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A randomized clinical trial of intravesical instillation of MMC and combination of MMC and Ara-C in non-muscle invasive bladder cancer

  • Miyata Y.,
  • Matsuo T.,
  • Ohba K.,
  • Mitsunari K.,
  • Keisuke T.,
  • Hayashida Y.,
  • Tsurusaki T.,
  • Watanabe J.,
  • Nishimura N.,
  • Nishikido M.,
  • Sakai H.,
  • Nagasaki Urological Oncology Research Group

Introduction & Objectives

Intravesical instillation of mitomycin (MMC) after Transurethral Resection (TUR) is often performed to suppress the recurrence and progression in Non-Muscle Invasive Bladder Cancer (NMIBC); however, its anti-cancer effect is not satisfactory. We paid special attention to the fact that urine pH is closely associated with anti-cancer effects of MMC. In fact, oral sodium bicarbonate administration was performed in intravesical MMC therapy for urine alkalization. However, improvement of the anticancer effects is minimum because urine pH was unstable. Cytarabine (Ara-C) is used as intravesical therapy, and interestingly, pH of Ara-C solution is 8.0 ~ 9.3. From these facts, we hypothesized that combination of Ara-C increases anti-cancer effects of MMC via urine alkalization, and we investigated the this hypothesis by a randomized study in patients with NMIBC.

Materials & Methods

A total of 165 patients with NMIBC were randomly allocated to MMC (40 mg/40ml; n=79) and MMC+Ara-C (40 mg+200mg/40 ml; n=86) intravesical therapy group. Intravesical therapy was performed once a week for 6 weeks. We investigated Recurrence-Free Survival (RFS), up-stage and -grade in recurrent tumour, toxicity, and influence of urine pH were investigated.


There was no difference on clinicopathological features including grade, pT stage, and frequencies of recurrent and multiple tumour between 2 groups. Kaplan-Meier survival curves showed that RFS in MMC+Ara-C group was significantly longer (P=0.018) compared to those in MMC group. In addition, multi-variate analysis model including all clinicopathological features showed that MMC+Ara-C therapy was identified as a significant factor for better RFS (hazard ratio: HR=0.42, 95% confidential interval: 95% CI=0.23–0.76, P=0.004). On the other hand, such difference of anti-recurrence effect was remarkable from 3 years after the TUR. In patients with recurrence (n=47), frequency of up-grade in MMC+Ara-C group (2/18; 11.1%) had a trend to be lower than that in MMC group (10/29; 34.5%); however, the difference was no significant level (P=0.741). Likewise, there was no significant difference on frequency of up-stage to muscle invasive disease between them (P=0.556). Urine PH in MMC+Ara-C group (mean/SD: 6.6/0.6) was significantly higher (P<0.001) compared to MMC group (5.8/0.6), and high urine pH is associated with better RFS in both of MMC and MMC+Ara-C group. There was no significant difference on toxicities between them (MMC: 13/79=16.5%, MMC+Ara-C: 9/86=10.5%).


Intravesical therapy of MMC and Ara-C showed better PFS periods, especially in late-onset recurrence) compared to that of MMC without increasing of toxicity. Increasing of urine pH by Ara-C instillation was associated with such finding. We suggest that combination of MMC and Ara-C is effective and safety as intravesical therapy in NMIBC patients.

Tags: EAU21