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Clinicopathological Evaluation of Repeated Courses of Intravesical Bacillus Calmette-Guerin Instillation for Preventing Recurrence of Initially Resistant Superficial Bladder Cancer
0022-5347/96/1563-0967$03.00/0 "HE J O U R N A L OF UROLOGY
Vol. 156,967-971,September 1996 Printed in U.S.A.
Copynght 0 1996 by AMERICAN UROLOCICAL ASSOCIATION, INC
CLINICOPATHOLOGICAL EVALUATION OF REPEATED COURSES OF INTRAVESICAL BACILLUS CALMETTE-GUERIN INSTILLATION FOR PREVENTING RECURRENCE OF INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER TAKEHIKO OKAMURA,* KEXICHI TOZAWA, YASUYUKI YAMADA, HIROSHI SAKAGAMI, KOUSUKE UEDA AND KENJIRO KOHRI From the Department of Urology, Nagoya City University Medical School, Nagoya and Anjo-kosei Hospital, Anjo, Japan
ABSTRACT
Purpose: The efficacy of repeated courses of intravesical bacillus Calmette-Guerin (BCG) for superficial bladder cancer was assessed with particular attention to initially resistant cases. Materials and Methods: A total of 75 patients with stages T a to T l b superficial transitional cell bladder carcinoma received 6 weekly instillations of 80 mg. Tokyo strain BCG in 40 ml. saline followed by 6 instillations a t monthly intervals. If tumors recurred, another course of treatment was given with surgery. Results: Of 17 patients (22.7%)with recurrent tumor a t followup periods of u p to 84 months 12 received a n additional course of BCG instillations according to the same protocol after transurethral resection of bladder tumors, and 10 (83.3%)showed no further recurrence with or without additional surgery and BCG therapy after a median followup of 42.9 months. Thus, the overall success rate with this approach was 90.7% (68 of 75 patients). Comparison of patients with and without recurrence revealed a significant difference in number of tumors before therapy ( p <0.05), and a pronounced tendency (p = 0.00507) for recurrence after prior systemic chemotherapy or intravesical instillation. Conclusions: The results suggest that u p to 3 courses of repeated intravesical instillation of BCG are effective even for cases that initially did not respond, and that best results may be achieved if no other prior chemotherapy has been attempted. KEY WORDS:BCG vaccine, immunotherapy, bladder neoplasms
In 1976 bacillus Calmette-Guerin (BCG) was first used intravesically in patients with superficial bladder cancer.' Since then, this therapeutic approach has become popular, and it is now widely used to prevent recurrent superficial bladder cancer after transurethral resection of bladder tumors, as well as for therapy of carcinoma in situ.2-6 Direct anticarcinogenic effects against superficial bladder tumors have been reported,7 and BCG bladder instillation has become standard for therapeutic and prophylactic control of superficial bladder cancers. However, posttreatment recurrence is not uncommon, and it is important to investigate the initially noneffective cases to ascertain the feasibility of repeated2 or multiple courses of therapy as advocated by some: and also what pre-BCG variables might exert an influence on the success of treatment. There are serious complications in some cases, even leading t o fatalities after BCG therapy,839 and it is clearly of interest to determine any relationship between susceptibility to adverse reactions and treatment success. Therefore, we evaluated a series of patients given intravesical BCG, usually prophylactically after surgery, compared to those who had recurrence after effective therapy to determine any clinical and pathological differences. PATIENTS AND METHODS
From March 1989 to August 1994 we treated 75 patients 33 to 85 years old (average age 65.6) with superficial bladder
