EAU 2021: A Randomized Clinical Trial of Intravesical Instillation of Mitomycin-C and Combination of Mitomycin-C and Cytarabine (Ara-C) in Non-Muscle Invasive Bladder Cancer

(UroToday.com) Yasuyoshi Miyata from Japan presented results of a randomized clinical trial of intravesical mitomycin C plus cytarabine (Ara-C) versus mitomycin C for patients with non-muscle invasive bladder cancer (NMIBC) at the European Association of Urology 2021 annual meeting. Intravesical instillation of mitomycin after transurethral resection of bladder tumor is often performed to suppress the recurrence and progression in NMIBC, however, its anti-cancer effect is not satisfactory. Urine pH is closely associated with anti-cancer effects of mitomycin C, and oral sodium bicarbonate administration has been performed in intravesical mitomycin C therapy for urine alkalization. Ara-C is used as intravesical therapy, and interestingly, the pH of Ara-C solution is 8.0 ~ 9.3. Based on this, Dr. Miyata and colleagues hypothesized that the combination of Ara-C increases the anti-cancer effects of mitomycin C via urine alkalization, and they investigated this hypothesis by a randomized study in patients with NMIBC.

A total of 165 patients with NMIBC were randomly allocated to mitomycin C (40 mg/40ml; n=79) and mitomycin C plus Ara-C (40 mg+200mg/40 ml; n=86) intravesical therapy group. As follows is a flow chart for the trial:


Intravesical therapy was performed once a week for six weeks. Outcomes assessed included recurrence-free survival, up-stage and -grade in recurrent tumor, toxicity, and influence of urine pH.

There was no difference in clinicopathological features including grade, pT stage, and frequencies of recurrent and multiple tumors between the two groups. Kaplan-Meier survival curves showed that in the entire cohort recurrence-free survival in mitomycin C + Ara-C group was significantly longer (p=0.018) compared to those in mitomycin C group. This benefit was also significant in patients with intermediate-risk disease (p=0.008), but not in high-risk patients (p=0.315):


A multivariable analysis model including all clinicopathological features showed that mitomycin C + Ara-C therapy was not a significant factor for improved recurrence-free survival (HR 0.83, 95% CI 0.21–3.25, p=0.794). In patients with recurrence (n=47), frequency of up-grading in mitomycin C + Ara-C group (2/18; 11.1%) had a trend to be lower than that in mitomycin C group (10/29; 34.5%), however, the difference was not significant (p=0.741). Furthermore, there was no significant difference in frequency of up-staging to muscle-invasive disease between the treatment groups (p=0.556). Urine PH in mitomycin C + Ara-C group (mean/SD: 6.6/0.6) was significantly higher compared to mitomycin C group (mean/SD: 5.8/0.6), and high urine pH was associated with better recurrence-free survival in both the mitomycin C and mitomycin C + Ara-C group (HR 0.12, 95% CI 0.05-0.32, p<0.001). There was no significant difference in toxicities between the mitomycin C group (13/79=16.5%) and the mitomycin C + Ara-C group (9/86=10.5%) (p=0.113).

Dr. Miyata concluded his presentation with several key take-home messages:

  • Recurrence-free survival in the mitomycin C plus Ara-C group was better than that in the mitomycin C group in patients with intermediate-risk NMIBC
  • This randomized clinical trial suggests that intravesical therapy with mitomycin C and Ara-C is useful and safe for these patients
  • Increasing urine pH by Ara-C instillation is speculated to be a main mechanism of increased anti-cancer effects of mitomycin C

Presented By: Yasuyoshi Miyata, MD, Ph.D., Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.