Ten years experience with intravesical thermo-chemotherapy MMC 40mg for Non Muscle Invasive Bladder Cancer high/intermediate risk

Giorgio Canepa1, Fabio Campodonico1, Stefania Tamagno1, Carlo Introini2, Matteo Puntoni3
  • 1 E.O. Ospedali Galliera, S.C. Urologia (Genova)
  • 2 Ospedale Evangelico Internazionale, S.C. Urologia (Genova Voltri)
  • 3 E.O. Ospedali Galliera, Direzione Scientifica e Biostatistica (Genova)


Management of non muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor generally consists of surveillance and intravesical therapy (1). Particularly challenging is the treatment of patients who have not responded to first-line intravesical bacillus Calmette-Guerin (BCG) or that have high-risk features. For such patients, radical cystectomy remains a commonly recommended alternative treatment. High risk Non Muscle Invasive Bladder Cancer (HR-NMIBC), as stated by EORTC, is an important challenge for urologist and oncologist to avoid tumor progression and to preserve the bladder. The aim of the study is to evaluate the long-term experience on a treatment combining intravesical hyperthermia with Mytomicin C (HT-MMC) delivered with the Synergo® device.

Materials and Methods

In a period between August 2004 and November 2015 a group of 146 patients (108 male and 38 female, mean age 68+/- 9 y.o. Range 40 -84y.o.) affected by high risk NMIBC were recruited. All of them were treated with endovesical thermo-chemotherapy MMC C 40mg (HT-MMC) performing more than 1600 treatment sessions using the Synergo® device. After an initial induction of 4 weekly treatments with 2 x 40mg MMC, the efficacy was checked in tumor eradication by TUR B and cytology at week 6. Tumor-free patients continued with the maintenance therapy every 15 days with 3 sessions 2 x 40mg MMC, then every 21 days with 3 sessions 2 x 40mg MMC, and every 45 days with 3 sessions 2 x 40mg MMC and in parallel cystoscopy and urine cytology every 3 months. The follow-up was conducted over an average period of 39.2months (Range 2.4 months – 7.9 years). The majority of patients were at high-risk including G3 (64 – 44%), T1 (79 – 54%) and Cis (22 – 15%), high frequency of recurrences (2,1 +/- 2,7 – Range 0-17 n° of recurrences before the first treatment). First aim of the study was the Recurrence-Free Survival (RFS) and disease progression for stage and grade (PFS), the secondary aim was the tolerability and adherence to the proposed schedule of treatment.

Patients characterisrics N=146
Male 108 (74%)
Female 38 (26%)
Age (at the start of treatment)
mean (SD) 68 (9)
median (min-max) 70 (40-84)
Smoking habit*
Non smoker 47 (32%)
Smoker 98 (68%)
*(1 missing data)
Ta 45 (31%)
Cis 22 (15%)
T1 79 (54%)
Grade (Without Cis)
G1 13 (9%)
G2 47 (32%)
G3 64 (44%)


After the first treatment of 4 weekly sessions of HT-MMC, only 11 patients (7.5%) were stopped for recurrences: 3 progressions and 8 recurrences. At the end of each treatment 37/146 patients reported a recurrence and 14/146 patients presented a progression. The RFS at 1, 2 and 5 years was 89.6%, 79.2 and 68.3 respectively. The PFS at 1, 2 and 5 years was 98%, 96.2 and 83.7 respectively. The number of treatment sessions for each patients were 10.4+/- 4.7 with a median of 11 sessions (Range 4-31). The time of exposure over 42°C was 37.4+/-7.4 mins. and the mean temperature was 42.0+/-0.8°C. The safety profile showed mainly grade 1 and 2 side effects. Ten patients complained grade 3 side-effects, including 1 patient bladder spasms/pain during treatment, 3 patients dysuria and 6 patients urgency after treatment.

Treatment (Synergo) characteristics: N=146
Number of treatments (per patient)
mean (sd) 10.4 (4.7)
median (min-max) 11 (4-31)
Time (minutes) over 42°C
mean (sd) 37.4 (7.4)
median (min-max) 38.6 (6.8-55)
Mean temperature (°C)
mean (sd) 42.0 (0.8)
median (min-max) 42.0 (38.2-45.9)
Power (Watt)
mean (sd) 18.7 (2.8)
median (min-max) 18.3 (10.9-26.8)


We evaluated treatment efficacy and tolerability with intravesical HT-MMC in this retrospective cohort of high-risk NMIBC patients. In the high-risk NMIBC the expected recurrence rate is 49% at 5 years (2, 3). In patients affected by high-risk urotelial bladder tumour intravesical Bacillus Calmette-Guerin (BCG) is indicated (4). Intravesical BCG prevents 31% to 50% of tumour recurrence, compared to TUR alone (5). The side-effect of BCG are remarkable, and treatment discontinuation rate of BCG for toxicity is 7% to 19% (6). In a meta-analysis, 32% reduction in tumour recurrence for BCG maintenance compared to MMC was found (7). MMC is considered a less effective alternative treatment for patients intolerant to BCG. Colombo and coll. found out that HT-MMC is more effective than MMC alone (8). The 10-year disease-free survival rate for HT-MMC and MMC alone was 53% and 15% respectively (8). So HT-MMC has shown to be an effective treatment for intermediate and high-risk NMIBC with a good RFS especially in the first two years (9). In our retrospective HT-MMC treatments study the PFS was high considering the percentage of high-risk patients. Tolerability was good without relevant systemic side-effects and most of the patients demonstrated a complete adherence to the proposed schedule of treatment.


Endovesical thermo-chemotherapy MMC 40mg seems to be an effective treatment for NMI Bladder Cancer. Patients affected by highly recurrent disease before chemo-hyperthermia have a lower recurrence free survival. Although the 5-year survival to NMIBC is more than 90%, the survival period is not disease-free (10, 4). BCG intravesical is considered more effective than chemotherapy for NMIBC, representing the first line approach in high-risk patients (4, 7). Due to side-effects and failure of BCG, new chemotherapy agents and device-assisted instillation have been tested in high-risk patients (1). To enhance the efficacy of MMC, a valid method for intravesical HT-MMC delivering was adopted in our department from 2004. We reported our experience over a period of more than 10 years. The results of RFS and PFS are encouraging to maintain this kind of protocol of treatment, although the high dosage of MMC used with ablative intent is well tolerated by a good percentage of patients.


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