tumors using intravesical Tokyo 172 strain BCG instillations. Informed consent was obtained from all patients. There were 67 men and 8 women, for a male-to-female ratio of 8.4:l. All patients had a history of multifocal or recurrent papillary transitional cell carcinoma (stage Ta in 18, stage Tla in 41 and stage Tlb in 10) without any other concurrent malignancies or active tuberculosis infection. BCG (80 mg. suspended in 40 ml. physiological saline) was instilled at 1-weekintervals for 6 weeks and then a t 1-month intervals for up to 6 months. The dose was selected based on results of extensive studies by Akaza et a1.10,11In some cases treatment was concluded earlier but all patients received at least 6 instillations. Patients were asked to refrain from urination when possible within 2 hours a h r drug instillation, and they were monitored for bladder irritation, temperature and other clinical symptoms. A tuberculin reaction, blood examinations, chest x-rays, cystoscopy and urinary cytology were performed at least before, and after 6 and 12 instillations. Followup was done on a regular weekly basis. If disease recurred surgery was performed followed by another course of BCG when applicable (table 1). Adjuvant chemotherapeutic agents were administered in some cases (table 2). Further recurrence was treated with surgery and another course of BCG (up to 4 times). Surgically resected material was routinely fixed in 10% buffered formalin, embedded in paraffin, stained with hematoxylin and eosin, and sectioned for histopathological analysis. Tumor grade and stage were assessed according to the general rules for clinical and pathological studies on bladder cancer. For statistical comparisons, data were analyzed US-
Accepted for publication March 29, 1996. * Requests for reprints: Department of Urology, Nagoya City University Medical School, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467, Japan. 967
BACILLUS CALMETTE-GUERIN FOR INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER
969
TABLE2 . Further treatments and prognosis of recurrent cases afrer BCG intravesical instillation BCG
Pt.No.
Operation (No.)
No. Instillations
Dosage (mg.)
Other Treatments
1 8 9 10 17 21 23
Transurethral resection of bladder tumor Transurethral resection of bladder tumor (2) Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor (2) Transurethral resection of bladder tumor Transurethral resection of bladder tumor (3), total cystectomy Transurethral resection of bladder tumor Total cystectomy
18 9 12 12 20 12 9
40 80 80 80 80 80 80
-
No No No
-
No
5-Fluorouracil Tegafur-uracil, systemic chemotherapy
No No No
5
80
25 30 33 39 47 51 52 54
-
0 5 0 12
Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor Total cystectomy Transurethral resection of bladder tumor (2). total cystectomy 74 Transurethral resection of bladder tumor (3) * Due to aortic aneurysm. t Intravesical instillation.
No
-
No
80
Tegafur-uracil
Yes bladder
Alive (17)
0
-
0
3
R.currenl oasa8(17) Hyperlh?rmla(l) I
I Total cyslbctomy(2)
I
Non-lumor daalh
No raaurranai(8)
I
I
I I
A
No raourrenca(2)
Intrwbslcal Ins1111allon of o l h w drugS(1) TUR-El
TUR-EI(~)
Hyperthermia
-
5-Fluorouracil, intra-arterial (liver) -
-
No No Yes bladder No Yes liver
No No
TABLE3. Comparison of patients with and without recurrence undergoing intravesical BCG instillation 58 Pts. Without 17 pts. With Recurrence
Disease recurred in 17 of the 75 patients (22.7%).Individual data for times to recurrence are shown in table 1, with followup for nonrecurrent cases ranging from 8 to 73 months (average 47.2). There were 13 men and 4 women with, and 54 men and 4 women without recurrence (male-to-female ratios 3.3:l and 13.5:1, respectively, not significant). Of the 17 patients 16 underwent additional surgery, including transurethral resection of bladder tumors in 14 and total cystectomy in 2. A second course of BCG instillations according to the same protocol was given to 12 of the former 14 patients (see figure). Disease recurred again in 4 patients, who underwent transurethral resection of bladder tumors with another course of BCG instillations. There were no further recurrences in 10 patients (83.3%),while 2 failed to respond to additional treatment. Details of the treatment schedules for each individual with recurrence are shown in table 2. The recurrence and no recurrence groups are compared in table 3. No significant differences in average age, sex ratio, and interval between tumor diagnosis and initial BCG treatment were noted. While prior treatments did not significantly differ between the 2 groups, comparison revealed a pronounced tendency for an association with elevated risk of recurrence (4 of 17 versus
Tumor damlh
-
80 80
8
Alive (84) Alive (68) Alive (53) Alive (33) Alive (79) Alive (44) Alive (66)
5-Fluorouracil Rrarubicint
-
RESULTS
TUR-El(14)
-
80
ing computer software, with p <0.05 considered statistically significant.
