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Indications for BCG use in carcinoma in situ
INDICATIONS FOR BCG USE IN CARCINOMA IN SITU STANLEY A. BROSMAN, M . D . F r o m the D e p a r t m e n t of Urology, Kaiser Hospital, Kaiser Medical G r o u p , Los Angeles, California
There are three basic indications for the use of bacillus Calmette-Gu6rin (BCG) in patients with bladder cancer: to prevent recurrences; to eliminate an existing tumor in either the bladder or the upper Urinary tract; and to eliminate and prevent carcinoma in situ (CIS). The last indication is the subject of this report. Incidence of Carcinoma In Situ Over the past ten years, there has been a 35 percent increase in the number of new eases of bladder cancer, an 11.5 percent increase in deaths due to bladder cancer, and a 28.5 percent increase in the probability that transitional cell eareinorna (TCC) will develop in an individual born in 1985. Careinorna in situ represents 5-10 percent of all TCC, and its recognition is increasing. The reasons for this are not dear, but they are probably related to the way pathologists make the diagnosis. For some years, pathologists have disagreed about the histopathologic features of carcinoma in situ. Grades 1, 2, and 3 (G1, G2, or G3) have been assigned according to the degree of cellular atypia or dysplasia. The inclusion of patients with atypia or dysplasia may have biased much of the earlier data and is probably continuing to do so. Whether or not pathologists will be able to agree on these histologic distinctions is not clear, but when responses to BCG treatment are studied, those with lower grades of disease tend to have good responses to BCG. Effect of BCG on Carcinoma In Situ
Material and methods The study population in this series comprised 48 patients who had unequivocal CIS. Those with dysplasia of any degree were excluded. Patients were observed for a mean duration of thirty-five months. A total of 29 patients had a combination of TCC and CIS. Chemotherapy had previously been administered in 7 patients.
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Patients underwent twelve instillati. tion therapy. This was followed by o n e tenanee therapy consisting of monthly The induction phase did not neeessar twelve consecutive weeks of treatmen ment sometimes was interrupted for weeks because of severe bladder reaetic infection, or because the patient or doe1 town. The purpose of the induct an inflammatory/immunolo: der. It is likely that once this the maximum BCG effect how many weeks of therapy the maximum response rem~ bly varies from patient to p Patients underwent eysto biopsy, every six weeks fo: weeks, and every three to six years. Biopsy specimens wer with the patients under eft none at all. A total of three ( mens of suspicious areas epithdium were obtained. Results (Table I) Forty patients (83 %) eomp] phase, and normal biopsy speeir complete response to BCG thei from 28 (70 %) patients. This f5 sistent with the results of other patients, 7 received double-dose no indieation of an inflammato patients after the first six instill meditation was increased to t~ BCG in 50 mL of saline. The tained in the bladder for two hc this weekly treatment was ton flammatory response was detec required two to four instillatiol treatments, 5 patients had a 50 1
SUPPLEMENT TO UROLOGY / MAY1991 / VOLUMExXXVIIiI ~ { ~
-
~se to B C G therapy in 40 patients in situ w h o completed protocol
No. of Pts. (%)
ponse complete response) 1 response)$ eks of therapy ~nse) response
28* (70) 5 (12.5) 3:~ (7.5) 31 (77.5)
(28 ÷ 3) esponse or progression 9 (22.5) disease (2 + 7) ~eyenpatients received double-dosetherapy. i~tial response" signifies 50 percent reduction in tumor ~WOpatients received double-dosetherapy.
