60 MITOMYCIN C AND BACILLUS CALMEWE-GUERIN FOR BLADDER CANCER

BCG to combine more successfully with the suburothelial tissues and initiate an immunological response.

In this study the regimen used is interesting but somewhat illog- ical. In the combined arm the mitomycin C and BCG are given 1 month apart, thereby perhaps nullifying the additive qualities. It may have been more logical to give mitomycin C followed by BCG in 1 week, a t monthly intervals, and compare that to pure mitomycin C monthly instillations. The numbers of patients are too small to incorporate a third arm but the logical progression would be to have a third arm treated with BCG alone.

The conclusions drawn, comparing the side effects in patients receiving sequential mitomycin and BCG to those receiving BCG alone, are somewhat spurious, since the study comparing to this was one in which BCG was used to treat primary carcinoma in situ, which is an entirely different group of patients known to have a comparatively high incidence of side effects following BCG therapy (reference 21 in article). Nevertheless, this article is significant and the first such comparative phase 111 study. Presently, it is not pos- sible to draw statistically significant conclusions, other than to say that the 2 treatment regimens are equivalent. A larger study is needed with more patients and possibly a third arm as described to capture the significant benefit for combination therapy with mito- mycin C and BCG.

D. Newling Free University Hospital Amsterdam, The Netherlands

1. van der Meijden, A. and Hall, R. R.: A EORTC GU-Group phase I1 study of the sequential use of mitomycin C and BCG on a marker lesion of Ta or T1 transitional cell carcinoma of the bladder. Eur. Urol., in press.

REPLY BY AUTHORS

We agree that the EORTC is a meaningful group studying the treatment of bladder cancer. A significant study is that of Oosterlinck et a1 in 1993 (reference 16 in article), which began in 1986. Our present study with perioperative chemotherapy was be- gun in 1987. The literature also includes earlier reports on the benefit of perioperative chemotherapy.1.2

Newling raises the question of whether it is necessary to give more than 1 instillation as induction treatment. We cannot answer this question because it was not the subject of our study. Oosterlinck et al (reference 16 in article) randomized 420 patients in their study, the majority ofwhom had a primary tumor and 92 had recurrent disease. Of these patients only 29 (7%) had more than 1 recurrence per year, while the remainder had 1 or no tumor per year. As Dalesio et a1

noted in 1983, such patients have a prognosis similar to those with primary tumor.3 Furthermore, Oosterlinck et a1 reported that 310 patients had stage pTa disease and 187 had grade 1 tumor. The recurrence rate per year was significant only for primary tumors. Therefore, we ask whether it is necessary to give chemotherapy to patients with primary single low risk tumor. Furthermore, according to the study of Oosterlinck et al, it is hard t o conclude that 1 instillation is enough. We treated only frequently recurrent bladder cancer, and believe that more than 1 induction instillation is neces- sary in these patients with clearly worse prognostic factors than those with a primary tumor.

To our knowledge our study was the first report of alternating chemotherapy and immunotherapy. The synergic effect also was confirmed in vitro and, likewise, the alternating schedule was supe- rior to mitomycin C in patients with carcinoma in situ (references 14 and 6 in article). Therefore, it is difficult to presume that the efficacy of these Merent agents will be nullified after 1 week or 1 month, if a t all. We agree that it is difficult to know the optimal interval and number of dosages, and that a larger study with BCG as the refer- ence agent is needed. We also await with interest the results of EORTC phase I1 study with combined cytotoxic therapy and BCG.

We disagree that our reference study included only patients with primary carcinoma in situ. The study to which we compared side effects included 109 patients: 91 with recurrent stages Ta and T1 cancer, and only 18 with primary and secondary carcinoma in situ (reference 5 in article). The patients were treated randomly with same doses of mitomycin C or BCG as in our study. We believe that there are an adequate number of papillary tumors treated with BCG to make our comparison. Another study of carcinoma in situ with alternating BCG and mitomycin C showed no serious side effects (reference 6 in article).

1. Burnand, K. G., Boyd, P. J. R., Mayo, M. E., Shuttleworth, K E. D. and Lloyd-Davies, R. W.: Single dose intravesical thiotepa as an adjuvant to cystodiathermy in the treatment of transitional cell bladder cancer. Brit. J. Urol., 48 55, 1976.

2. Soloway, M. S. and Masters, S.: Urothelial susceptibility to tu- mor cell implantation: influence of cauterization. Cancer, 4 6 1158, 1980.

3. Dalesio, O., Schulman, C. C., Sylvester, R., De Pauw, M., Robinson, M., Denis, L., Smith, P., Viggiano, G. and members of the European Organization for Research on Treatment of Cancer, Genitourinary Tract Cancer Cooperative Group: Prog- nostic factors in superficial bladder tumors. A study of the European Organization for Research on Treatment of Cancer, Genitourinary Tract Cancer Cooperative Group. J. Urol., 129 730, 1983.