I
-
Prognosis (mos.)
Alive (50) Alive (56) Dead (50)' Alive (8) Dead (16) Alive (64) Alive (76) Alive (63) Alive (30)
-
0
Tumor
Recurrence
65.5 (3&85) Av. pt. age (range) 65.8 (33-84) 13:4 54:4 Sex ratio (M:F) 15.2 (0.5-114.0) Av. mos. from diagnosis to treat21.1 (0.5-125.5) ment before BCG (range) No. before treatment (5%): 4 (6.9) Systemic chemotherapy 4 (23.5) 4 (6.9) Intravesical instillation* 4 (23.5) (11.8) 0 (0.0) 2 Hyperthennia 56 (96.6) Transurethral resection of blad15 (88.2) der tumor 2 (3.4) Total nephroureteredomy 3 (17.6) 1 (5.9) 0 (0.0) Partial cystectomy 0.6 (0-6) Av. recurrent episodes before 1.5 (0-9) BCG (range) No. history of tuberculosis (%) 0 (0.0) 3 (5.2) No. side effects (5%): Bladder imtation 6 (35.3) 30 (51.7) (11.8) 9 (15.5) Fever (38C or more) 2 Contracted bladderhberculosis 1 (5.9) 1 (1.7) There were no significant differences. * Doxorubicin, mitomycin C plus cytosine arabinoside, cytosine arabinoside or epirubicin.
4 of 58, p = 0.0507) for patients receiving other intravesical chemotherapeutic agents, as well as for those on other systemic chemical pretreatment regimens. There was no significant correlation between history of recurrences or tuberculosis and likelihood of recurrence. Side effects were noted equally in both groups (table 3). Grading and staging of initial lesions, as well as number of tumors at diagnosis immediately before BCG therapy are summarized in table 4. No significant variation between the groups was noted for tumor grade or stage. However, the no recurrence group had significantly fewer tumors before BCG treatment. Comparison of tuberculin reactions revealed an increase after 6 and 12 treatments in the majority of cases in both groups (data not shown).
Total cy!lactomY
TUR-EI(2)
I
Course of recurrent caws after intravesical instillation of BCG. TUR-Bt,transurethral resection of bladder tumors.
DISCUSSION
Our study provides clear evidence that repeated courses of intravesical BCG provide an effective and safe approach to control initially recurrent superficial bladder cancer. In addition, and most importantly, we found that prior chemotherapy may exert a negative influence on the success rate. No
970
BACILLUS CALMETTE-GUERIN FOR INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER
TABLE4. Histopathological comparison between patients with and without recurrence No. Without Recurrence
Grade 1 2 3 Stage: Ta Tla Tlb No. tumors? 1 2-5 6 9 10 or More * p c0.05.
