0022-5347 /90/1431-0034$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 143, January Printed in U.S.A.
TOPICAL MITOMYCIN C THERAPY FOR CARCINOMA IN SITU OF THE BLADDER: A FOLLOWUP P. D. STRICKER, A. B. F. GRANT, B. M. HOSKEN AND J. S. TAYLOR From the Department of Urology, Royal Newcastle Hospital, Newcastle, New South Wales, Australia
ABSTRACT
We studied 15 patients with histologically proved multifocal carcinoma in situ of the bladder who were in remission at a mean followup of 21 months after induction intravesical chemotherapy with mitomycin C. These patients have been followed for a further 28 months, for a total mean duration of 49 months. Of the 15 patients 4 suffered new areas of carcinoma in situ, including 3 who subsequently required cystectomy (2 after unsuccessful intravesical bacillus Calmette-Guerin therapy and 1 with a simultaneous invasive tumor). One patient underwent transurethral resection of the prostate for carcinoma in situ of the prostatic urethra, which subsequently was shown to be limited to mucosa and not involving the deeper ducts nor the stroma. Of the remaining 11 patients 1 died of unrelated disease and 2 suffered recurrent papillary transitional cell carcinoma treated successfully with a combination of intravesical bacillus Calmette-Guerin therapy and resection. The other 8 patients have remained free of tumor. None of the 15 patients had metastatic cancer. We believe that these results support the durability of response after induction mitomycin C therapy. We stress the necessity for prolonged close followup to detect recurrent tumor and to avoid metastatic disease. (J. Ural., 143: 34-36, 1990) The malignant potential and natural history of carcinoma in situ of the bladder are extremely variable.'· 2 It is well established that numerous chemotherapeutic and immunotherapeutic agents are capable of at least initially eradicating the bladder of carcinoma in situ. 3 However, the question remains as to whether this simply is a delay in progression or whether these agents can truly modify the natural history of carcinoma in situ. Long-term followup for greater than 4 years has been performed in a number of studies in patients with carcinoma in situ after intravesical chemotherapy, with reported durable remissions of 40 to 60%. 3 - 5 Little is known about the long-term course of patients with carcinoma in situ after a single induction course of mitomycin C. 6 We report on 15 patients whose carcinoma in situ of the bladder was in remission at a mean of 21 months after previous induction intravesical mitomycin C. All 15 patients have been followed for a further 28 months.
RESULTS
The results are summarized in the figure. Areas of carcinoma in situ recurred in 4 of the 15 patients and eventually led to cystectomy in 3. In 2 patients recurrent papillary tumors were treated with a combination of intravesical bacillus CalmetteGuerin (BCG) and endoscopic resection. One patient died of an unrelated disorder. Eight patients have remained free of tumor with no further treatment and no further recurrences.' Of the 4 patients with recurrent carcinoma in situ 2 had recurrences after prolonged remission (2 to 3 years) and after a complete initial response. One of these 2 patients had a mucosal recurrence in the prostatic urethra and transurethral resection of the prostate revealed no stromal or ductal invasion. Since that time he has remained with no evidence of disease histologically and cytologically, and with no further chemotherapy. The other patient had widespread carcinoma in situ and despite BCG therapy the disease recurred rapidly, and the patient required cystectomy and urethrectomy for extensive carcinoma in situ. At cystectomy there was no nodal involvement and no invasive tumor, although the carcinoma in situ had extended into the ducts of the prostate. Of the 2 other patients with recurrent carcinoma in situ 1 had rapidly recurrent carcinoma in situ despite treatment with mitomycin C, doxorubicin and BCG. At that stage the patient had a grade 3 stage T2 carcinoma and because of extreme obesity she was treated with external beam radiotherapy. A small contracted bladder and a radiation ulcer subsequently developed. At cystectomy there was no nodal involvement and the pathological specimen revealed tumor at the base of the radiation ulcer. Finally, 1 patient with recurrent carcinoma in situ had a short initial remission. Further induction therapy with mitomycin C followed by monthly maintenance mitomycin C induced remission for 36 months, when an invasive transitional cell tumor associated with carcinoma in situ developed. Cystectomy was performed and the bladder contained a stage T3 bladder carcinoma. There was no nodal involvement. Multiple papillary tumors without carcinoma in situ developed in 2 patients: 1 has undergone a course of BCG therapy and presently is free of tumor, while 1 had occasional small grades 1 to 2 papillary lesions in the prostatic urethra that were resected and no further tumor occurred.
