Articles

The Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review

By: Rianne J.M. Lammersa, J. Alfred Witjesa lowast , Brant A. Inmanb, Ilan Leibovitchc, Menachem Lauferd, Ofer Native and Renzo Colombof

Published online: 01 July 2011

Keywords: Adverse events, Chemohyperthermia, Device-assisted therapy, Hyperthermia, Intravesical chemotherapy, Mitomycin C, Non-muscle-invasive bladder cancer, Progression, Recurrence, Thermochemotherapy

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Abstract

Context

Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings.

Objective

To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC.

Evidence acquisition

The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate.

Evidence synthesis

A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant.

Conclusions

Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated.

Take Home Message

This review on chemohyperthermia (C-HT) with mitomycin C (MMC) as treatment for non-muscle-invasive bladder cancer shows that meta-analysis is difficult due to incomparability. However, C-HT showed fewer recurrences than MMC alone in an adjuvant setting and showed consistent ablative effects in neoadjuvant settings.

Keywords: Adverse events, Chemohyperthermia, Device-assisted therapy, Hyperthermia, Intravesical chemotherapy, Mitomycin C, Non-muscle-invasive bladder cancer, Progression, Recurrence, Thermochemotherapy.

1. Introduction

Management of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor generally consists of surveillance and intravesical therapy. Unfortunately, current intravesical therapies are associated with undesirable toxicities and suboptimal efficacy. Particularly challenging is the treatment of patients who have not responded to first-line intravesical bacillus Calmette-Guérin (BCG) or that have high-risk features [1]. For such patients, radical cystectomy remains a commonly recommended treatment alternative [1] and [2].

One of the developing treatments for high-risk NMIBC is the combination of intravesical chemotherapy and hyperthermia (HT), called chemohyperthermia (C-HT). The most common form of C-HT uses the Synergo HT system, in which local HT is administered via direct microwave irradiation of the urothelium by means of a 915-MHz intravesical microwave applicator. The target intravesical temperature is set between 41°C and 44°C and is measured by five thermocouples integrated in a 20-F treatment catheter. To avoid injury, the urethra is continuously cooled (Fig. 1) [3]. Due to extensive global experience with its use and a significant amount of preclinical data demonstrating improved antineoplastic efficacy when heated, mitomycin C (MMC) is the most common intravesical chemotherapy agent used in conjunction with HT.

gr1

Fig. 1 Synergo SB-TS 101 system during treatment. Applicator heats bladder wall. Thermocouples measure temperature of different areas of bladder surface and bladder neck. Intravesical cytostatic agent solution (most commonly mitomycin C) circulates in this closed circuit. Solution is cooled through the catheter to prevent overheating of the urethra and disintegration of the solution. Reproduced with permission of Elsevier [26].

There are several potential reasons for improved MMC efficacy when combined with heat. One explanation is that heat increases the penetration of MMC into the urothelium due to increased cellular membrane permeability and/or modified blood perfusion. HT is also directly cytotoxic and is known to alter intracellular metabolism, to damage DNA, to impair cellular proliferation, and to increase tumor cell apoptosis [4] and [5]. Lastly, HT has been shown to increase the cytotoxicity of MMC, making the drug itself more effective [4] and [5].

This collaborative review provides a critical overview of current literature concerning the role of HT for the treatment of NMIBC.

2. Evidence acquisition

Although the term thermochemotherapy has been used to describe the combination of HT and intravesical chemotherapy, in this review we preferentially use the terms HT and C-HT to describe supraphysiologic HT given in the 40–45°C range. Unless otherwise stated, C-HT in this manuscript refers to the combination of HT and MMC.

A search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken in January 2011. Candidate manuscripts were limited to the English language with a publication range between 1990 and 2011. The Journal of Urology and European Urology were searched manually for manuscripts. Additionally, abstracts from the annual meetings of the European Association of Urology and the American Urological Association were searched manually. A detailed description of the search strategy is given in Appendix A. Authors and experts in the field were asked for additional studies.

Candidate manuscripts were reviewed according to the Cochrane Collaboration criteria and reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [6] and [7]. Two reviewers (RL and BI) independently performed database searches, assessed candidate manuscripts for inclusion criteria, and extracted primary data. The primary end point was time to recurrence, with recurrence defined as the presence of positive cytology, positive bladder biopsy, or tumor at cystoscopy. Secondary end points were time to progression, bladder preservation rate, and adverse events (AEs), with progression defined as worsening pathologic stage, including muscle invasion or metastases.

