Chemohyperthermia in non-muscle-invasive bladder cancer: An overview of the literature and recommendations

Figures & data

Figure 1. Available hyperthermia systems. (A) A schematic overview of the Synergo^® system. A triple lumen catheter with integrated RF antenna and multiple thermocouples connected to the device. (B) COMBAT BRS^® system. (C) Unithermia^® system and schematic overview. MMC is heated via heat exchanger and pumped around via a 3-way catheter. (D) BSD-2000^® system. (E) AMC 70 MHz system.

Table 1. Overview of outcomes of clinical trials concerning chemohyperthermia for non-muscle-invasive bladder cancer.

Treatment	Reference	Study type	No. of patients	Study description	Patient population	Temp. (°C)	Follow-up, median (months)	Outcome: recurrence	Outcome: progression	Treatment not completed
Synergo^®
Prophylaxis: 8× weekly,  40-60 min 2 × 20 mg MMC  Maintenance: 4× monthly,  40-60 min 2 × 40 mg MMC	Colombo et al., 2003 [21]	Prospective	83	Multicentre, comparing CHT (n = 42) vs MMC (n = 41)	Intermediate or high risk	42 ± 2	>24	Recurrence: CHT 17.1% MMC 57.5%	CHT: none MMC: 1 patient G2→G3	8 of 83 (9.6%)
Prophylaxis: 8× weekly,  40 min 2 × 20 mg  Ablative: 8× weekly,  40 min 2 × 40 mg MMC  Maintenance: 4× monthly,  40 min 2 × 20 mg MMC	Gofrit et al., 2004 [9]	Prospective	52	Multicentre, prophylaxis (n = 24), ablative (n = 28)	High risk (Ta-T1, G3)	42 ± 2	15.2 (6-90)	Overall: recurrence-free survival rate 71% Prophylaxis: 62% recurrence-free Ablative: 75% complete response, 80.9% recurrence-free	None	7 of 52 (13.5%)
Prophylaxis: 6-8× weekly,  60 min 2 × 20 mg MMC  Maintenance: 4-6×  monthly, 60 min 2 ×   20 mg MMC	Van der Heijden et al., 2004 [23]	NA	90	Multicentre, adjuvant	Intermediate or high risk	41-44	18 (4-24)	1-year risk of recurrence 14.3% 2-year risk of recurrence 24.6	None	NA
Prophylaxis: 6-8× weekly, 60 min 2 × 20 mg MMC Ablative: 8× weekly, 2 × 40 mg MMC Maintenance: 4-6× monthly, 60 min 2 ×   20 mg MMC	Moskovitz et al., 2005 [10]	Prospective	47	Single centre, prophylaxis (n = 22), Ablative (n = 10)	Intermediate or high risk	42 ± 2	10	Prophylaxis: 91% recurrence-free Ablative: 80% complete response	None	7 of 39 (17.9%)
Prophylaxis: 6× weekly,  60 min 2 × 20 mg MMC  Maintenance: 6× every  4-6 weeks, 60 min  2 × 20 mg MMC	Halachmi et al., 2009 [26]	Retrospective	56	Multicentre, adjuvant	High risk (T1G3)	42 ± 2	18 (2-49)	2-year recurrence rate 42.9% 4-year recurrence rate 51.0%	4 muscle-invasive (7.8%)	5 of 56 (8.9%)
Prophylaxis: 6× weekly,  60 min 2 × 20 mg MMC  Ablative: 8× weekly,  60 min 2 × 40 mg MMC  Maintenance: 6× every  6 weeks, 60 min 2 ×   20 mg MMC	Witjes et al., 2009 [11]	Retrospective	51	Multicentre, prophylaxis (n = 18), ablative (n = 33)	High risk (CIS)	41-44	22 (3-77)	Overall: Complete response 92% Recurrence 49%	NA	2 of 51 (3.9%)
Prophylaxis: 6× weekly,  60 min 2 × 20 mg MMC  Maintenance: 6× every  4-6 weeks, 60 min  2 × 20 mg MMC	Nativ et al., 2009 [30]	Retrospective	111	Multicentre, adjuvant	Recurrence after BCG	42 ± 2	16 (2-74)	1-year recurrence-free probability 85% 2-year recurrence-free probability 56%	3 muscle-invasive (2.9%)	6 of 111 (5.4%)
Prophylaxis: 8× weekly,  40-60 min 2 × 20 mg MMC  Maintenance: 4× monthly,  40-60 min 2 × 40 mg MMC	Colombo et al., 2010 [22]	Prospective	83	Multicentre, comparing CHT (n = 42) vs MMC (n = 41) Long-term follow-up Colombo et al. 2003[22]	Intermediate or high risk	42 ± 2	90 (6-154)	Recurrence: CHT 14 of 35 (40%) MMC 32 of 40 (80%) 10-year disease-free survival rate: CHT 53% MMC 15%	5 patients (6.7%) CHT: 2 MMC: 3	8 of 83 (9.6%)
