UROCIIEMOTIIERAPY
LONG .. TERM OBSERVATION AFTER INTRAVESICAL METAPHYLAXIS WITH MITOMYCIN C IN PATIENTS WITH SUPERFICIAL BLADDER TUMORS ULRICH MAIER, M.D. KARL HOBARTH, M.D. From the Department of Urology, University of Vienna, Medical School, Vienna, Austria
ABSTRACT-After transurethral resection of a superficial bladder tumor 63 patients were treated by chemoprophylaxis with mitomycin C over a period of two years: 33.3 percent experienced recurrent disease under metaphylaxis and 42 patients who remained recurrence-free during instillatioll therapy were observed further for an average of 26.4 months. During this period 26.2 percent of the patients showed recurrences ranging between two to forty-four months after completing instillation. The majority of the patients in whom recurrent tumors developed also had recurrent tumor processes before the instillation therapy was begun. Of the 42 patients 73.8 percent stayed recurrence-free during the observation period of twelve to fifty-four months after completing instlllation therapy. In conclusion, during an average observation period of 50.4 months, 52.4 percent of the patients in this study showed recurrences.
Based on the favorable experience with mitomycin C in the metaphylaxis of superficial bladder tumors l - 7 and our own observations in a randomized study, 8 all patients in our department underwent this intravesical chemoprophylaxis since 1982 following transurethral resection of superficial bladder tumors. Since most of the studies published so far had limited follow-up, in most cases equal to the period of treatment, we analyzed retrospectively the later course of the disease in those patients who were initially recurrence-free while on a mitomycin C regimen, to show the percentage and time span in which a recurrence after completion of instillation could be expected and to point out any relations between relapse tendency and risk factors (stage, grade of differentiation, recidivity). Material and Methods Follow-up was possible in 63 patients. All patients had received 20 mg mitomycin C dissolved in 20 mL distilled water via a disposable catheter one week after transurethral resection. UROLOGY I
MAY 1991 I
VOLUME XXXVII, NUMBER 5
Further instillations were every two weeks during the first half year, and every four weeks until the end of the second year. During the first two years, cystoscopy and bladder wash cytology were done every three months ?nd la~er every six months. Annual sonographlc studies and urography were also recommended for the same time period. The average age for the 45 men and 18 women was 68.6 years (46-82 years). Staging and grading were done according to the WHO and UICe criteria (Table I). Thirty were primary tumors and 33 recurrent tumors (1.0-14.0 recurrences; 2.6 relapses). Average observation period after completing therapy was 26.4 months (12-54 mos.). TABLE I. Stage
TA Tl Tis TOTALS
Staging and grading oj 63 bladder tumors I
Grade II
20 22
42
III
Total
15
2
23 39
18
-31
-631
3
481
Results In one third of the patients (21/63), recurrent tumor was found after an average of 14.3 months (4-24) during metaphylaxis. Fifteen of these 21 patients (71.4 %) already had had a recurrent tumor prior to metaphylaxis. Ten tumors showed the same grading and staging seen at the last resection; lower grading and!or staging was seen in 5 cases, and 6 tumors ha~ an increase in grading and!or staging. One patIent with recurrence died of the carcinoma fiftyfour months after the relapse under mitomycin C· he had one recurrence before chemoprophyla~is and proceeded to have a total of five recurrences prior to his death. Eleven of 42 patients (26.2 %) had recurrences in an average of 14.2 months (2-44 months) after discontinuing mitomycin instillation. Seven of these 11 patients (63.6 %) had antecedent recurrent carcinoma before mitomycin C prophylaxis. Six tumors showed no change in staging or grading; two had a lower staging/ grading and three had a higher staging! grading. Thirty-one of 42 patients (73.8 %) exhibited no further recurrence after discontinuation of the instillation therapy during an observation period of twelve to fifty-four months (26.4 months). Before mitomycin prophylaxis, 13 of these patients had a recurrent tumor and 18 patients had a primary carcinoma. In summary, 33 of 63 patients (52.4 %) had recurrence of tumor during or after the metaphylaxis in an average observation period of 50.4 months after the onset of therapy, whereas 47.6 percent exhibited no recurrences during the thirty-six to fifty-four months of observation. The following side effects were noted: 2 x skin allergy (3.2%); 3 x bacterial cystitis (4.8%); 2 x chemocystitis (3.2%). Therapy was interrupted for an average of fourteen days, maximally four weeks when side effects developed. Comment The value of chemoprophylaxis with mitomycin for superficial bladder tumors has been increasingly questioned in the recent past. A longer follow-up after metaphylaxis is therefore important. Of the 150 patients who underwent instillation therapy in a randomized study where the reported results were encouragingB 63 patients have had reasonable lengths of follow-up. Our data showed essentially higher rates of recUrrences during instillation therapy 482