A random effects meta-analysis was performed on the recurrence rate by comparing C-HT with MMC alone, using the method of DerSimonian and Laird implemented in MetaAnalyst Beta v.3.13 [8] and [9].

3. Evidence synthesis

3.1. Search results

The search strategy generated 68 hits, of which 38 were excluded because the abstract or the manuscript did not meet inclusion criteria [3], [5], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], and [36]. Of the remaining 30 eligible publications, full review determined that 11 were reviews. Another four articles were excluded because they were about preclinical work. Consequently, 15 original articles were eligible for analysis [3], [11], [14], [16], [19], [22], [23], [24], [27], [28], [29], [30], [32], [33], and [36]. Manual searches did not result in additional clinical studies on C-HT. Two studies were added by authors of this review [37] and [38]. An interim analysis from the Lombardia project was added (unpubl. data, R. Colombo, Milan, Italy), and the AE results from one clinic were contributed (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands). Additionally, CancerLit and ClinicalTrials.gov searches identified three ongoing clinical trials, bringing the total number of studies discussed in this review to 22. Appendix B shows the flow diagram of evidence acquisition. Some studies were executed by the same groups [3], [14], [19], [27], [28], and [37], but the authors of these articles have confirmed that there was either no overlap [3], [27], and [28] or minimal overlap [14] and [19] of patients.

3.2. Chemohyperthermia versus mitomycin C alone and recurrences

Table 1 provides an overview of all clinical trials concerning clinical outcome after treatment with C-HT for NMIBC.

Table 1 Overview of all clinical trials concerning initial response, recurrence, and progression chances after chemohyperthermia treatment in patients with non-muscle-invasive bladder cancer*