MATERIALS AND METHODS
Patients. Topical intravesical chemotherapy with mitomycin C was used in 19 patients with histologically proved carcinoma in situ of the bladder from 1982 to 1985. Details of these patients have been reported previously. 7 Of these 19 patients 15 were in remission at a mean followup of 21 months. Remission was defined as negative cytology results and no evidence of carcinoma in situ or severe dysplasia in any of the biopsies taken at 3 monthly intervals. Of the remaining 4 patients 3 died of intercurrent illnesses and 1 died of metastatic bladder cancer. These 4 patients have been discussed in detail previously.7 All patients at initial biopsy had diffuse carcinoma in situ defined as involving at least 2 quadrants of the bladder or a single large area of the bladder for which fulguration alone would be too extensive. No patient had received prior intravesical chemotherapy or imrnunotherapy. Clinical followup with repeat cystoscopy, biopsy and cytology ranged from 36 to 76 months, with an average of 49 months. Techniques. Dosages of 30 mg. mitomycin C diluted in 30 ml. were administered weekly for 8 consecutive weeks. Each treatment lasted 2 hours. Further details have been reported previously.7 Accepted for publication April 21, 1989. 34
TOPICAL I¼ITOf.AYCIN C TI-fERAPY FOR CARCltJO:tvlA If.J SITU OF BLADDER
A
PATHOLOGY
6
12
1a
24
30
36
42
48
54
60
66
12
78
Cis + Ta
*-*~
Cis + Ta
-
Cis
~
CisR
Cis + Ta Cis + Ta Cis+ Ti Cis+ T1
Cis:f:cis~
..
Cis + Ta Cis
...
Cis + T1 Cis+ T1
B
PATHOLOGY
6
~----
12
18
24
-
30
36
42
48
54
60
66
72
78
30
36
42
48
54
60
66
72
78
Cis + Ta Cis + Ta Cis
f------M
Cis + Ta
C
PATHOLOGY
6
12
18
24
Cis + Ta
**------------------
Cis + T1
Cis-~---------
Cis + Ta
Cis_ilLCisli~~j--------~
Cis
Cis_j_Ci~Cis+T,)L T,-@]--
A, complete response and no relapse until June 1986. Pathological diagnosis either is primary carcinoma in situ (Cis) or secondary carcinoma in situ (Cis + Ta or Cis + Tl, depending on highest stage tumor associated with Cis). Followup is in months since completion of mitomycin C therapy. Horizontal arrows indicate patients free of tumor. Asterisks indicate papillary recurrence. -, alive after cystectomy with no metastases. -II, died of unrelated disease. V, 6-week intravesical BCG. P, prostatic resection.@), cystectomy. B, complete initial response with relapse before June 1986 in 4 patients. C, cytology positive only. J, monthly mitomycin C therapy. M, metastatic bladder carcinoma. J,, foll course of mitomycin C therapy. T 3 , stage T 3 carcinoma of bladdef. C, failure to respond initially to mitomycin C therapy in 4 patients. ~' full course of doxorubicin therapy. T 2, T,, stages T 2 and T 3 bladder carcinoma. X, external beam radiotherapy.
