-year RFS in patients with high-grade disease were 53% and 35%, respectively. Notably, the CR for subjects with CIS was 70% at 6 months, 45% at 12 months, and 33% at 18 months. Pignot et al. also described their multicenter experience of treating 116 patients with BCG-unresponsive disease at standard dosing of 40 mg of MMC via HIVEC [37]. Thirty-six patients (31%) had CIS and 14 patients (12%) had a prior history of upper tract carcinoma. After a median follow-up of 20.6 months, the 1- and 2-year RFS were 63% and 39%, respectively.

The safety profile of HIVEC is similar to that noted in other forms of CHT. It has been tolerated well across different dosages, with the most common symptoms being the lower urinary tract symptoms of urinary tract pain, frequency, and hematuria. An adverse event of note for this therapy is a pruritic rash, thought to be attributable to a MMC allergy. This was noted from 4–29% of patients across the different dosing groups in the various prospective studies [31, 32, 35].

Regarding optimal dosing, recent porcine studies have demonstrated that the standard 40 mg MMC in a 60-minute hyperthermic dwell time show only a modest increase in median bladder wall MMC concentration when compared to the same dose and time in normothermic conditions (471 ng/mL vs 329 ng/ml; p = 0.012) [38]. However, when the doses are increased to 80 mg MMC, there is a considerable increase in bladder wall concentration in the hyperthermic group (7135 ng/mL vs 617 ng/ml; p = 0.004), and this is similarly mirrored with a 120 mg dose. Of note, these porcine studies also utilized priming solutions of 40 mg of MMC in 40 mg of saline in addition to the experimental dose, further increasing the working concentration of the reported dose.

Overall, the role of the Combat BRS HIVEC system is evolving, but a number of clinical trials and prospective studies have identified disease states in which there is potential and those in which there is likely little benefit. The HIVEC-I and II studies assessing EAU intermediate-risk NMIBC have not demonstrated any benefit in this group, even with the inclusion of maintenance therapy. The HIVEC-II study actually demonstrated a worse PFS, which was thought to be attributed in part to the inability of some patients to complete therapy. This has led the authors to conclude that there is no role for HIVEC MMC over normothermic MMC in this patient population. The HIVEC-HR trial demonstrated that 40 mg of MMC via HIVEC had comparable results to BCG in the high-risk population, and this seems to be in-line with other studies demonstrating a more encouraging efficacy in higher-risk patients. The most promising results of the BRS HIVEC system are observed in the higher dose chemoablative neoadjuvant setting and in the BCG-unresponsive setting, where higher doses of 80 mg of MMC are generally utilized. Both settings have shown promising results; however, prospective phase 2 or 3 studies in the BCG-unresponsive setting are lacking. Given the evidence from the pre-clinical porcine studies and the aforementioned clinical studies, focusing on higher-risk patients with increased dosages may play a key role in future studies.

Unithermia

The Unithermia Bladder Wall Thermo-chemotherapy (BWT, Elmedical Ltd, Hod-Hasharon, Israel) is another system reliant on conductive heating of the bladder via externally heated chemotherapy. The device is a compact module consisting of a peristaltic pump and an external heat exchanger to circulate temperature modulated chemotherapy within the bladder. Specialized 3-way 16 Fr Tiemmen tip and 18 Fr Nelaton tip catheters are compatible with the system, and a needle-tip temperature probe is placed within the catheter for temperature sensing. The device maintains stable hyperthermia with a goal temperature of 42.5±1°C and a maximum safety peak of 44.5°C. Instillation time varies between 45–50 minutes, and dosages vary between 40–80 mg of MMC.

Soria et al. reported on the original pharmacokinetic and clinical results in a phase 1-2 single-arm study utilizing BWT [39, 40]. A total of 34 patients who had recurrence after prior induction course of BCG were enrolled on this trial. The pharmacokinetic profile demonstrated minimal systemic absorption with BWT, and plasma levels of MMC were much lower than the reported concentration concerning for toxicity (400 ng/ml). At a median follow-up of 41 months, 44% of patients remained disease free. Median time to recurrence was 10.5 months and median time to progression was 29.5 months. The treatment was well tolerated, with four patients experiencing grade 3 adverse events consisting of bladder spasms (n = 2) and systemic cutaneous rash (n = 2). Head-to- head trials of BWT against other intravesical therapies have yet to be reported on; however, propensity matched studies have been performed to compare the efficacy of BCG-naïve NMIBC patients to either BWT or BCG [41]. The 2-year RFS was more favorable in the BCG arm (93.9% vs 76.2%, p = 0.02) with both use of BWT (HR: 5.2) and the presence of high-grade tumors (HR: 4.6) demonstrating considerably worse outcomes in univariate, but not multivariate, Cox regression analysis.

A subsequent study by Gözen et al. reported on the safety and clinical outcomes of utilizing 80 mg of MMC in a six-week induction course followed by a monthly maintenance dose for 1 year and a quarterly dose thereafter [42]. A total of 18 patients were included in the analysis with 66% of patients with T1 disease, 66% being treatment-naïve, and no patients with prior BCG treatment. At a median follow-up of approximately 15 months, 83.3% of patients did not experience a recurrence and no patients experienced disease progression. Patients tolerated the instillation well, and all adverse events experienced on study were grade 1 or 2.

BSD-2000

The BSD-2000 (BSD Medical, Salt Lake City, UT) is a deep regional hyperthermia system that utilizes an external radiofrequency delivery system, which allows for conformation of the heated zone agnostic of the targeted organ system. The setup has a patient support table, which allows for patient positioning through an external annular phased array applicator and a distilled water bolus. RF waves from 80–120 MHz are utilized to create a customizable hyperthermia plan that allows for a maximum specific absorption rate to be focused on the bladder. Inman et al. detailed the results of a pilot study assessing 15 patients with BCG-unresponsive or intolerant disease [43]. Subjects underwent an induction course of 40 mg of MMC weekly for six weeks with 60-minute dwell time followed by a 4-month maintenance course of monthly doses. The procedure was tolerated well with no subjects discontinuing therapy due to adverse events, of which none above grade 3 were noted. After a median follow-up of 3.2 years, 10 (67%) of patients experienced a recurrence and no patients progressed to muscle-invasive disease. Wen et al. detailed their retrospective single-institution results which compared a cohort of patients with intermediate- to high-risk NMIBC who were treated with normothermic MMC or hyperthermic MMC delivered via the BSD-2000 system [44]. Subjects were administered 30 mg of MMC for a six-week induction period followed by a once monthly instillation for 10 months. A total of 43 patients were assessed (25 normothermic and 18 hyperthermic). Recurrence rates were significantly lower in the hyperthermic group than the normothermic group at 12 months (11.1% vs 44%; p = 0.048) and 24 months (11.1% vs 48%; p = 0.027). The treatment was tolerated well with all patients completing both maintenance and induction courses with no adverse events above grade 3 noted. The most common adverse events in the hyperthermic arm were urinary frequency (67%), gross hematuria (11%) and suprapubic soreness (11%). The BSD-2000 is continuing to be investigated for its role in NMIBC and in organ preservation in muscle-invasive disease.