Reference Study type No. of patients Patient population Study description Treatment Follow-up, median (range) Outcome: recurrence Outcome: progression
Duration, min Temperature, degrees Celcius Dose No. of treatment Maintenance
Rigatti et al, 1991 [36] Prospective 12 Ta/1 G1–3 Phase 1 study 60 41.5–43.5 30mg in 60 ml 6–8 No 16 (NA) CR in 5 of 12 patients NA
Preoperative treatment Recurrence: 1 of 5 (20%), 3 mo after TURBT
1–3 wk after last treatment TURBT
Colombo et al, 1995 [32] Prospective 44 Ta/1 G1–3 Phase 1 study 60 42.5–44.5 30mg in 60 ml 8 No 24 (3–57) CR in 31 of 44 patients None
Preoperative treatment Recurrence: 7 of 31 (22.6%), within 24-mo follow-up
<3 wk after last treatment TURBT
Colombo et al, 1996 [30] Retrospective 52 Ta/1 G1–3 Marker lesion study 60 42.5–46.0 40mg in 50 ml 6–8 No 38 in group 1 (NA); 36 (NA) in group 2 CR in group 1 is 19 of 29 (66%) vs 5 of 23 (22%) in group 2 (p < 0.001) NA
Comparison of C-HT with MMC (group 1; n=29) vs MMC alone (group 2; n=23) Recurrence: 8 of 29 in group 1 (27%) after 7–22 mo vs 9 of 23 in group 2 (39%) after 7–19 mo
1–3 wk after last treatment TURBT
Colombo et al, 1998 [28] NA 19 Multifocal, therapy-resistant T1 tumors for which complete TURBT seemed technically impossible and for which the patient refused cystectomy C-HT as debulking therapy 40–60 42.5–46.0 40mg in 40 ml 8 No 33 (12–60) In 16 of 19 TURBT was possible after treatment with C-HT None
When possible: 2 wk after last treatment TURBT. When TURBT impossible: cystectomy after last treatment. CR in 9 of 16 (47%)
Recurrence: 8 of 9 patients
Colombo et al, 2001 [27] Retrospective 80 Single, small (<2 cm) Ta/1 G1–2 that were not earlier treated with MMC Marker lesion study MMC alone and C-HT with MMC: 60 Mean: 42.5 MMC alone and C-HT with MMC: 40mg in 50 ml 4 No None CR in 10 of 36 in group 1 (27.7%), in 19 of 29 in group 2 (66.0%), and in 6 of 15 in group 3 (40.0%) (p=NA) NA
Comparison of MMC alone (group 1; n=36) vs C-HT with MMC (group 2; n=29) and vs EMDA with MMC (group 3; n=15) EMDA: 20 EMDA: 40mg in 150ml Recurrence: NA
Colombo et al, 2003 [3] Prospective 83 Intermediate- or high-risk UCC, with confirmed complete TURBT Multicenter study 40–60 40–44 20mg in 50 ml 8 Yes: four times monthly >24 (NA) Total evaluable patients: 75 Total evaluable patients: 75
Phase 3 study Recurrence: 6 of 35 in group 1 (17.1%) vs 23 of 40 in group 2 (57.5%) (p=0.002) Progression: 1 of 40 in group 2; none in group 1
Comparison of C-HT with MMC (group 1; n=42) vs MMC alone (group 2; n=41)
Randomization with closed envelopes
Gofrit et al, 2004 [23] Prospective 52 Ta/1 G2–3 high-risk Multicenter study 40 40–44 Group 1: 20mg in 50 ml 8 Yes: four times monthly 15.2 (6–90) CR in group 2: 21 of 28 (75%) None in both groups
Prophylactic schedule compared to ablative schedule Group 2: 40mg in 50 ml Recurrence: 9 of 24 (37.5%) in group 1 after mean 10 mo; 4 of 21 in group 2 (19%) after mean 13.7 mo
Prophylactic schedule in case of confirmed complete TURBT (group 1; n=24); ablative in other patients (group 2; n=28) RFS in group 1: 15 of 24 (62.5%)
Van der Heijden et al, 2004 [22] NA 90 Intermediate- or high-risk Ta/1, with confirmed complete TURBT Multicenter study 60 41–44 20mg in 50 ml 6–8 Yes: four to six times monthly 18 (2–24) Recurrence: 14 of 90 patients None
Kaplan-Meier recurrence chance: 14.3% after 1 yr; 24.6% after 2 yr
Moskovitz et al, 2005 [19] Prospective 47 Intermediate- and high-risk Prophylactic schedule compared to ablative schedule 60 40–44 Group 1: 20mg in 50 ml 6–8 Yes: only in case of CR; four to six times monthly 10 (NA) Total evaluable patients: 32 Total evaluable patients: 32
Overlap in patients (n=7) between Moskovitz et al and Halachmi et al Prophylactic schedule in case of confirmed complete TURBT (group 1; n=22); ablative schedule in other patients (group 2; n=10) Group 2: 40mg in 50 ml Recurrence: 2 of 22 (9%) in group 1 after 10 mo; 2 of 10 (20%) in group 2 after 9 mo Progression: none
Witjes et al, 2009 [16] Retrospective 51 Only CIS Multicenter study 60 41–44 Group 1: 20mg in 50 ml Group 1: 6 Yes: six times, every 6 wk 22 (3–77) Total evaluable patients: 49 Total evaluable patients: 49
Prophylactic schedule compared to ablative schedule Group 2: 40mg in 50 ml Group 2: 8 Because no difference between group 1 and group 2, data were analyzed together Because no difference between Group 1 and Group 2, data were analyzed together
Ablative schedule in case of concomitant papillary lesions or many CIS lesions (group 2; n=33); prophylactive schedule in other patients (group 1; n=18) CR: 45 of 49 (92%) after 3 mo Progression: NA
Recurrence: 22 of 45 (49%) after 2 yr
Halachmi et al, 2009 [14] Retrospective 56 Only T1G3, after complete TURBT Multicenter study 60 40–44 20mg in NA ml 6 Yes: six times, every 4–6 wk >24 (2–49) Total evaluable patients: 51 Total evaluable patients: 51
Overlap in patients (n=7) between Moskovitz et al and Halachmi et al Recurrence: 3 of 51 (6%) after 3 mo; 17 of 51 (33%) after median 9 mo Progression: 4 of 51 (8%)
Kaplan-Meier recurrence chance: 45.9% after 2 yr; 51.0% after 4 yr
Nativ et al, 2009 [11] Retrospective 111 Ta/1 G1–3, after confirmed complete TURBT Multicenter study 60 40–44 20mg in 50ml 6 Yes: six times, every 4–6 wk 16 (2–74) Total evaluable patients: 105 Total evaluable patients: 105
Kaplan-Meier RFS: 85% after 1 yr; 56% after 2 yr Progression: 3 of 105 (3%)
Recurrence: median time to recurrence is 16 mo
Ayres et al, 2009 [38] Prospective 38 Only high risk with failure after BCG NA 60 40–44 Induction: 40mg in NA ml 8 Yes: three times monthly 9 (2–34) DFS: 50% after 2 yr 1 of 38 (3%)
Maintenance: 20mg in NA ml
Colombo et al, 2010 [37] Prospective 83 Intermediate or high risk, with complete TURBT Long-term follow-up of 2003 study 60 40–44 20mg in 50 ml 8 Yes: four times monthly 90 (6–154) Total evaluable patients: 75 Total evaluable patients: 75
Multicenter study Recurrence: 14 of 35 (40%) in group 1 vs 32 of 40 (80%) in group 2 Progression: 2 of 35 (5.7%) in group 1 vs 3 of 40 (7.5%) in group 2 (p=NA)
Randomization with closed envelopes DFS after 10 yr: 52.8% in group 1 vs 14.6% in group 2
Comparison of C-HT with MMC (group 1; n=42) vs MMC alone (group 2; n=41)
Lombardia project (unpubl. data, R. Colombo, Milan, Italy) Prospective 169 Ta/1 G1–3, after confirmed complete TURBT Multicenter study NA NA NA 6 Yes: six times, every 6 wk 23 (NA) Total evaluable patients: 152 Total evaluable patients: 152
Ongoing Recurrence: after median 11.6 mo Progression: 3 of 152 (2.0%)
Interim analysis: September 2010 DFS: 70.0% after 2 yr