~0r area. Of these patients, 3 subsequently had evidence of carcinoma in biopsy specimens. Eight patients did not complete the induction iase but had three to eight instillations each. Comte responses were observed in 3 patients, and 5 ~:no response. In total, 34/48 (70.8%)patients iieved complete responses, regardless of whether not they completed the protocol. ~he observation that 3 patients who did not com~!~te the protocol h a d normal" biopsy results, eas some patients required more than twelve ~ l l a t i o n s to achieve a complete response, lends ~}~dence to the belief that the duration of effective ~CG therapy varies from patient to patient. ~!~;Disease::recurred in 14 of the 34 (41% ) tumor-free ~afi~nts. Most of these tumors recurred within the ~S~,year to year and a half after treatment. ~!!::he sites of recurrence demonstrate the insidious~ : ~ o f bladder cancer. Tumors recurred in the upper ~iS~ary tract or the ureter in 6 patients, in the prosurethra or within the prostate in 7 patients, ~ d in the bladder in 1 patient who had a G3 TCC ~'~i~i,thoutevidence of associated CIS. "°"~!i The~:i: 14 patients in whom disease subsequently red e d despite normal biopsy findings, initially were ~anaKed in a variety of ways . In 8 p atients c Y sto~.~ :~Pr0stateetomy was performed; in 4, nephroureterec~y and cystectomy; in 1, transurethral resection ~ d additional BCG therapy; and in 3, infusion of ~ C C into the kidneys Of the 14, 3 patients ulti-
~h~r
mately died of cancer, and 6 have had positive cytologic findings for extended periods of time. Of the 14 patients who did not complete the protocol or demonstrate a response to BCG, 9 had cysteetomy with prostateetomy and 5 received a combination of chemotherapy or radiation therapy. Two of these 14 patients ultimately died of cancer, and positive cytologic findings persist in 7. Conclusion The effectiveness of intravesieal instillations of BCG in the eradication of CIS has been demonstrated in this and other studies. Using a variety of protocols with six to twelve instillations, approximately 70 percent of patients can expect their cancer to be treated effectively. However, the tumor may recur in other sites of the urinary tract as it did in 13 patients whose bladders were free of cancer. A fourteenth patient had a recurrence in the bladder. Because this disease can be very aggressive in its behavior, careful follow-up is necessary. Deaths from cancer occurred in 5 of 48 patients (10.4%) despite extensive surgical therapy and chemotherapy. Three of these patients had no recurrence in the bladder after completing BCG therapy, Although the patients in this study received maintenance or booster therapy with BCG, there is no evidence that this is of any benefit. Factors which might predict local success or failure remain elusive. It is clear that patients with CIS can benefit from BCG therapy as first-line treatment. 1304 15th Street Santa Monica, California 90403 Bibliography American Cancer Society: Cancer Statistics. Bladder Cancer, 1989. Brosman SA: Experiencewith BCG in patients with superficial bladder carcinoma, J Urol 128:27 (1982). Brosman SA: The use of Bacillus Calmette-Gu6rin in the therapy of bladder carcinoma in situ, J Urol 134:a6-39 (1985). Lamm DL: BCG in carcinoma in situ and superficialbladder tumors. EOBT Genitourinary Group Monograph 5, 5:497-507 (1988). Lamm DL, et ah Southwest Ontology Group comparison of bacillus Calmette-Gu6rin and doxorubicinin the treatment and prophylaxis of superficial bladder cancer, J Urol 137: 178A (1987). Moni K, Lamm DL, and Crawford ED: A trial of bacillus Calmette-Gu6rin versus Adriamyein in superficial bladder cancer. A Southwest OneologyGroup Study, Urol Int 41. 254-289 (1986).
.~,~!iI~PLEMENTTO UROLOGY / MAY 1991 / VOLUMEXXXVII, NUMBER5
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There are three basic indications for the use of bacillus Calmette-Gu6rin (BCG) in patients with bladder cancer: to prevent recurrences; to eliminate an existing tumor in either the bladder or the upper Urinary tract; and to eliminate and prevent carcinoma in situ (CIS). The last indication is the subject of this report. Incidence of Carcinoma In Situ Over the past ten years, there has been a 35 percent increase in the number of new eases of bladder cancer, an 11.5 percent increase in deaths due to bladder cancer, and a 28.5 percent increase in the probability that transitional cell eareinorna (TCC) will develop in an individual born in 1985. Careinorna in situ represents 5-10 percent of all TCC, and its recognition is increasing. The reasons for this are not dear, but they are probably related to the way pathologists make the diagnosis. For some years, pathologists have disagreed about the histopathologic features of carcinoma in situ. Grades 1, 2, and 3 (G1, G2, or G3) have been assigned according to the degree of cellular atypia or dysplasia. The inclusion of patients with atypia or dysplasia may have biased much of the earlier data and is probably continuing to do so. Whether or not pathologists will be able to agree on these histologic distinctions is not clear, but when responses to BCG treatment are studied, those with lower grades of disease tend to have good responses to BCG. Effect of BCG on Carcinoma In Situ
Material and methods The study population in this series comprised 48 patients who had unequivocal CIS. Those with dysplasia of any degree were excluded. Patients were observed for a mean duration of thirty-five months. A total of 29 patients had a combination of TCC and CIS. Chemotherapy had previously been administered in 7 patients.