than that published by Huland and coworkers. 4-6 It was apparent that despite chemoprophylaxis, a previously recurrent tumor will exhibit a much higher relapse rate (71.4 % of the recurrences had an average of 2.0 tumor manifestations before beginning instillation therapy). A similar behavior was seen in the recurrences after instillation-free interval. Of these patients 63.6 percent showed a previously recurrent tumor before beginning the metaphylaxis. Interestingly, in 75 percent of all patients who remained recurrence-free during the instillation period (2 years) recurrent carcinomas did not develop in the next two years (average observation period after completion of instillation therapy was 26.4 months). In conclusion, it can be stated that a 52.4 percent rate of recurrence after more than four years observation after beginning instillation therapy is relatively high. But it must also be emphasized that mitomycin C, applied in this dosage and in these intervals, has only a minimal rate of side effects (11.2%). Preliminary data on the addition of hyaluronidase appears to indicate an essentially improved response rate and also a longer recurrence-free interval. 9 After one year, when an adequate observation period has been achieved, data on this subject will then be presented. Vrologische Vniv. Klinik Alser Strasse 4 A-lOgO Wien, Austria (DR. MAIER) References
1. Devonec M, et all Intravesical instillation of mitomycin C in the prophylactic treatment of recurring superficial transitional cell carcinoma of the bladder, Dr J Uro155: 382 (1983). 2. F1iichter Stll, et all Lokale Chemotherapie des lIarnblasenkarzlnoms mit Mitomycin, Urologe A 21: 24 (1982). 3. Ciesbers AACM, Van Helsdingen PJRO, and Kramer AEJL: Recurrence of superficial bladder carcinoma after intravesical instillation of mitomycin-C, Dr J Uro163: 176 (1989). 4. lIuland II, and Otto U: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma, Eur Urol 9: 84 (1983). 5. IIuland II, Otto U, Droese M, and Kloppel C: Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma, J Uro1132: 27 (1984). 6. IIuland II, and Otto U: Use of mitomycin as prophylaxis following endoscopic resection of superficial bladder cancer, Urol. ogy (Suppl) 26(4): 32 (1985). 7. Zincke II Benson RC Jr, IIilton IF, and Taylor WF: Intra· vesical thiotep~ and mitomycin C treat~e~t immediately after transurethral resection and later for superfiCial (Stages Ta and Tis) bladder cancer J Uro1134: 1110 (1985). 8. Maier U: and I10lzner III: Stellenwert der Urot.heldyspl~. sien in makroskopisch normaler Schleimhaut bei Patienten mit B1asentumoren Onkologie 8: 232 (1985). 9. Maier U, ~nd Baumgartner G: Metaphylactic effect of mitomycin C with and without hyaluronidase after transurethral reo section of bladder cancer, I Uro1141: 529 (1988).
UROLOGY
I
MAY 1991
I
VOLUME XXXVII. NUMBER 5
LONG .. TERM OBSERVATION AFTER INTRAVESICAL METAPHYLAXIS WITH MITOMYCIN C IN PATIENTS WITH SUPERFICIAL BLADDER TUMORS ULRICH MAIER, M.D. KARL HOBARTH, M.D. From the Department of Urology, University of Vienna, Medical School, Vienna, Austria
ABSTRACT-After transurethral resection of a superficial bladder tumor 63 patients were treated by chemoprophylaxis with mitomycin C over a period of two years: 33.3 percent experienced recurrent disease under metaphylaxis and 42 patients who remained recurrence-free during instillatioll therapy were observed further for an average of 26.4 months. During this period 26.2 percent of the patients showed recurrences ranging between two to forty-four months after completing instillation. The majority of the patients in whom recurrent tumors developed also had recurrent tumor processes before the instillation therapy was begun. Of the 42 patients 73.8 percent stayed recurrence-free during the observation period of twelve to fifty-four months after completing instlllation therapy. In conclusion, during an average observation period of 50.4 months, 52.4 percent of the patients in this study showed recurrences.