* All treatments were performed with mitomycin C and the Synergo SB-TS 101 system.

CIS=carcinoma in situ; CR=complete response; DFS=disease-free survival; EMDA=electromotive drug administration; NA=not available; RFS=recurrence-free survival; TURBT=transurethral resection of bladder tumor; UCC=urothelial cell carcinoma.

To investigate whether outcomes are really better when combining C-HT with MMC, a meta-analysis was performed on four primary studies [3], [27], [30], and [37]. A marker lesion study demonstrated significantly more complete response (CR) rates after C-HT compared to MMC alone (Table 1) [30]. Additionally, the recurrence rate appeared lower with C-HT (27% vs 39%), although time to recurrence was similar [30]. However, the reporting of this study was inadequate, and details about randomization procedures and inclusion/exclusion criteria were lacking. In 2001, Colombo et al compared the efficacy of C-HT to electromotive drug administration (EMDA) with MMC and to MMC [27]. CR was observed in 27.7% (10 patients) after MMC alone versus 40.0% (6 patients) after EMDA and 66.0% (19 patients) after C-HT [27]. Several problems with this study merit mention. First, patients were free to choose their treatment. Second, duration of therapy and MMC concentration were different among the three arms (Table 1). Finally, these patients were not followed for long-term risk of recurrence or progression.

Several of these methodological problems were addressed in a prospective, multicenter, randomized clinical trial that compared C-HT and MMC alone [3]. With an overall follow-up of 24 mo, the recurrence rate after MMC alone was several-fold higher than that of C-HT (17.1% vs 57.5%; hazard ratio [HR]: 4.821; 95% confidence interval [CI], 1.953–11.899). After a long follow-up (median: 90 mo), recurrences were noted in 40% of C-HT patients and 80% of patients treated with MMC alone [39]. The 10-yr disease-free survival rate was estimated at 52.8% for the C-HT arm versus 14.6% for the MMC arm (p<0.001) [37]. It is noteworthy that follow-up procedures after 2 yr were not standardized and could have introduced bias. It is also important to note that all studies mentioned in this section were executed by the same group (although patient groups did not overlap) and were performed with the Synergo system.

The studies are summarized in Table 2, and C-HT and MMC alone are compared graphically in Figure 2. The overall risk ratio was 0.410 (95% CI, 0.290–0.579), which indicates 59.0% less recurrence after C-HT compared with MMC alone.