Of the 4 patients who did not achieve an initial complete response to induction intravesical mitomycin C only 1 has required cystectomy, while 3 underwent further mitomycin C therapy and/or transurethral resection of tumor. All 3 patients were rendered free of tumor within 6 months of induction therapy and have remained so for 34 to 68 months. DISCUSSION
The purpose of this followup report not only is to gain further insight into the course of carcinoma in situ of the bladder after intravesical mitomycin C but also to analyze further whether cystectomy and/or progression to muscle invasion can be avoided in this higher risk group. Considering our results, after an average observation of 49 months several points deserve mention. Of the 15 patients who did not die of unrelated diseases 8 (55%) are presently free of tumor. However, 3 of these 8 patients required further chemotherapy and/or endoscopic diathermy at the initial second induction cystoscopy. Cant and associates reported a durable response of 42% in 12 patients with carcinoma in situ after mitomycin C therapy with a mean followup of 48 months. 8 What, then, is the risk of a trial of intensive intravesical chemotherapy? 3 Of the 15 patients who did not die of intercur-
35
rent illnesses 3 (20%) underwent cystectomy and none of these 3 subsequently had metastatic disease. Only 1 patient died of metastatic bladder cancer and, as discussed in our original article, 7 there was no evidence of urothelial tumor at the time of the metastases. Presumably, the metastases had occurred before chemotherapy was commenced. Therefore, we believe that with close monitoring, including 3 monthly cystoscopic evaluations with particular emphasis on cytology results and prostatic biopsy, as well as regular upper tract assessment, the risk of intravesical mitomycin C therapy is low. Recurrence may be unexpected in patients who have had remissions of greater than 2 years, even after initial complete response to induction chemotherapy. Of our patients 3 had late recurrence, with 1 requiring cystectomy. Although a complete response may predict the durability of remission, delayed relapses after initial complete responses do occur as in our study, which illustrates the necessity for vigilant followup for a prolonged period even in patients with a complete response. Not all of our patients underwent cytology study immediately after induction therapy. Therefore, the significance of a positive cytological partial response cannot be interpreted in this report. However, during the followup involved in our study all patients have undergone urine cytology studies for the last 30 months. In conclusion, we strongly believe that patients with multifocal carcinoma in situ are served best initially by intensive intravesical chemotherapy. This is supported first by the fact that many of these patients are in poor health and die of other unrelated disorders. Also, with close followup progression can be detected at an early stage and metastatic disease may be prevented. Finally, approximately half of the patients treated will remain in remission for prolonged periods. REFERENCES 1. Utz, D. C. and Farrow, G. M.: Carcinoma in situ of the urinary
tract. Urol. Clin. N. Amer., 11: 735, 1984. 2. Riddle, P. R., Chisholm, G. D., Trott, P. A. and Pugh, R. C. B.: Flat carcinoma in situ of the bladder. Brit. J. Urol., 47: 829, 1985. 3. Soloway, M. S.: Introduction and overview of intravesical therapy for superficial bladder cancer. Urology, suppl. 3, 31: 5, 1988. 4. Jakse, G., Hofstadter, F. and Marberger, H.: Topical doxorubicin hydrochloride therapy for carcinoma in situ of the bladder: a followup. J. Ural., 131: 41, 1984. 5. Herr, H. W., Pinksy, C. M., Whitmore, W. F., Jr., Sogani, P. C., Oettgen, H.F. and Melamed, M. R.: Long-term effect of intravesical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J. Urol., 135: 265, 1986. 6. Van der Meijden, A. P. M. and DeBruyne, F. M. J.: Treatment schedule of intravesical chemotherapy with mitomycin C in superficial bladder cancer: short-term courses or maintenance therapy. Urology, suppl. 3, 31: 26, 1988. 7. Stricker, P. D., Grant, A. B. F., Hosken, B. M. and Taylor, J. S.: Topical mitomycin C therapy for carcinoma of the bladder. J. Urol., 138: 1164, 1987. 8. Cant, J. D., Murphy, W. M. and Soloway, M. S.: Prognostic significance of urine cytology on initial followup after intravesical mitomycin C for superficial bladder cancer. Cancer, 57: 2119, 1986.
EDITORIAL COMMENTS The authors have confirmed the report by Soloway of long-term (4year) complete response of carcinoma in situ in 42% of the patients treated with a single course of mitomycin C. They effectively illustrate that, with meticulous followup with cystoscopy, bladder and prostate urethral biopsy, and urinary cytology, this conservative approach is associated with a low risk of disease progression and mortality. Considering the quality of life associated with preservation of the bladder, this would appear to be a most reasonable and cost-effective approach. Donald L. Lamm Department of Urology West Virginia University Morgantown, West Virginia
Vol. 143, January Printed in U.S.A.