12
Patients underwent twelve instillati. tion therapy. This was followed by o n e tenanee therapy consisting of monthly The induction phase did not neeessar twelve consecutive weeks of treatmen ment sometimes was interrupted for weeks because of severe bladder reaetic infection, or because the patient or doe1 town. The purpose of the induct an inflammatory/immunolo: der. It is likely that once this the maximum BCG effect how many weeks of therapy the maximum response rem~ bly varies from patient to p Patients underwent eysto biopsy, every six weeks fo: weeks, and every three to six years. Biopsy specimens wer with the patients under eft none at all. A total of three ( mens of suspicious areas epithdium were obtained. Results (Table I) Forty patients (83 %) eomp] phase, and normal biopsy speeir complete response to BCG thei from 28 (70 %) patients. This f5 sistent with the results of other patients, 7 received double-dose no indieation of an inflammato patients after the first six instill meditation was increased to t~ BCG in 50 mL of saline. The tained in the bladder for two hc this weekly treatment was ton flammatory response was detec required two to four instillatiol treatments, 5 patients had a 50 1
SUPPLEMENT TO UROLOGY / MAY1991 / VOLUMExXXVIIiI ~ { ~
-
~se to B C G therapy in 40 patients in situ w h o completed protocol
No. of Pts. (%)
ponse complete response) 1 response)$ eks of therapy ~nse) response
28* (70) 5 (12.5) 3:~ (7.5) 31 (77.5)
(28 ÷ 3) esponse or progression 9 (22.5) disease (2 + 7) ~eyenpatients received double-dosetherapy. i~tial response" signifies 50 percent reduction in tumor ~WOpatients received double-dosetherapy.
~0r area. Of these patients, 3 subsequently had evidence of carcinoma in biopsy specimens. Eight patients did not complete the induction iase but had three to eight instillations each. Comte responses were observed in 3 patients, and 5 ~:no response. In total, 34/48 (70.8%)patients iieved complete responses, regardless of whether not they completed the protocol. ~he observation that 3 patients who did not com~!~te the protocol h a d normal" biopsy results, eas some patients required more than twelve ~ l l a t i o n s to achieve a complete response, lends ~}~dence to the belief that the duration of effective ~CG therapy varies from patient to patient. ~!~;Disease::recurred in 14 of the 34 (41% ) tumor-free ~afi~nts. Most of these tumors recurred within the ~S~,year to year and a half after treatment. ~!!::he sites of recurrence demonstrate the insidious~ : ~ o f bladder cancer. Tumors recurred in the upper ~iS~ary tract or the ureter in 6 patients, in the prosurethra or within the prostate in 7 patients, ~ d in the bladder in 1 patient who had a G3 TCC ~'~i~i,thoutevidence of associated CIS. "°"~!i The~:i: 14 patients in whom disease subsequently red e d despite normal biopsy findings, initially were ~anaKed in a variety of ways . In 8 p atients c Y sto~.~ :~Pr0stateetomy was performed; in 4, nephroureterec~y and cystectomy; in 1, transurethral resection ~ d additional BCG therapy; and in 3, infusion of ~ C C into the kidneys Of the 14, 3 patients ulti-
~h~r
mately died of cancer, and 6 have had positive cytologic findings for extended periods of time. Of the 14 patients who did not complete the protocol or demonstrate a response to BCG, 9 had cysteetomy with prostateetomy and 5 received a combination of chemotherapy or radiation therapy. Two of these 14 patients ultimately died of cancer, and positive cytologic findings persist in 7. Conclusion The effectiveness of intravesieal instillations of BCG in the eradication of CIS has been demonstrated in this and other studies. Using a variety of protocols with six to twelve instillations, approximately 70 percent of patients can expect their cancer to be treated effectively. However, the tumor may recur in other sites of the urinary tract as it did in 13 patients whose bladders were free of cancer. A fourteenth patient had a recurrence in the bladder. Because this disease can be very aggressive in its behavior, careful follow-up is necessary. Deaths from cancer occurred in 5 of 48 patients (10.4%) despite extensive surgical therapy and chemotherapy. Three of these patients had no recurrence in the bladder after completing BCG therapy, Although the patients in this study received maintenance or booster therapy with BCG, there is no evidence that this is of any benefit. Factors which might predict local success or failure remain elusive. It is clear that patients with CIS can benefit from BCG therapy as first-line treatment. 1304 15th Street Santa Monica, California 90403 Bibliography American Cancer Society: Cancer Statistics. Bladder Cancer, 1989. Brosman SA: Experiencewith BCG in patients with superficial bladder carcinoma, J Urol 128:27 (1982). Brosman SA: The use of Bacillus Calmette-Gu6rin in the therapy of bladder carcinoma in situ, J Urol 134:a6-39 (1985). Lamm DL: BCG in carcinoma in situ and superficialbladder tumors. EOBT Genitourinary Group Monograph 5, 5:497-507 (1988). Lamm DL, et ah Southwest Ontology Group comparison of bacillus Calmette-Gu6rin and doxorubicinin the treatment and prophylaxis of superficial bladder cancer, J Urol 137: 178A (1987). Moni K, Lamm DL, and Crawford ED: A trial of bacillus Calmette-Gu6rin versus Adriamyein in superficial bladder cancer. A Southwest OneologyGroup Study, Urol Int 41. 254-289 (1986).
.~,~!iI~PLEMENTTO UROLOGY / MAY 1991 / VOLUMEXXXVII, NUMBER5
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