Table 2 Recurrence risk in patients with non-muscle-invasive bladder cancer after chemohyperthermia with mitomycin C (MMC) versus MMC alone*

Study Patient population C-HT with MMC MMC alone Weight, % Odds ratio (95% CI)
No. patients treated No. patients with recurrences No. patients treated No. patients with recurrences
Colombo et al, 1996 [30] Ta/1 G1–3 29 10 23 18 40.0 0.441 (0.400–0.761)
Colombo et al, 2001 [27] Single, small (<2 cm) Ta/1 G1–2 that was not earlier treated with MMC 29 10 36 26 40.8 0.477 (0.278–0.820)
Colombo et al, 2003 [3] Intermediate or high risk, with confirmed complete TURBT 35 6 40 23 19.2 0.255 (0.116–0.560)

* Recurrence risk was in all three studies lower after C-HT with MMC, compared with MMC alone. Heterogeneity is given as random effects variance (τ2=0) and degree of agreement (I2=0%). Heterogeneity is very low, which means that all single studies show same odds ratios. Studies are sorted by year of publication.

CI=confidence interval; C-HT=chemohyperthermia; MMC=mitomycin C; TURBT=transurethral resection of bladder tumor.

gr2

Fig. 2 Forest plot for risk of recurrence in patients with non-muscle-invasive bladder cancer after treatment with chemohyperthermia (C-HT) and mitomycin C (MMC) versus MMC alone. Overall risk ratio is 41.0%, which means recurrence risk is 59.0% lower after C-HT with MMC compared with MMC alone. Studies are sorted by year of publication.

3.3. Chemohyperthermia after intravesical treatment failure

The outcome for patients who fail intravesical therapy and progress to muscle-invasive disease is poor. Schrier et al found a 3-yr bladder cancer–specific survival of 37% for patients with NMIBC that progressed to muscle-invasive bladder cancer (MIBC) compared with 67% for patients presenting with MIBC [39]. These results have been confirmed by Guzzo et al [40].

Several studies have investigated the role of C-HT in salvaging NMIBC that has not responded to other intravesical regimens. Van der Heijden et al examined 90 patients treated with C-HT (Table 1) of which 76 had failed prior intravesical therapy [22]. Patients that had failed BCG fared significantly worse than other patients (2-yr Kaplan-Meier recurrence: 41.2% vs 24.6%) [22]. Witjes et al treated 49 carcinoma in situ (CIS) patients with C-HT but did not observe a difference in response rate between patients that had failed BCG and those that had not (p=0.63) [16]. Similarly, Halachmi et al reported on 56 high-grade T1 patients treated with C-HT and noted no difference in the 4-yr recurrence rate between those that had failed BCG and those that had not (46% vs 44%, respectively; p=0.54) [14]. Ayres et al prospectively evaluated 38 high-risk patients that had failed BCG and were treated with C-HT and found a 2-yr recurrence rate of 50% [38]. Finally, an interim analysis of an ongoing multicenter Italian study (ie, the Lombardia project) showed that patients treated with C-HT after failing a previous intravesical therapy regimen did substantially worse than patients treated with C-HT de novo, with 2-yr recurrence-free survival rates of 62% and 91%, respectively (p=0.006) (unpubl. data, R. Colombo, Milan, Italy).

The results of C-HT in patients that have previously failed other intravesical regimens are heterogeneous. Despite this, a significant number of these patients are salvaged with C-HT, and this appears to be a major advantage of this treatment regimen.

3.4. Progression after chemohyperthermia

Most studies assessing C-HT consider progression to MIBC as a secondary end point (Table 1). Reported progression varies between 0% and 8% [3], [11], [14], [19], [22], [23], [28], [32], [37], and [38] (unpubl. data, R. Colombo, Milan, Italy). In general, although most studies of C-HT have a follow-up duration that is too short to detect progression reliably, studies with adequate follow-up show lower progression rates with C-HT than with MMC alone [37].

3.5. Chemohyperthermia as bladder-sparing therapy

Bladder preservation is another important end point to consider when managing NMIBC because both recurrence and progression can lead to radical cystectomy. Table 3 summarizes available data concerning C-HT as bladder-sparing therapy.