TOPICAL MITOMYCIN C THERAPY FOR CARCINOMA IN SITU OF THE BLADDER: A FOLLOWUP P. D. STRICKER, A. B. F. GRANT, B. M. HOSKEN AND J. S. TAYLOR From the Department of Urology, Royal Newcastle Hospital, Newcastle, New South Wales, Australia
ABSTRACT
We studied 15 patients with histologically proved multifocal carcinoma in situ of the bladder who were in remission at a mean followup of 21 months after induction intravesical chemotherapy with mitomycin C. These patients have been followed for a further 28 months, for a total mean duration of 49 months. Of the 15 patients 4 suffered new areas of carcinoma in situ, including 3 who subsequently required cystectomy (2 after unsuccessful intravesical bacillus Calmette-Guerin therapy and 1 with a simultaneous invasive tumor). One patient underwent transurethral resection of the prostate for carcinoma in situ of the prostatic urethra, which subsequently was shown to be limited to mucosa and not involving the deeper ducts nor the stroma. Of the remaining 11 patients 1 died of unrelated disease and 2 suffered recurrent papillary transitional cell carcinoma treated successfully with a combination of intravesical bacillus Calmette-Guerin therapy and resection. The other 8 patients have remained free of tumor. None of the 15 patients had metastatic cancer. We believe that these results support the durability of response after induction mitomycin C therapy. We stress the necessity for prolonged close followup to detect recurrent tumor and to avoid metastatic disease. (J. Ural., 143: 34-36, 1990) The malignant potential and natural history of carcinoma in situ of the bladder are extremely variable.'· 2 It is well established that numerous chemotherapeutic and immunotherapeutic agents are capable of at least initially eradicating the bladder of carcinoma in situ. 3 However, the question remains as to whether this simply is a delay in progression or whether these agents can truly modify the natural history of carcinoma in situ. Long-term followup for greater than 4 years has been performed in a number of studies in patients with carcinoma in situ after intravesical chemotherapy, with reported durable remissions of 40 to 60%. 3 - 5 Little is known about the long-term course of patients with carcinoma in situ after a single induction course of mitomycin C. 6 We report on 15 patients whose carcinoma in situ of the bladder was in remission at a mean of 21 months after previous induction intravesical mitomycin C. All 15 patients have been followed for a further 28 months.
RESULTS
The results are summarized in the figure. Areas of carcinoma in situ recurred in 4 of the 15 patients and eventually led to cystectomy in 3. In 2 patients recurrent papillary tumors were treated with a combination of intravesical bacillus CalmetteGuerin (BCG) and endoscopic resection. One patient died of an unrelated disorder. Eight patients have remained free of tumor with no further treatment and no further recurrences.' Of the 4 patients with recurrent carcinoma in situ 2 had recurrences after prolonged remission (2 to 3 years) and after a complete initial response. One of these 2 patients had a mucosal recurrence in the prostatic urethra and transurethral resection of the prostate revealed no stromal or ductal invasion. Since that time he has remained with no evidence of disease histologically and cytologically, and with no further chemotherapy. The other patient had widespread carcinoma in situ and despite BCG therapy the disease recurred rapidly, and the patient required cystectomy and urethrectomy for extensive carcinoma in situ. At cystectomy there was no nodal involvement and no invasive tumor, although the carcinoma in situ had extended into the ducts of the prostate. Of the 2 other patients with recurrent carcinoma in situ 1 had rapidly recurrent carcinoma in situ despite treatment with mitomycin C, doxorubicin and BCG. At that stage the patient had a grade 3 stage T2 carcinoma and because of extreme obesity she was treated with external beam radiotherapy. A small contracted bladder and a radiation ulcer subsequently developed. At cystectomy there was no nodal involvement and the pathological specimen revealed tumor at the base of the radiation ulcer. Finally, 1 patient with recurrent carcinoma in situ had a short initial remission. Further induction therapy with mitomycin C followed by monthly maintenance mitomycin C induced remission for 36 months, when an invasive transitional cell tumor associated with carcinoma in situ developed. Cystectomy was performed and the bladder contained a stage T3 bladder carcinoma. There was no nodal involvement. Multiple papillary tumors without carcinoma in situ developed in 2 patients: 1 has undergone a course of BCG therapy and presently is free of tumor, while 1 had occasional small grades 1 to 2 papillary lesions in the prostatic urethra that were resected and no further tumor occurred.