No. With Recurrence
16 32 10
5 8 3
16 29 9
2 12 1
23 23 7 6
1
a
2 6
association between side effects of BCG and the predilection for recurrence was evident. The initial positive response rate of 77.3% in our series generally agrees with that in the literature. Our rate was somewhat greater than that reported by Kavoussi et al, who showed that a single 6-week treatment course is less effective than 2,6-week courses,4 and almost exactly the same as the 78% rate described by Sarosdy and Lamm.5 Our results also generally agree with those of Akaza et a1 using the same Tokyo strain.7 The positive response of the majority of initially resistant cases was similar to that of previous findings, with the increase from an initial success rate of 78 to 89% reported by Sarosdy and Lamm5 being directly comparable to our final 90.7% rate. Since some of our patients without recurrence have been followed for 73 months (average almost 4 years), our results also provide strong support for the previous conclusion,2 based on followup for just more than 1 year, that the beneficial response is durable rather than simply being a delay until eventual recurrence. In a 10-year followup study, Herr et a1 found that approximately a third of patients remained free of tumors, and that most recurrence or progression was within the first 5 years.12 Considering the observed efficacy, our data suggest that a maximum of 3 courses of the described protocol can be recommended. With regard to progression of tumors after BCG therapy, which is used as an argument for limitation of the number of courses of intravesical BCG? we found that subsequent tumors occurred no more frequently in patients with increased than with decreased grade or stage of malignancy. In fact, the general trend was for no change (table 1).Progression was also rare in the report of Akaza et al,7 and of the stage T1 lesions investigated by Cookson and Sarosdy only 7% progressed to stage T2.6 Even if there is some risk for more advanced lesions with repeated therapy, this approach may still be preferable to no treatment at all. Of the available measures, BCG treatment appears to offer the best promise. Many of the anticancer drugs that might alternatively be applied are, in fact, carcinogenic.13 Another point that must be considered in this context is the strain of bacteria used. The Tokyo strain used in our study may provide good protection against recurrence and progre~sion.~.ll This area clearly warrants further investigation. Another factor that should be investigated in the future is the possible hazard influence of saline, shown experimentally to promote bladder lesions in rats after treatment with N-butyl-N-(4-hydroxybutyl) nitrosamine14 and its replacement by distilled water. Distilled water has been shown to be a more effective medium for BCG against exfoliated bladder cells in vitro.15 However, it should be remembered that other factors may operate in vivo, as suggested by the improved attachment of BCG to bladder epithelium with saline administration.16 The side effects of BCG experienced in our series agree with those reported previously?, l7 including bladder irritation and a subsequent contracted bladder. Pneumonitis and
hepatitis, which have been reported in only 0.9% of cases,17 were not detected in our series. Similarly, sepsis as described by Rawls et a1 in a large series Of Casess was not found. However, they cautioned that BCG should not be given if there is severe cystitis. None of our patients had such a serious complaint. No relationship between side effects found in our study and the propensity for recurrence could be established. Thus, minor complications may not be a contraindication for continuing treatment. Clearly, this factor will depend on the individual case and requires careful consideration. However, adverse effects of prior chemotherapy were strongly indicated by our results, which must be stressed. The association with recurrence was not significant (p = 0.00507) but appeared similar for intravesical and systemic instillation of agents. A positive link was suggested even with hyperthermia therapy. It is well known that multiple drug resistance can be induced readily in tumors by selection