Table 3 Rate of bladder preservation in various studies using chemohyperthermia for treatment of non-muscle-invasive bladder cancer

Study Follow-up, mo, median No. patients with bladder in situ (%)
Colombo et al [28] 0 9/19 (47.4)
Gofrit et al [23], prophylactic treatment 15.2 23/24 (95.8)
Gofrit et al [23], ablative treatment 20 22/28 (78.6)
Witjes et al [16] 22 40/45 (88.9)
Halachmi et al [14] 18 45/51 (88.2)
Ayres et al [38] 9 31/38 (81.6)
Colombo et al [37] 90 NA (86.1)
Lombardia project (unpubl. data R. Colombo, Milan, Italy) 23 149/152 (98.0)
Overall NA 87.6

NA=not available.

Of the 357 patients treated in all studies, 38 patients (10.6%) underwent radical cystectomy: 11 (3.1%) for progression to MIBC, 25 (7.0%) for highly recurrent disease, 1 (0.003%) for disease-worsening lower urinary tract symptoms (LUTS), and 1 (0.003%) for contracted bladder. At meta-analysis, a pooled bladder preservation rate of 87.6% was found after C-HT. This rate appears higher than after MMC alone, but comparison is difficult due to differences in patient characteristics and in median follow-up duration (Table 1).

3.6. Adverse events associated with chemohyperthermia

Comparison of AEs is difficult because older studies used nonvalidated questionnaires, whereas more recent studies used the Common Toxicity Criteria for Adverse Effects (CTCAE). Moreover, some studies used intention-to-treat analysis, whereas other studies used per-protocol analysis. The prophylactic use of anticholinergic drugs and pain medication was not mentioned in most reports, and this could have led to underestimation of the true AE rate.

The most common AEs during treatment were bladder spasms and bladder pain (Table 4). Bladder spasms occurred in 21.6% of patients, and bladder pain occurred in 17.5%. Bladder spasms tended to occur more frequently with the prophylactic schedule (17.8% vs 10.7%; p=0.398), whereas pain was present equally in the prophylactic and ablative schedules but more commonly after the ablative schedule (17.0% vs 15.6%; p=0.366).

Table 4 Overview of the adverse effects patients experience during chemohyperthermia with mitomycin C

Study No. patients with bladder spasms (%) No. patients with pain (%)
Rigatti et al [36] 5/12 (40.0) 3/12 (25.0)
Gofrit et al [23] 8/52 (15.4) 12/52 (23.1)
Moskovitz et al [19] 8/398 (2.0) 31/398 (7.8)
Witjes et al [16] 66/503 (13.1) 64/503 (12.7)
Nativ et al [11] 34/111 (30.6) 30/111 (27.0)
Halachmi et al [14] 13/56 (23.8) 6/56 (10.7)
Lombardia project (unpubl. data, R. Colombo, Milan, Italy) 483/1354 (35.7) 278/1354 (20.5)
Witjes et al (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands) 202/968 (20.9) 65/968 (6.7)
Overall 21.6% 17.5%

In the first days following C-HT, storage LUTS (frequency, dysuria, urgency, nocturia) and hematuria are the most common AEs (Table 5). Storage LUTS occurred in 25.6% of patients, and hematuria occurred in 6.0%. Most studies mention that these symptoms were mild (CTCAE grade 1) and transient, resolving spontaneously within a few days of treatment. One study described severe cystitis complaints in three patients (16%), but other studies have not confirmed this AE [28].

Table 5 Overview of adverse events that patients experience after chemohyperthermia with mitomycin C

Study No. patients with storage LUTS (%) No. patients with hematuria (%)
Gofrit et al [23] 30/52 (57.7) NA
Van der Heijden et al [22] 22/90 (24.4) 8/90 (8.9)
Moskovitz et al [19] 2/47 (4.3) 8/398 (2.0)
Witjes et al [16] 50/503 (9.9) 15/503 (3.0)
Halachmi et al [14] 7/56 (12.1) 1/56 (2.0)
Nativ et al [11] 18/111 (16.2) 21/111 (18.9)
Ayres et al [38] 28/38 (73.7) 10/38 (26.3)
Witjes et al (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands) 407/968 (42.0) NA
Overall 25.6% 6.0%

LUTS=lower urinary tract symptoms; NA=not available.

*Storage LUTS include frequency, dysuria, urgency, and nocturia.

Less common AEs include nonspecific rash, which was noted in 7.5% of patients [14], [19], [22], [23], [32], [36], and [38] (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands; unpubl. data, R. Colombo, Milan, Italy). The incidence of rash is comparable with that observed after MMC alone (12%) [41]. The overall rate of urethral strictures was 3.5% [11], [14], [19], [22], and [23] (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands; unpubl. data, R. Colombo, Milan, Italy).