MATERIALS AND METHODS
Patients. Topical intravesical chemotherapy with mitomycin C was used in 19 patients with histologically proved carcinoma in situ of the bladder from 1982 to 1985. Details of these patients have been reported previously. 7 Of these 19 patients 15 were in remission at a mean followup of 21 months. Remission was defined as negative cytology results and no evidence of carcinoma in situ or severe dysplasia in any of the biopsies taken at 3 monthly intervals. Of the remaining 4 patients 3 died of intercurrent illnesses and 1 died of metastatic bladder cancer. These 4 patients have been discussed in detail previously.7 All patients at initial biopsy had diffuse carcinoma in situ defined as involving at least 2 quadrants of the bladder or a single large area of the bladder for which fulguration alone would be too extensive. No patient had received prior intravesical chemotherapy or imrnunotherapy. Clinical followup with repeat cystoscopy, biopsy and cytology ranged from 36 to 76 months, with an average of 49 months. Techniques. Dosages of 30 mg. mitomycin C diluted in 30 ml. were administered weekly for 8 consecutive weeks. Each treatment lasted 2 hours. Further details have been reported previously.7 Accepted for publication April 21, 1989. 34
TOPICAL I¼ITOf.AYCIN C TI-fERAPY FOR CARCltJO:tvlA If.J SITU OF BLADDER
A
PATHOLOGY
6
12
1a
24
30
36
42
48
54
60
66
12
78
Cis + Ta
*-*~
Cis + Ta
-
Cis
~
CisR
Cis + Ta Cis + Ta Cis+ Ti Cis+ T1
Cis:f:cis~
..
Cis + Ta Cis
...
Cis + T1 Cis+ T1
B
PATHOLOGY
6
~----
12
18
24
-
30
36
42
48
54
60
66
72
78
30
36
42
48
54
60
66
72
78
Cis + Ta Cis + Ta Cis
f------M
Cis + Ta
C
PATHOLOGY
6
12
18
24
Cis + Ta
**------------------
Cis + T1
Cis-~---------
Cis + Ta
Cis_ilLCisli~~j--------~
Cis
Cis_j_Ci~Cis+T,)L T,-@]--
A, complete response and no relapse until June 1986. Pathological diagnosis either is primary carcinoma in situ (Cis) or secondary carcinoma in situ (Cis + Ta or Cis + Tl, depending on highest stage tumor associated with Cis). Followup is in months since completion of mitomycin C therapy. Horizontal arrows indicate patients free of tumor. Asterisks indicate papillary recurrence. -, alive after cystectomy with no metastases. -II, died of unrelated disease. V, 6-week intravesical BCG. P, prostatic resection.@), cystectomy. B, complete initial response with relapse before June 1986 in 4 patients. C, cytology positive only. J, monthly mitomycin C therapy. M, metastatic bladder carcinoma. J,, foll course of mitomycin C therapy. T 3 , stage T 3 carcinoma of bladdef. C, failure to respond initially to mitomycin C therapy in 4 patients. ~' full course of doxorubicin therapy. T 2, T,, stages T 2 and T 3 bladder carcinoma. X, external beam radiotherapy.