of sublines with resistant properties. Presently, the mechanisms of how exposure to a chemotherapeutic agent influences response to BCG are not clear but our results suggest that further studies in this area are warranted. It should be mentioned that doxorubicin can exert promoting effects on experimental bladder tumors. l4 The most important finding in our study is that multiple courses of BCG are feasible for control of superficial bladder cancer. Furthermore, consideration should be given to this approach before recourse to other therapeutic procedures that might, indeed, exert promotional effects. Another possibility is that BCG should be applied in combination with chemotherapeutic agents, since beneficial effects have already been described for such therapy in experimental animals.18 A recent report by the Finnbladder group suggested that alternating mitomycin C and BCG provides effective control of carcinoma in situ with only few side effects.19 Confirmation of this finding by the ongoing phase 11 study of sequential mitomycin C and BCG for control of bladder lesions as mentioned by Balemans et a1,20and the randomized multicenter trial begun in Scandinavian countries for carcinoma in situ noted by Rintala et al,19 will obviously stimulate more such investigations in this promising area. CONCLUSIONS
Our study reveals firm evidence that repeated courses of BCG associated with surgery provide a reliable approach to control of superficial bladder cancer, with a success rate of more than 90%. Comparison of patients who did and did not have recurrence indicated a significant adverse influence of prior intravesical instillation, which suggests that BCG should be the initial choice in future. REFERENCES
A.,Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116 180, 1976. 2. Haaff, E. O., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: T w o courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136 820, 1986. 3. Catalona, W.J.,Hudson, M. A,, Gillen, D. P., Andriole, G. L. and Ratliff, T. L.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 137: 220, 1987. 4. Kavoussi, L. R., Torrence, R. J., Gillen, D. P., Hudson, M. A., Haaff, E. O., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Results of 6 weekly intravesical bacillus Calmette-Guerin instillations on the treatment of superficial bladder tumors. J. Urol., 139 935, 1988. 5. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142 719, 1989. 6. Cookson, M. S. and Sarosdy, M. F.: Management of stage “1 superficial bladder cancer with intravesical bacillus CalmetteGuerin therapy. J. Urol., 148 797, 1992. 1. Morales,
971
BACILLUS CALMETTE-GUERIN FOR INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER
7. Akaza, H., Hinotsu, S., Aso, Y., Kakizoe, T. and Koiso, K: Badrugs-a survey. J . Clin. Hosp. Pharm., 1 0 223,1985. cillus Calmette-Guerin treatment of existing papillary bladder 14. Ohtani, M., Fukushima, S., Okamura, T., Sakata, T., Ito, N., cancer and carcinoma in situ of the bladder. Four-year results. Koiso, K and Niijima, T.: Effects of intravesical instillation of The Bladder Cancer BCG Study Group. Cancer, 7 5 552,1995. antitumor chemotherapeutic agents on bladder carcinogenesis in rats treated with N-but~l-N-(4-h~drox~butvl)nitrosamine. 8. Rawls, W. H., Lamm, D. L., Lowe, B. A,, Crawford, E. D., " Sarosdy, M. F., Montie, J. E., Grossman, H. B. and Scardino, Cancer, 54: 1525,1984. P. T.: Fatal sepsis following intravesical bacillus Calmette- 15. Bolkier. M.. Moskovitz. B.. Ginesin. Y. and Levin, D. R.: Effect of distilled 'water and' bacillus Calmette-GuCrin on exfoliated Guerin administration for bladder cancer. J. Urol., 144:1328, bladder tumor cells. Eur. Urol., 1 9 319,1991. 1990. 9. Smith, R. L., Alexander, R. F. and Aranda, C. P.: Pulmonaq 16. Hudson, M. A,, Catalona, W. J., Ritchey, J . K., Aslanzadeh, J., Brown, E. J. and Ratliff, T. L.: Choice of a n optimal diluent for granulomata. A complication of intravesical administration of intravesical bacillus Calmette-Guerin administration. bacillus Calmette-Guerin for superficial bladder carcinoma. J. Urol., 142: 1438,1989. Cancer, 71: 1846,1993. 