Serious burn injuries to the bladder were not reported, but posterior wall thermal reaction (PWTR) was commonly seen. At cystoscopy, PWTR appears as a small, superficial, darkly discolored patch surrounded by hyperemia in the location where the heating device contacted the bladder wall during treatment. PWTR is normally not associated with symptoms and disappears spontaneously after several months. The overall rate of PWTR was 40.2% [19], [22], and [23] (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands; unpubl. data, R. Colombo, Milan, Italy), and most cases were mild, with only two cases of severe and prolonged (asymptomatic) PTWR reported [3] and [22].

Two studies report the development of a contracted bladder and severe urinary incontinence after ablative C-HT [3] and [28]. However, the possibility cannot be excluded that previous transurethral resection and intravesical chemotherapy might have contributed to this event [28].

The overall AE-related dropout rate during C-HT was 3.8% [3], [11], [14], [16], [23], [27], [28], [30], [32], [36], and [38] (unpubl. data, J.A. Witjes, Nijmegen, the Netherlands; unpubl. data, R. Colombo, Milan, Italy).

Four studies compared the AE rates of C-HT and MMC alone and collected subjective symptom scores using a nonvalidated questionnaire. The questionnaire graded symptoms on a 4-point scale (1, better; 4, worse) for frequency, nocturia, and dysuria. Urgency, hematuria, and pain were ranked on a 3-point scale (1, better; 3, worse). Colombo et al found a score of 10.5 in C-HT patients and 9.8 in patients treated with MMC alone. During active treatment, C-HT patients were more symptomatic (symptom score: 18.3) than MMC patients (symptom score: 13.1). Following treatment, the symptom scores improved to pretreatment levels (C-HT: 12.6; MMC: 10.7). The differences in AE scoring between the groups were not statistically significant [30]. The same group found several years later that local toxicity was slightly (but not significantly) higher after C-HT than after EMDA or MMC alone: the symptom score was 17.4 after C-HT, 13.2 after MMC alone, and 14.6 after EMDA [27]. However, the differences in symptom score could be due to the lower dose of MMC and the shorter treatment time used in the EMDA arm (Table 1). One study found only significant differences between C-HT and MMC alone in pelvic pain and PWTR, both of which were more prevalent after C-HT [3]. Long-term follow-up of this last study found no delayed treatment-related toxicity [37].

In summary, although studies inadequately report AEs, C-HT appears to cause more symptoms than MMC alone and may be associated with slightly more but mild and reversible AEs. We believe structured questionnaires for AEs should be developed according to the CTCAE and should be used in future research.

3.7. Ongoing research

Currently there are two studies in which C-HT is compared with other treatment. In 2002, a multicenter phase 3 study was started to compare 1 yr of BCG with 1 yr of C-HT (using MMC). A total of 300 high-risk patients will be randomized. Primary outcome measures will be recurrence-free survival, time to CR (for CIS), and progression rate. Secondary outcomes include local and systemic AEs [42].

Another phase 3 study started in 2009 compares C-HT with MMC to BCG or standard therapy after failure of intravesical therapy. A total of 242 patients will be randomized to C-HT and either a second induction course of BCG with subsequent maintenance for patients that previously failed induction BCG or standard therapy for patients that previously failed maintenance BCG. Standard therapy is defined by the treating centers. Primary outcome measures are disease-free survival and CR rates (for patients with CIS). Secondary outcomes include recurrence-free survival, progression-free survival, overall survival, disease-specific survival, safety and tolerability, quality of life, cost effectiveness, and biomarkers of response [43].

A phase 1 trial investigating the role of deep regional (external) C-HT using MMC for treating NMIBC patients failing BCG has completed accrual and is in follow-up. In this trial HT was administrated with the BSD 2000 HT system, which is fundamentally different from the Synergo system. The BSD 2000 device uses external, phased-array radiofrequency antennae to focus HT into deep locations in the body [44]. Primary outcome measures are safety and tolerability. Secondary outcomes include time to second recurrence [45].