Of the 4 patients who did not achieve an initial complete response to induction intravesical mitomycin C only 1 has required cystectomy, while 3 underwent further mitomycin C therapy and/or transurethral resection of tumor. All 3 patients were rendered free of tumor within 6 months of induction therapy and have remained so for 34 to 68 months. DISCUSSION
The purpose of this followup report not only is to gain further insight into the course of carcinoma in situ of the bladder after intravesical mitomycin C but also to analyze further whether cystectomy and/or progression to muscle invasion can be avoided in this higher risk group. Considering our results, after an average observation of 49 months several points deserve mention. Of the 15 patients who did not die of unrelated diseases 8 (55%) are presently free of tumor. However, 3 of these 8 patients required further chemotherapy and/or endoscopic diathermy at the initial second induction cystoscopy. Cant and associates reported a durable response of 42% in 12 patients with carcinoma in situ after mitomycin C therapy with a mean followup of 48 months. 8 What, then, is the risk of a trial of intensive intravesical chemotherapy? 3 Of the 15 patients who did not die of intercur-
35
rent illnesses 3 (20%) underwent cystectomy and none of these 3 subsequently had metastatic disease. Only 1 patient died of metastatic bladder cancer and, as discussed in our original article, 7 there was no evidence of urothelial tumor at the time of the metastases. Presumably, the metastases had occurred before chemotherapy was commenced. Therefore, we believe that with close monitoring, including 3 monthly cystoscopic evaluations with particular emphasis on cytology results and prostatic biopsy, as well as regular upper tract assessment, the risk of intravesical mitomycin C therapy is low. Recurrence may be unexpected in patients who have had remissions of greater than 2 years, even after initial complete response to induction chemotherapy. Of our patients 3 had late recurrence, with 1 requiring cystectomy. Although a complete response may predict the durability of remission, delayed relapses after initial complete responses do occur as in our study, which illustrates the necessity for vigilant followup for a prolonged period even in patients with a complete response. Not all of our patients underwent cytology study immediately after induction therapy. Therefore, the significance of a positive cytological partial response cannot be interpreted in this report. However, during the followup involved in our study all patients have undergone urine cytology studies for the last 30 months. In conclusion, we strongly believe that patients with multifocal carcinoma in situ are served best initially by intensive intravesical chemotherapy. This is supported first by the fact that many of these patients are in poor health and die of other unrelated disorders. Also, with close followup progression can be detected at an early stage and metastatic disease may be prevented. Finally, approximately half of the patients treated will remain in remission for prolonged periods. REFERENCES 1. Utz, D. C. and Farrow, G. M.: Carcinoma in situ of the urinary
tract. Urol. Clin. N. Amer., 11: 735, 1984. 2. Riddle, P. R., Chisholm, G. D., Trott, P. A. and Pugh, R. C. B.: Flat carcinoma in situ of the bladder. Brit. J. Urol., 47: 829, 1985. 3. Soloway, M. S.: Introduction and overview of intravesical therapy for superficial bladder cancer. Urology, suppl. 3, 31: 5, 1988. 4. Jakse, G., Hofstadter, F. and Marberger, H.: Topical doxorubicin hydrochloride therapy for carcinoma in situ of the bladder: a followup. J. Ural., 131: 41, 1984. 5. Herr, H. W., Pinksy, C. M., Whitmore, W. F., Jr., Sogani, P. C., Oettgen, H.F. and Melamed, M. R.: Long-term effect of intravesical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J. Urol., 135: 265, 1986. 6. Van der Meijden, A. P. M. and DeBruyne, F. M. J.: Treatment schedule of intravesical chemotherapy with mitomycin C in superficial bladder cancer: short-term courses or maintenance therapy. Urology, suppl. 3, 31: 26, 1988. 7. Stricker, P. D., Grant, A. B. F., Hosken, B. M. and Taylor, J. S.: Topical mitomycin C therapy for carcinoma of the bladder. J. Urol., 138: 1164, 1987. 8. Cant, J. D., Murphy, W. M. and Soloway, M. S.: Prognostic significance of urine cytology on initial followup after intravesical mitomycin C for superficial bladder cancer. Cancer, 57: 2119, 1986.
EDITORIAL COMMENTS The authors have confirmed the report by Soloway of long-term (4year) complete response of carcinoma in situ in 42% of the patients treated with a single course of mitomycin C. They effectively illustrate that, with meticulous followup with cystoscopy, bladder and prostate urethral biopsy, and urinary cytology, this conservative approach is associated with a low risk of disease progression and mortality. Considering the quality of life associated with preservation of the bladder, this would appear to be a most reasonable and cost-effective approach. Donald L. Lamm Department of Urology West Virginia University Morgantown, West Virginia
