© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 20, 1575,
October 17, 2001
© 2001 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Methods to Improve Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase III Trial
Affiliation of authors: College of Pharmacy, The Ohio State University, Columbus.
Correspondence to: Jessie L.-S. Au, Pharm.D., Ph.D., College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210 (e-mail: au.1{at}osu.edu).
We agree with Dr. Masters that there has been a high degree of empiricism in intravesical therapy. To overcome this shortcoming, our laboratory has evaluated the physiologic factors (urine volume, urine pH, distension of bladder wall, integrity of urothelium, and blood perfusion to bladder), pharmacologic factors (rate, concentration dependence, and effect of physicochemical properties on drug penetration into bladder wall as well as the effect of pH on drug activity), and biochemical factors (expression of drug-activating enzyme in bladder tumors and bladder tissues) that could affect patient response (1–7). We then used these results to develop mathematical models, performed computer simulations to predict the effects of the various factors on treatment outcome, and designed the optimal treatment regimen of intravesical mitomycin C that was predicted to produce an 18%–20% higher response rate compared with the empirical treatment. The completed phase III trial confirmed this prediction and established the rationally designed regimen as superior to the empirically based regimen.
Dr. Masters proposes that the high drug concentration delivered during intravesical therapy may act as a "paint stripper." This concept is interesting and may explain the drug's effect on tumor cells in direct contact with it. On the other hand, the antitumor activity in human bladder tumors is determined by the cumulative drug exposure (C x T) (1). The C x T in bladder tumors after intravesical therapy is less than 2% of that in urine (3) and produces antiproliferation and apoptosis (1,7) rather than only necrosis, as would be expected for a paint stripper. Therefore, we believe that mitomycin C acts predominantly as a drug.
We disagree that the greater mitomycin C activity at acidic pH outweighs its lower stability. First, there is disagreement in the literature on the effect of pH on mitomycin C activity against monolayer tumor cell cultures; several groups showed enhanced drug activity at acidic pH, whereas others showed no pH effect. Second, a comparison of the pH effect in monolayer and multilayer cultures showed a pH-dependent response in monolayer cultures of human bladder tumor cells but not in multilayered cultures of the same cells or in bladder tumors of patients. Furthermore, under in vivo conditions, the pH of well-perfused tumors is regulated by the perfusing blood rather than by urine (5).
Dr. Masters suggests multicenter trials to test the effects of changing each treatment variable separately. Although this approach may provide a more definitive accounting of the effect of the various factors, we believe that the lessons learned from this exercise would not justify the consumption of the patient and financial resources. For example, our simulation results showed that simultaneous changes in several parameters (drug concentration in dosing solution, residual urine, urine production rate, and pH) were required to produce an 18%–20% higher response rate, detected with the use of 116 patients per arm. In contrast, changing an individual parameter yielded less improvement; e.g., increasing only the dose would result in an 8% higher response rate, requiring 450 patients per arm for detection (4). Testing the effect of the remaining parameters separately would require several thousand patients. Furthermore, the results of these studies would, in all likelihood, merely confirm our finding that increased drug delivery leads to increased response.
The resources can instead be more efficiently used to address new questions. First, can the empirically based six weekly treatments be replaced with fewer treatments? Second, the finding that African-American patients did not respond to mitomycin C warrants further investigation in larger studies. Third, the expression of the mitomycin C-activating enzymes is associated with drug activity in bladder tumors of patients (6); confirmation of this finding in patients may enable a pharmacogenomic approach to further improve response rate. Fourth, it may be worthwhile to compare the optimized mitomycin C regimen with BCG.
REFERENCES
1
Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res 1991;51:3849–56.
2
Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL. Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 1991; 51:5144–52.
3
Wientjes MG, Badalament RA, Wang RC, Hassan F, Au JL. Penetration of mitomycin C in human bladder. Cancer Res 1993;53:3314–20.
4 Wientjes MG, Badalament RA, Au JL. Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C treatment for superficial bladder cancer. Cancer Chemother Pharmacol 1993;32:255–62.[CrossRef][Medline]
5 Yen WC, Schmittgen T, Au JL. Different pH dependency of mitomycin C activity in monolayer and three-dimensional cultures. Pharm Res 1996;13:1887–91.[Medline]
6
Gan Y, Mo Y, Kalns JE, Lu J, Danenberg K, Danenberg K, et al. Expression of DT-diaphorase and cytochrome P450 reductase correlates with mitomycin C activity in human bladder tumors. Clin Cancer Res 2001;7:1313–9.
7 Highley MS, van Oosterom AT, Maes RA, De Bruijn EA. Intravesical drug delivery. Pharmacokinetic and clinical considerations. Clin Pharmacokinet 1999;37:59–73.[Medline]
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