3.8. Comments and future perspectives

The optimal treatment schedule for C-HT is unknown, and current schedules have been based largely on existing MMC trials. Additionally, just like MMC, it is not known whether or not maintenance treatments are valuable [26] and [46]. One article specifically mentioned the need for maintenance and found a higher risk of recurrence if <10 treatments were given (61% vs 39%; p=0.01) [11]. Colombo et al also found significantly fewer recurrences after 12 sessions compared with fewer sessions (p < 0.001) [3]. The data suggest that maintenance C-HT may be beneficial. The commonly used duration for HT is 40–60min, but this has not been studied prospectively in humans. Nakajima et al showed that 120min of HT was more toxic to bladder cancer cell lines than 30min of HT, suggesting that longer durations of treatment may be beneficial [47]. It is also unclear whether the target temperature of 42°C is the optimal temperature for HT. Moreover, it is uncertain if HT-related AEs increase as temperature rises.

All clinical trials evaluated in this review were performed with MMC. However, alternative intravesical agents that remain to be tested in combination with HT include gemcitabine and epirubicin as well as several other novel drugs, such as apaziquone (EOquin). Van der Heijden et al investigated the in vitro effect of HT on four chemotherapeutic agents and found that apaziquone was the most potent drug [4]. Uchibayashi et al investigated the combination of HT and peplomycin for NMIBC and found only a 9% CR rate. All initial responders had recurred with tumor 9 mo later [33]. HT can also be combined with radiation therapy and photodynamic therapy for treating bladder cancer [48].

The cost effectiveness of C-HT needs to be investigated because C-HT is more expensive than MMC alone. The increased initial cost of treatment needs to be balanced by the decreased costs of treating recurrences.

Finally, as mentioned, follow-up time of at least 5 yr is needed to draw conclusions about recurrence, progression, and survival.

4. Conclusions

Our systematic review indicates that C-HT reduces the risk of NMIBC recurrence by 59% when compared with MMC alone. Overall bladder preservation after C-HT is 87.6%. However, due to a limited number of randomized trials and different study designs, definitive conclusions cannot be drawn with respect to time to recurrence and time to progression. AEs are more common after C-HT than with MMC alone, but this difference is not statistically significant. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors (despite earlier treatment), for patients that are not candidates for radical cystectomy (because of medical reasons or refusal), and for high-risk patients with de novo bladder tumor with contraindications for BCG treatment.

Author contributions: J. Alfred Witjes had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ, Colombo.

Acquisition of data: Lammers, Witjes, Inman, Colombo.

Analysis and interpretation of data: Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ, Colombo.

Drafting of the manuscript: Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ, Colombo.

Critical revision of the manuscript for important intellectual content: Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ, Colombo.

Statistical analysis: Lammers, Witjes.

Obtaining funding: None.

Administrative, technical, or material support: Lammers, Witjes, Inman, Colombo.

Supervision: Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ, Colombo.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Alfred Witjes is an investigator for Medical Enterprise Ltd. Amsterdam, without financial compensation. The other authors have nothing to disclose.

Funding/Support and role of the sponsor: None.

Appendix A. – Literature analysis search terms and strategy

#1 Transitional cell carcinoma urinary bladder

#2 Urothelial cell carcinoma urinary bladder

#3 Urinary bladder cancer

#4 Urinary bladder neoplasm

#5 Urinary bladder tumor

#6 Urinary bladder tumour

#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6

#8 Papill*

#9 Superficial

#10 Non-muscle invasive

#11 Non-invasive

#12 Meta*

#13 Advanced

#14 #8 OR #9 OR #10 OR #11 NOT #12 NOT #13

#15 #7 AND #14

#16 Thermo-chemotherapy

#17 Thermo chemotherapy

#18 Microwave induced local hyperthermia

#19 Hyperthermia

#20 Synergo

#21 #16 OR #17 OR #18 OR #19 OR #20

#22 #15 AND #21

Appendix B. – Flow diagram of evidence acquisition

fx1

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Footnotes

a Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

b Division of Urology, Duke University Medical Center, Durham, NC, USA

c Department of Urology, Meir Medical Center, Kfar Saba, Israel

d Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel

e Department of Urology, Bnai Zion Hospital, Haifa, Israel

f Department of Urology, University’ Vita-Salute’ San Raffaele, Milan, Italy

lowast Corresponding author. Radboud University Nijmegen Medical Centre, Department of Urology, Geert Grooteplein Zuid 10 (659), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel. +31 24 361 37 35; Fax: +31 24 354 10 31.