TRANSURETHRAL RESECTION FOR BLADDER CANCER 1135 plantation or seeding in association with pr imary transure- thral resection.

There was no significant difference in recurrence among t h e 3 groups of pa t ien ts wi th multiple tumors . This finding may be explained by the limited number of patients in these subgroups, although probably the instabil i ty of the whole urothelium rather than the seeding phenomenon caused early recurrence in these patients. A single dose of 50 x lo6 IU interferon-a did not seem to have a sufficient effect aga ins t recurrence in our study. However, as Raitanen and Lukkar inen reported, interferon-a may have an augmenting effect when instilled repeatedly wi th epirubicin.11 They de- scribed a decreased number of patients with recurrence in the epirubicin p lus interferon group (50%) compared with controls (89%) or those who received only epirubicin (75%). The latter pa t ien ts had recurrent tumors in their series. The side effects of epirubicin as well as interferon-a were minimal in o u r study, which m a y be at least partially explained by the fact that most primary t rea tment was done using spinal anesthesia. Also, despite the relatively high dose of epirubi- cin, only 4 pat ien ts had primary dysuria.

CONCLUSIONS

Our s tudy shows a statistically significant decrease in the recurrence of superficial bladder cancer for u p to 2 years us ing a single preoperative 100 mg. intravesical dose of epi- rubicin. Because of minimal side effects, this t rea tment is recommended in cases of single stage Ta to T1 tumors. Interferon-a at a dose of 50 million units and as a single intravesical treatment seems to be ineffective. Our short- term results confirm those of other studies, which have dem- onstrated the positive preventive effects of single instillation chemotherapy in association with transurethral resection. The long-term effects of this s tudy wi th special emphas is on prognostic factors will be reported later.

REFERENCES

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2. Torti, F. M. and Lum, B. L.: The biology and treatment of superficial bladder cancer. J. Clin. Oncol., 2 505, 1984.

3. Soloway, M. S. and Masters, S.: Urothelial susceptibility to tu- mor cell implantation. Influence of cauterization. Cancer, 46. 1158, 1980.

4. Sidransky, D., von Eschenbach, A,, Tsai, Y. C., Jones, P., Summerhayes, I. and Marshall, F.: Identification of p53 gene mutations in bladder cancers and urine samples. Science, 252: 706, 1990.

5. 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 carcinoma. Brit. J. Urol., 48: 55,1976.

6. Abrams, P. H., Choa, R. G., Gaches, C. G. C., Ashken, M. H. and Green, N. A,: A controlled trial of single dose intravesical adriamycin in superficial bladder tumours. Brit. J. Urol., 5 3 585, 1981.

7. Zincke, H., Utz, D. C., Taylor, W. F., Myers, R. P. and Leary, F. J.: Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, con- trolled trial. J. Urol., 1 2 9 505, 1983.

8. Kurth, K. H., Maksimovic, P. A,, Hop, W. C. J., Schroder, F. H. and Bakker, N. J.: Single-dose intravesical epodyl after TUR of Ta TCC bladder carcinoma. World J. Urol., 1: 89, 1983.

9. Oosterlink, W., Kurth, K. H., Schroder, F. H., Bultinck, J., Hammond, B., Sylvester, R. and Members of the EORTC-GU Group: A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intra- vesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J. Urol., 1 4 9 749, 1993.

10. Rajala, P., Kaasinen, E., Rintala, E., Jauhiainen, K., Nurmi, M.,

Alfthan, 0. and Lahde, M.: Cytostatic effect of different strains of bacillus Calmette-Guerin on human bladder cancer cells in vitro alone and in combination with mitornycin C and inter- feron alpha. Urol. Res., 2 0 215, 1992.

11. Raitanen, M.-P. and Lukkarinen, 0.: A controlled study of intra- vesical epirubicin with or without alpha2b-interferon as pro- phylaxis for recurrent superficial transitional cell carcinoma of the bladder. Brit. J. Urol., 7 6 697, 1995.

12. Harmer, M. H.: TNM Classification of Malignant Tumours, 3rd ed. Union Internationale Contre le Cancer. Geneva: World Health Organization, p. 113, 1978.

13. Mostofi, F. K., Sobin, L. H. and Torloni, H.: Histological Typing of Urinary Bladder Tumours. International Histological Clas- sification of Tumours. Geneva: World Health Organization, 1973.

14. The effect of intravesical thiotepa on tumour recurrence after endoscopic treatment of newly diagnosed superficial bladder cancer. A further report with long-term follow-up of a Medical Research Council randomized trial. Medical Research Council Working Party on Urological Cancer, Subgroup on Superficial Bladder Cancer. Brit. J. Urol., 73: 632, 1994.

15. Tolley, D. A., Parmar, M. K. B., Grigor, K. M., Lallemand, G. and the Medical Research Council Superficial Bladder Cancer Working Party: The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer. a further report with 7 years of followup. J. Urol., 155 1233, 1996.

EDITORIAL COMMENTS

These authors report a 3-arm prospective randomized study of transurethral resection only, transurethral resection plus a single postoperative dose of interferon-a and transurethral resection plus a single dose of epirubicin. The study included patients with superfi- cial bladder cancer (clinical stage Ta or T1) who presented with an initial tumor. Patients with history of bladder cancer were excluded from study, as were those with invasive tumors or concomitant carcinoma in situ. Although the withdrawal rate was high (83 pa- tients), 200 patients were evaluable and the study showed a signif- icantly lower rate of disease recurrence in those who received a single postoperative dose of epirubicin.

These clinically significant results provide further evidence that a single postoperative dose of an active intravesical agent may de- crease the risk of recurrence. This study also supports the earlier prospective randomized European Organization for Research and Treatment of Cancer trial in which a single postoperative dose of epirubicin decreased the recurrence rate compared with water (ref- erence 9 in article). Other prospective randomized (references 5 and 7 in article) and nonrandomized controlled (references 6 and 8 in article1 studies have shown that a single postoperative dose of thio- tepa, doxorubicin or ethoglucid similarly decreases the recurrence rate.

The concept that a single postoperative dose of an active intraves- ical agent alters the natural history of superficial bladder cancer is not new and dates back 20 years or longer. However, such treatment is rarely given despite a growing body of evidence supporting its use. In an era when continuous improvements in patient outcome, cost- effectiveness and patient convenience are important we should be open to change and should consider this concept.

Louis Pisters M. D. Anderson Cancer Center Houston, Texas

In this well designed study the authors clearly demonstrate that a single dose of epirubicin at the time of tumor resection is highly effective in reducing tumor recurrence. Immunotherapy with inter- feron was ineffective when given as a single immediate instillation. Considering the mechanisms of action of cytotoxic chemotherapy and immunotherapy, this distinction is not unexpected. Due to the lim- ited numbers of patients in the various subgroups with multiple and higher grade tumors, we should not conclude that immediate che- motherapy is necessarily without benefit in such patients. As the authors note, the data on thiotepa, doxorubicin and mito-

mycin as well as epirubicin suggest that optimal time for initiation of chemotherapy is within 6 hours of transurethral resection. Further treatment does not appear to improve significantly the results of chemotherapy, as illustrated by the study on mitomycin by Tolly et