Correspondence to: John R. Masters, Ph.D., FRCPath., Institute of Urology, University College London, 3rd Floor, 67 Riding House St., London W1W 7EY, U.K. (e-mail: J.Masters{at}ucl.ac.uk)
It is remarkable that intravesical chemotherapy has been administered to patients with superficial bladder cancer for 40 years with so little research to optimize the many variables that could influence the response of the cancer. This failure has been due in part to misunderstanding of the relationships among drug concentration, volume of instillate, and dose of drug reaching the cancer (1). For example, the U.S. National Bladder Cancer Group study (2) compared two doses of thiotepa (i.e., 30 mg in 30 mL of instillate versus 60 mg in 60 mL) and failed to show any difference in response. Perhaps it is not surprising that similar concentrations of drug gave similar response rates, despite the difference in volume. The recent important study by Au et al. (3) in the Journal is one of few attempts to optimize some of the variables.
There are many potential variables in intravesical chemotherapy, including drug concentration (4), exposure period, volume of instillate, nature of solvent (5), pH, and osmolality. Because most of these variables have not been investigated in patients, it is not known which drug is most effective. In addition, because the drugs are administered at far higher concentrations than are achieved during systemic chemotherapy, it is not certain that the drugs are acting in a conventional chemotherapeutic manner. Intravesical chemotherapy may instead act as an expensive "paint stripper," denuding the surface of the bladder and thereby removing cancer cells.
One of the variables addressed in the study by Au et al. (3) was pH. These investigators alkalinized the urine to stabilize the drug, mitomycin C. In contrast, it is known that mitomycin C is more cytotoxic in vitro at acid pH (6). It is conceivable that the greater cytotoxicity in acidic conditions might outweigh the lower stability and result in a higher response rate. This observation demonstrates the need to assess the importance of each variable individually.
Beyond the issue of pH, many questions remain concerning optimization of intravesical chemotherapy. Perhaps the most important is whether there is a dose response for intravesical chemotherapy. Our results (7) comparing 1 and 2 mg/mL epirubicin were disappointing because we found no difference in the response at 3 months of a marker tumor left in the bladder or in the recurrence rate over a 2-year period following treatment, but we did find greater toxicity with the higher concentration. Multicenter trials addressing the influence of each variable on response rate to intravesical chemotherapy are needed.
REFERENCES
1 Masters JR. Intravesical chemotherapy [letter]. Lancet 1986;1:740.[Medline]
2 Koontz WW Jr, Prout GR Jr, Smith W, Frable WJ, Minnis JE. The use of intravesical thio-tepa in the management of non-invasive carcinoma of the bladder. J Urol 1981;125:30712.[Medline]
3
Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001;93:597604.
4 Masters JR, McDermott BJ, Harland S, Bibby MC, Loadman PM. ThioTEPA pharmacokinetics during intravesical chemotherapy: the influence of dose and volume of instillate on systemic uptake and dose rate to the tumour. Cancer Chemother Pharmacol 1996;38:5964.[Medline]
5 Masters JR, McDermott BJ, Jenkins WE, Fenwick E, Shah PJ, Mundy AR, et al. ThioTEPA pharmacokinetics during intravesical chemotherapy and the influence of Tween 80. Cancer Chemother Pharmacol 1990;25:26773.[Medline]
6 Groos E, Walker L, Masters JR. Intravesical chemotherapy. Studies on the relationship between pH and cytotoxicity. Cancer 1986;58:1199203.[Medline]
7 Masters JR, Popert RJ, Thompson PM, Gibson D, Coptcoat MJ, Parmar MK. Intravesical chemotherapy with epirubicin: a dose response study. J Urol 1999;161:14903.[Medline]
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