Intravesical radiofrequency-induced hyperthermia combined with chemotherapy for non-muscle-invasive bladder cancer

Figures & data

Figure 1. Schematic illustration of the Synergo® SB-TS 101 system during treatment.

Table 1. Overview of all clinical trials since January 2011 concerning initial response, recurrence and progression chances after RF-induced chemo-hyperthermia in non-muscle-invasive bladder cancer patients.

					Treatment						Outcome
Reference	Study type	No. of patients	Patient population	Study description	Duration (min)	Temperature (°C)	Dose	No. of treatments	Maintenance	Follow-up median (range)	Recurrence	Progression	Cystectomy
Moskovitz et al., 2012 [25]	Retrospective	88	Intermediate and high risk NMIBC (EAU criteria)	Single centre Adjuvant (n = 64) and neo-adjuvant (n = 24) treatment with MMC	2 × 30 = 60	42 ± (N/A)	Adjuvant: 20 + 20 mg Neo-adjuvant: 40 + 40 mg Both in 50 mL	Adjuvant: 6× weekly Neo-adjuvant: 8× weekly	Adjuvant or if CR in neo-adjuvant: 6× every 6 weeks, 1 year	23 months (3 months up to 7 years)	Adjuvant: Recurrence in 18/64 (28%) Neo-adjuvant: CR in 19/24 (79%) Recurrence: 3/19 (16%)	Adjuvant: 3/64 (4.7%) Neo-adjuvant: 0/19 (0%)	Adjuvant: 3/64 (4.7%) Neo-adjuvant: 2/24 (8.3%)
Volpe et al., 2012 [26]	Prospective	30	Ta/1 G2/3 or Tis	Single centre CHT with MMC Prophylactic (n = 16) and ablative (n = 14) treatment. Both had TURBT before start	2 × 20 − 30  = 40 − 60	42 ± 2	Prophylactic: 20 + 20 mg Ablative: 40 + 40 mg Both in 50 mL	Prophylactic: 6× weekly Ablative: 8× weekly	Yes 6× monthly	Mean: 14 ± 8.48 months	Prophylactic: 9/16 (56.25%) Ablative: CR in 6/14 (42.85%) Overall recurrence: 17/30 (56.7%). Overall DFS: 77% after 12 months, 55% after 24 months	Prophylactic: 0/16 (0%) Ablative: 3/14 (17.64%) Overall: 3/30 (10%)	N/A
Maffezzini et al., 2014 [27]	N/A	42	High risk NMIBC (EAU criteria): EORTC recurrence score ≥5 or progression score ≥7	Single centre CHT with MMC in adjuvant setting. Epirubicin in cases of persistent intolerance to MMC (n = 10)	2 × 30 = 60	42.5 ± 1.5	MMC: 40 + 40 mg If epirubicin: 50 + 50 mg Both in 50 mL	4× weekly, 6 every 2 weeks: total = 10	Yes 4× every 3 weeks	38 (4–73) months	32 patients completed protocol. ITT: 1-year DFS before study 14.9% vs 88.8% after CHT. Recurrence 13/42 (30.9%)	ITT: 5/42 (11.9%)	ITT: 7/42 (16.6%)
Arends et al., 2014 [28]	Prospective	160	Intermediate and high risk NMIBC (EAU criteria)	Single centre CHT with MMC in adjuvant setting. Epirubicin in cases of persistent intolerance to MMC (n = 20)	2 × 30 = 60	42 ± 2	Prophylactic: 20 + 20 mg MMC or 25 + 25 mg epi Ablative: 40 + 40 mg MMC or 50 + 50 mg epi All in 50 mL	6–8× weekly	Yes, every 6 weeks, up to 1 year	75.6 months(N/A)	Overall 1- and 2-year RFS: 60% and 47%, respectively 1-year RFS: 59% vs 64%, and 2-year RFS: 46% vs 55% for MMC and epirubicin, respectively (p = 0.30)	7/160 (4%)	N/A
Nair et al., 2014, conference abstract EAU [44]	Prospective	103 + 51	High risk NMIBC (EAU criteria) Overlap in patients with Sooriakumaran 2015 [30]	Single centre CHT (n = 103) matched with RC (n = 51) 5-year survival	2 × 30 = 60	42 ± 2	MMC: 40 + 40 mg in 50 mL saline	6–8 ×  weekly, median: 6×	If CR or PR: 20 mg MMC in 50 mL, every 6 weeks (year 1) and every 8 weeks (year 2)	40 (4–92) months	5-year DSS, RC vs CHT: 74.6% vs 85.2% 5-year OS, RC vs CHT: 68.4% vs 61.9% 90-day mortality: 4% RC, 0% CHT Significant AE: RC 21%, CHT 0%	N/A	N/A
Kiss et al., 2015 [29]	Prospective	21	Intermediate and high risk NMIBC (EAU criteria)	Single centre CHT in prophylactic (n = 10) and ablative (n = 11) setting	2 × 30 = 60	42 ± 2	Prophylactic: 20 + 20 mg Ablative: 40 + 40 mg All in 50 mL	Prophylactic: 6× weekly Ablative: 12× weekly Overall median: 6×	N/A	50 (1–120) months	Overall: 15/21 (71%) DSS: 19/21 (90%) OS: 14/21 (67%)	4/21 (19%)	6/21 (29%) due to multifocal recurrence or progression