Prophylaxis: 6× weekly,  40-60 min 2 × 20 mg MMC  Ablative: 8× weekly,  40-60 min 2 × 40 mg MMC  Maintenance: 6× monthly,  40-60 min 2 × 40 mg MMC	Volpe et al., 2012 [28]	Prospective	30	Single centre, prophylaxis (n = 16), ablative (n = 14)	High risk, not responding to previous chemo- or immunotherapy	42 ± 2	14	Prophylaxis: 43.8% recurrence free Ablative: 42.9% complete response Overall:  1-year disease-free  survival 77%  2-year disease-free  survival 55%	3 muscle-invasive (10%)	NA
Prophylaxis: 6× weekly,  60 min 2 × 20 mg MMC  Ablative: 8× weekly,  60 min 2 × 40 mg MMC  Maintenance: 6× every  6 weeks, 2 × 20 mg MMC	Moskovitz et al., 2012 [27]	Retrospective	92	Single centre, prophylaxis (n = 66, ablative (n = 26)	Intermediate or high risk	42.2	23 (3-84)	Prophylaxis: 2-year recurrence-rate 32.8% Ablative: complete response 79%. Recurrence 16%	3 muscle-invasive (3.4%)	4 of 92 (4.4%)
Phase 1: 4× weekly,  60 min 40 mg MMC  Phase 2: 6× every 2 weeks,  60 min 40 mg MMC  Phase 3: 4× monthly,  60 min 40 mg MMC	Maffezzini et al., 2014 [27]	Prospective	42	Single centre, adjuvant	High risk	42.5 ± 1.5	38 (4-73)	Recurrence: 30.9%	7 muscle-invasive and/or CIS (16.7%)	10 of 42 (23.8%)
Prophylaxis: 6-8× weekly,  60 min 2 × 20 mg MMC or  2 × 25 mg EPI  Ablative: 6-8× weekly,  60 min 2 × 40 mg MMC or  2 × 50 mg EPI  Maintenance: every  6 weeks for 1 year,  2 × 20 mg MMC or  2 × 25 mg EPI	Arends et al., 2014 [29]	Retrospective	160	Single centre, prophylaxis (n = NA), ablative (n = NA)	Refractory to regular intravesical treatment	42 ± 2	76	Overall: 1-year recurrence-free survival 60% 2-year recurrence-free survival 47% Ablative: 77.5% complete response	7 muscle-invasive (4.3%)	10 of 160 (6.3%)
Prophylaxis: 6× weekly,  60 min 2 × 20 mg MMC  Ablative: 12× weekly,  60 min 2 × 40 mg MMC	Kiss et al., 2015 [25]	Prospective	21	Single centre, prophylaxis (n = 10), ablative (n = 11)	Recurrent NMIBC	42 ± 2	50 (1-120)	Recurrence-free 29%	6 radical cystectomy (multifocal recurrence, or muscle-invasive) (29%)	8 of 21 (38.1%)
COMBAT-BRS^®
Ablative, before TURB:  8× weekly, 60 min  80 mg MMC	Sousa et al., 2014 [13]	Prospective	15	Pilot, neoadjuvant	Intermediate or high risk	43 ± 1	29	Complete response 53% 3-year cumulative incidence of recurrence 15%	NA	None
Unithermia^®
Prophylaxis: 6× weekly,  45 min 40 mg MMC	Soria et al., 2015 [14]	Prospective	34	Single centre, phase I-II, adjuvant	Non-G3 recurrence after BCG	42.5 ± 1	41 (18-78)	Recurrence: 35.3%	6 - G3 (17.6%) 2 - ≥T2 (5.9%)	4 of 34 (11.8%)
Prophylaxis: 6× weekly,  60 min 40 mg MMC  Maintenance: 3× weekly at  3 and 6 months, 60 min  40 mg MMC	Ekin et al., 2015 [31]	Retrospective	43	Multicentre, adjuvant	High risk	42.5-45	30 (9-39)	Recurrence: 32.5% 1-year recurrence-free rate 82% 2-year recurrence-free rate 61%	2 muscle-invasive (5.0%)	3 of 43 (7.0%)
BSD-2000^®
Prophylaxis: 6× weekly,  40-60 min 40 mg MMC  Maintenance: 4× monthly,  40-60 min 40 mg MMC	Inman et al., 2014 [16]	Prospective	15	Pilot, adjuvant	BCG refractory	42 ± 2	38	Recurrence: 66.7%	None	1 of 15 (6.7%)
AMC 70 MHz
Prophylaxis: 6× weekly,  60-90 min 40 mg MMC  Maintenance: once every  3 months for 1 year,  60-90 min 40 mg MMC	Geijsen et al., 2015 [18]	Prospective	18	Pilot, adjuvant	Intermediate or high risk	41.6 ± 1.5	46 (21-60)	2-year recurrence-free survival rate 78%	NA	3 of 18 (16.7%)

BCG, bacillus Calmette-Guérin; CHT, chemohyperthermia; EPI, epirubicin; MMC, mitomycin-C; NA, not available.

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