Re: Urinary pH is Highly Associated With Tumor Recurrence During Intravesical Mitomycin C Therapy for Nonmuscle Invasive Bladder Tumor

The authors should be congratulated for their attention to basic and open questions on intravesical therapy of nonmuscle invasive bladder cancer. Intravesical delivery of chemotherapy remains partly empirical, and the pharmacokinetics poorly understood. Every attempt to optimize intravesical therapy should be welcomed. Expensive new strategies to deliver an effective therapeutic tumor dose are currently being explored.1,2 It is reasonable (and mandatory) first to consider and study the basic principles of pharmacokinetics. In this retrospective study Maeda et al investigate the role of pH on the efficacy of intravesical mitomycin C (MMC) in vivo. Their experience shows that urinary pH higher than 5.5 is associated with a decreased risk of tumor recurrence, and they suggest that monitoring urinary pH and urine alkalization may improve the efficacy of mitomycin C intravesical adjuvant treatment. A marked influence of pH solution on the activity of the most commonly used drugs (doxorubicin, epirubicin, MMC and thiotepa) against human transitional cell carcinoma lines has been recognized for 30 years.3 MMC and thiotepa show a stronger cytotoxic activity in acid media, and doxorubicin and epirubicin in alkaline media. On the other hand, the instability of MMC in acidic urine is an additional problem.4 The effectiveness of MMC can probably be enhanced by adjusting solvent and urine pH to the optimum value. Dalton et al found that the recovery of MMC after 2 hours increased with increasing urine pH (less than 30% at pH 5 to 5.5 and greater than 80% at pH 6.5 to 8).5 The most relevant factor accounting for this finding is the nonenzymatic pH dependent degradation of MMC. To decrease the nonenzymatic degradation, it would be logical to buffer the bladder instillate to pH 7. However, the activity ofMMCis pH dependent and related to its enzymatic activation under acidic pH.6 Therefore, the optimal pH for intravesical MMC should be carefully selected to achieve a balance between nonenzymatic degradation and enzymatic activation. The ideal urinary pH value to achieve the highest activity of MMC has yet to be found. Excessive urine alkalization might be useless or harmful. Although buffered solutions at alkaline pH are commercially available in some countries, tailoring urine pH to the optimum value (when identified) by oral sodium bicarbonate would be the best solution. We must also remember that urinary pH is only one of several factors to consider for optimizing intravesical chemotherapy.