Based on the favorable experience with mitomycin C in the metaphylaxis of superficial bladder tumors l - 7 and our own observations in a randomized study, 8 all patients in our department underwent this intravesical chemoprophylaxis since 1982 following transurethral resection of superficial bladder tumors. Since most of the studies published so far had limited follow-up, in most cases equal to the period of treatment, we analyzed retrospectively the later course of the disease in those patients who were initially recurrence-free while on a mitomycin C regimen, to show the percentage and time span in which a recurrence after completion of instillation could be expected and to point out any relations between relapse tendency and risk factors (stage, grade of differentiation, recidivity). Material and Methods Follow-up was possible in 63 patients. All patients had received 20 mg mitomycin C dissolved in 20 mL distilled water via a disposable catheter one week after transurethral resection. UROLOGY I
MAY 1991 I
VOLUME XXXVII, NUMBER 5
Further instillations were every two weeks during the first half year, and every four weeks until the end of the second year. During the first two years, cystoscopy and bladder wash cytology were done every three months ?nd la~er every six months. Annual sonographlc studies and urography were also recommended for the same time period. The average age for the 45 men and 18 women was 68.6 years (46-82 years). Staging and grading were done according to the WHO and UICe criteria (Table I). Thirty were primary tumors and 33 recurrent tumors (1.0-14.0 recurrences; 2.6 relapses). Average observation period after completing therapy was 26.4 months (12-54 mos.). TABLE I. Stage
TA Tl Tis TOTALS
Staging and grading oj 63 bladder tumors I
Grade II
20 22
42
III
Total
15
2
23 39
18
-31
-631
3
481
Results In one third of the patients (21/63), recurrent tumor was found after an average of 14.3 months (4-24) during metaphylaxis. Fifteen of these 21 patients (71.4 %) already had had a recurrent tumor prior to metaphylaxis. Ten tumors showed the same grading and staging seen at the last resection; lower grading and!or staging was seen in 5 cases, and 6 tumors ha~ an increase in grading and!or staging. One patIent with recurrence died of the carcinoma fiftyfour months after the relapse under mitomycin C· he had one recurrence before chemoprophyla~is and proceeded to have a total of five recurrences prior to his death. Eleven of 42 patients (26.2 %) had recurrences in an average of 14.2 months (2-44 months) after discontinuing mitomycin instillation. Seven of these 11 patients (63.6 %) had antecedent recurrent carcinoma before mitomycin C prophylaxis. Six tumors showed no change in staging or grading; two had a lower staging/ grading and three had a higher staging! grading. Thirty-one of 42 patients (73.8 %) exhibited no further recurrence after discontinuation of the instillation therapy during an observation period of twelve to fifty-four months (26.4 months). Before mitomycin prophylaxis, 13 of these patients had a recurrent tumor and 18 patients had a primary carcinoma. In summary, 33 of 63 patients (52.4 %) had recurrence of tumor during or after the metaphylaxis in an average observation period of 50.4 months after the onset of therapy, whereas 47.6 percent exhibited no recurrences during the thirty-six to fifty-four months of observation. The following side effects were noted: 2 x skin allergy (3.2%); 3 x bacterial cystitis (4.8%); 2 x chemocystitis (3.2%). Therapy was interrupted for an average of fourteen days, maximally four weeks when side effects developed. Comment The value of chemoprophylaxis with mitomycin for superficial bladder tumors has been increasingly questioned in the recent past. A longer follow-up after metaphylaxis is therefore important. Of the 150 patients who underwent instillation therapy in a randomized study where the reported results were encouragingB 63 patients have had reasonable lengths of follow-up. Our data showed essentially higher rates of recUrrences during instillation therapy 482
than that published by Huland and coworkers. 4-6 It was apparent that despite chemoprophylaxis, a previously recurrent tumor will exhibit a much higher relapse rate (71.4 % of the recurrences had an average of 2.0 tumor manifestations before beginning instillation therapy). A similar behavior was seen in the recurrences after instillation-free interval. Of these patients 63.6 percent showed a previously recurrent tumor before beginning the metaphylaxis. Interestingly, in 75 percent of all patients who remained recurrence-free during the instillation period (2 years) recurrent carcinomas did not develop in the next two years (average observation period after completion of instillation therapy was 26.4 months). In conclusion, it can be stated that a 52.4 percent rate of recurrence after more than four years observation after beginning instillation therapy is relatively high. But it must also be emphasized that mitomycin C, applied in this dosage and in these intervals, has only a minimal rate of side effects (11.2%). Preliminary data on the addition of hyaluronidase appears to indicate an essentially improved response rate and also a longer recurrence-free interval. 9 After one year, when an adequate observation period has been achieved, data on this subject will then be presented. Vrologische Vniv. Klinik Alser Strasse 4 A-lOgO Wien, Austria (DR. MAIER) References
1. Devonec M, et all Intravesical instillation of mitomycin C in the prophylactic treatment of recurring superficial transitional cell carcinoma of the bladder, Dr J Uro155: 382 (1983). 2. F1iichter Stll, et all Lokale Chemotherapie des lIarnblasenkarzlnoms mit Mitomycin, Urologe A 21: 24 (1982). 3. Ciesbers AACM, Van Helsdingen PJRO, and Kramer AEJL: Recurrence of superficial bladder carcinoma after intravesical instillation of mitomycin-C, Dr J Uro163: 176 (1989). 4. lIuland II, and Otto U: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma, Eur Urol 9: 84 (1983). 5. IIuland II, Otto U, Droese M, and Kloppel C: Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma, J Uro1132: 27 (1984). 6. IIuland II, and Otto U: Use of mitomycin as prophylaxis following endoscopic resection of superficial bladder cancer, Urol. ogy (Suppl) 26(4): 32 (1985). 7. Zincke II Benson RC Jr, IIilton IF, and Taylor WF: Intra· vesical thiotep~ and mitomycin C treat~e~t immediately after transurethral resection and later for superfiCial (Stages Ta and Tis) bladder cancer J Uro1134: 1110 (1985). 8. Maier U: and I10lzner III: Stellenwert der Urot.heldyspl~. sien in makroskopisch normaler Schleimhaut bei Patienten mit B1asentumoren Onkologie 8: 232 (1985). 9. Maier U, ~nd Baumgartner G: Metaphylactic effect of mitomycin C with and without hyaluronidase after transurethral reo section of bladder cancer, I Uro1141: 529 (1988).
UROLOGY
I
MAY 1991
I
VOLUME XXXVII. NUMBER 5