10. Akaza, H., Kameyama, S., Kakizoe, T., Kojima, H., Koiso, K., 17. L a m . D. L.. Stondill. V. D.. Sto~dill.B. J. and Crispen, R. G.: Complications o? bacillus Calmitte-Guerin immundtherapy in Aso, Y. and Niijima, T.: Ablative and prophylactic effects of 1,278patients with bladder cancer. J . Urol., 135 272,1986. BCG Tokyo 172 strain for intravesical treatment in patients with superficial bladder cancer and carcinoma in situ of the 18. Steinberg, G.D., Brendler, C. B., Squire, R. A. and Isaacs, J . T.: Experimental intravesical therapy for superficial transitional bladder. Bladder Cancer BCG Study Group. Jap. J. Urol., 83: cell carcinoma in a rat bladder tumor model. J. Urol., 145 647, 183, 1992. 1991. 11. Akaza, H., Kameyama, S., Koiso, K., Kakizoe, T., Kojima, H., Umeda, T., Kawabe, K., Fujita, K., Nishimura, Y., Yokoyama, 19.Rintala, E., Jauhiainen, K, Rajala, P., Ruutu, M., Kaasinen, E., Alfthan, 0. and the Finnbladder Group.: Alternating mitomyM., Kawamura, T., Mikata, N., Ishii, Y.,Nakauchi, K, Nito, cin C and bacillus Calmette-Guerin instillation therapy for H., Kinoshita, K., Kishi, H., Hara, T., Aso, Y. and Niijima, T.: carcinoma in situ of the bladder. J. Urol., 154.2050, 1995. Analyses of the effects of intravesical bacillus CalmetteGuerin (Tokyo 172 strain) therapy of superficial bladder can- 20. Balemans, L. T., Vegt, P. D., Steerenberg, P. A., De Boer, E. C., Van Swaaij, A., De Vries, R. E., Van der Meijden, A. P. and cer. Jap. J . Urol., 80 167,1989. Den Otter, W.: Effects of sequential intravesical administra12. Herr, H. W., Wartinger, D. D., Fair, W. R. and Oettgen, H. F.: tion of mitomycin C and bacillus Calmette-Guerin on the imBacillus Calmette-Guerin therapy for superficial bladder canmune response in the guinea pig bladder. Urol. Res., 22: 239, cer: a 10-year followup. J . Urol., 147: 1020, 1992. 1994. 13. Lien, E. J. and Ou, X. C.: Carcinogenicity of some anticancer "
I
Vol. 156,967-971,September 1996 Printed in U.S.A.
Copynght 0 1996 by AMERICAN UROLOCICAL ASSOCIATION, INC
CLINICOPATHOLOGICAL EVALUATION OF REPEATED COURSES OF INTRAVESICAL BACILLUS CALMETTE-GUERIN INSTILLATION FOR PREVENTING RECURRENCE OF INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER TAKEHIKO OKAMURA,* KEXICHI TOZAWA, YASUYUKI YAMADA, HIROSHI SAKAGAMI, KOUSUKE UEDA AND KENJIRO KOHRI From the Department of Urology, Nagoya City University Medical School, Nagoya and Anjo-kosei Hospital, Anjo, Japan
ABSTRACT
Purpose: The efficacy of repeated courses of intravesical bacillus Calmette-Guerin (BCG) for superficial bladder cancer was assessed with particular attention to initially resistant cases. Materials and Methods: A total of 75 patients with stages T a to T l b superficial transitional cell bladder carcinoma received 6 weekly instillations of 80 mg. Tokyo strain BCG in 40 ml. saline followed by 6 instillations a t monthly intervals. If tumors recurred, another course of treatment was given with surgery. Results: Of 17 patients (22.7%)with recurrent tumor a t followup periods of u p to 84 months 12 received a n additional course of BCG instillations according to the same protocol after transurethral resection of bladder tumors, and 10 (83.3%)showed no further recurrence with or without additional surgery and BCG therapy after a median followup of 42.9 months. Thus, the overall success rate with this approach was 90.7% (68 of 75 patients). Comparison of patients with and without recurrence revealed a significant difference in number of tumors before therapy ( p <0.05), and a pronounced tendency (p = 0.00507) for recurrence after prior systemic chemotherapy or intravesical instillation. Conclusions: The results suggest that u p to 3 courses of repeated intravesical instillation of BCG are effective even for cases that initially did not respond, and that best results may be achieved if no other prior chemotherapy has been attempted. KEY WORDS:BCG vaccine, immunotherapy, bladder neoplasms