Sooriakumaran et al., 2015 [30]	Prospective	97	High risk NMIBC (EAU criteria)	Observational cohort study. time-to-progression study in ablative protocol	2 × 30 = 60	41–44	MMC: 40 + 40 mg In 50 mL saline	6–8× weekly, median: 6×	CR or PR: 20 mg MMC in 50 mL every 6 weeks (year 1) and every 8 weeks (year 2)	27 (16–47) months	OS: 80/97 (82) DSS: 90/97 (93)	35/97 (36)	18/97 (19)
Lüdecke et al., 2013, conference abstract, Genitourinary Cancers Symposium [31]	Prospective	138	High risk NMIBC (EAU criteria)	Multi-institutional study on long-term effects of CHT, for both the adjuvant (n = 52) and ablative (n = 86) protocol. 69/86 evaluable, because of protocol violations or extra-vesical UCC or second simultaneous malignancy	N/A	N/A	N/A	6–8× weekly	6× every 6 weeks	Mean: 2.9 years (range 3.6 months – 6.9 years)	Adjuvant: 10/52 (19.2) Recurrence free: 78.3% Ablative: 59/69 (85.5) CR at week 11 persisting for 21.6 months in mean	Adjuvant: 0/52 (0) Ablative: 11/69 (15.9)	Adjuvant: 0/52 (0) Ablative: 8/69 (11.6)
Lüdecke et al., 2013, conference abstract, EAU	Prospective	86	High risk NMIBC (EAU criteria) Overlap in patients with other 2013 abstract	First-line CHT in high risk patients, and in extremely high risk patients failing BCG (22/86)	N/A	N/A	MMC: 40 + 40 mg N/A mL	8× weekly	6× every 6 weeks with 2×20 mg MMC if tumour free	Mean: 24.1 months (1.7 months to 11.8 years)	Ablative: 59/69 (85.5) CR at week 11 persisting for 21.6 months in mean. 48/69 (69.6) tumour free during follow-up. Thus recurrence: 21/69 (30.4)	N/A	8/69 (11.6)
Lüdecke et al., 2015, conference abstract, EAU [49]	Prospective	271	High risk NMIBC (EAU criteria) Overlap in patients with other two abstracts likely	Multi-institutional (n = 7) study on long-term effect of CHT	N/A	N/A	MMC: 40 + 40 mg N/A mL	8× weekly	6× every 6 weeks with 2×20 mg MMC if tumour-free on re-TURBT	Mean: 2.2 years (range 28 days to 12.9 years)	206/271 (76.1) CR 21/271 (7.6) PR 2-year recurrence: 52/271 (19.4)	N/A	N/A
Arends et al., 2015, conference abstract, EAU [33, personal communication]	Prospective	190	Intermediate and high risk NMIBC (EAU criteria)	Multi-institutional (n = 11) Randomised controlled clinical trial comparing RF-induced CHT vs BCG in adjuvant setting over 1 year	2 × 30 = 60	42 ± 2	MMC: 20 + 20 mg in 50 mL	6× weekly	6× every 6 weeks	25.7 (3.9–34) months	24 months RFS per protocol: 81.8% vs 64.8% (CHT vs BCG, p = 0.0216). Recurrence: 18.2% vs 35.2% CR in CIS after 3 months: 88.9% vs 85.7% (CHT vs BCG, p > 0.1)	1.7% in CHT 2.8% in BCG (p = n.s.)	N/A
Kelly et al., 2015, conference abstract, BAUS [42]	Prospective	104	Recurrence after BCG, but unfit/unwilling for RC	Randomised controlled phase III, multicentre study. CHT after BCG vs second course BCG/institutional standard therapy	2 × 30 = 60	42 ± 2	MMC: 20+20mg in N/A mL	6× weekly	Every 6 weeks in year 1, every 8 weeks in year 2	N/A, but goal was 24 months	No difference in DFS. Improved DFS in papillary disease alone (HR 0.40, p = 0.05) CR in CIS patients (n = 71) at 3 months: 81% vs 86%. Worse DFS (HR 2.17, p = 0.02)	N/A	N/A

AE, adverse event; BAUS, British Association of Urological Surgeons; BCG, bacillus Calmette–Guérin; CHT, chemo-hyperthermia; CIS, carcinoma in situ; CR, complete response; DFS, disease-free survival; DSS, disease-specific survival; EAU, European Association of Urology; EORTC, European Organisation for Research and Treatment of Cancer; HR, hazard ratio; ITT, intention-to-treat analysis; MMC, mitomycin C; N/A, not available; NMIBC, non-muscle invasive bladder cancer; OS, overall survival; PR, partial response; RC, radical cystectomy; RF, radio-frequency; RFS, recurrence free survival; TURBT, transurethral resection of bladder tumour.

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