In 1976 bacillus Calmette-Guerin (BCG) was first used intravesically in patients with superficial bladder cancer.' Since then, this therapeutic approach has become popular, and it is now widely used to prevent recurrent superficial bladder cancer after transurethral resection of bladder tumors, as well as for therapy of carcinoma in situ.2-6 Direct anticarcinogenic effects against superficial bladder tumors have been reported,7 and BCG bladder instillation has become standard for therapeutic and prophylactic control of superficial bladder cancers. However, posttreatment recurrence is not uncommon, and it is important to investigate the initially noneffective cases to ascertain the feasibility of repeated2 or multiple courses of therapy as advocated by some: and also what pre-BCG variables might exert an influence on the success of treatment. There are serious complications in some cases, even leading t o fatalities after BCG therapy,839 and it is clearly of interest to determine any relationship between susceptibility to adverse reactions and treatment success. Therefore, we evaluated a series of patients given intravesical BCG, usually prophylactically after surgery, compared to those who had recurrence after effective therapy to determine any clinical and pathological differences. PATIENTS AND METHODS
From March 1989 to August 1994 we treated 75 patients 33 to 85 years old (average age 65.6) with superficial bladder
tumors using intravesical Tokyo 172 strain BCG instillations. Informed consent was obtained from all patients. There were 67 men and 8 women, for a male-to-female ratio of 8.4:l. All patients had a history of multifocal or recurrent papillary transitional cell carcinoma (stage Ta in 18, stage Tla in 41 and stage Tlb in 10) without any other concurrent malignancies or active tuberculosis infection. BCG (80 mg. suspended in 40 ml. physiological saline) was instilled at 1-weekintervals for 6 weeks and then a t 1-month intervals for up to 6 months. The dose was selected based on results of extensive studies by Akaza et a1.10,11In some cases treatment was concluded earlier but all patients received at least 6 instillations. Patients were asked to refrain from urination when possible within 2 hours a h r drug instillation, and they were monitored for bladder irritation, temperature and other clinical symptoms. A tuberculin reaction, blood examinations, chest x-rays, cystoscopy and urinary cytology were performed at least before, and after 6 and 12 instillations. Followup was done on a regular weekly basis. If disease recurred surgery was performed followed by another course of BCG when applicable (table 1). Adjuvant chemotherapeutic agents were administered in some cases (table 2). Further recurrence was treated with surgery and another course of BCG (up to 4 times). Surgically resected material was routinely fixed in 10% buffered formalin, embedded in paraffin, stained with hematoxylin and eosin, and sectioned for histopathological analysis. Tumor grade and stage were assessed according to the general rules for clinical and pathological studies on bladder cancer. For statistical comparisons, data were analyzed US-
Accepted for publication March 29, 1996. * Requests for reprints: Department of Urology, Nagoya City University Medical School, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467, Japan. 967
BACILLUS CALMETTE-GUERIN FOR INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER
969
TABLE2 . Further treatments and prognosis of recurrent cases afrer BCG intravesical instillation BCG
Pt.No.
Operation (No.)
No. Instillations
Dosage (mg.)
Other Treatments
1 8 9 10 17 21 23
Transurethral resection of bladder tumor Transurethral resection of bladder tumor (2) Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor (2) Transurethral resection of bladder tumor Transurethral resection of bladder tumor (3), total cystectomy Transurethral resection of bladder tumor Total cystectomy
18 9 12 12 20 12 9
40 80 80 80 80 80 80
-
No No No
-
No
5-Fluorouracil Tegafur-uracil, systemic chemotherapy
No No No
5
80
25 30 33 39 47 51 52 54
-
0 5 0 12
Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor Transurethral resection of bladder tumor Total cystectomy Transurethral resection of bladder tumor (2). total cystectomy 74 Transurethral resection of bladder tumor (3) * Due to aortic aneurysm. t Intravesical instillation.
No
-
No
80
Tegafur-uracil
Yes bladder
Alive (17)
0
-
0
3
R.currenl oasa8(17) Hyperlh?rmla(l) I
I Total cyslbctomy(2)
I
Non-lumor daalh
No raaurranai(8)
I
I
I I
A
No raourrenca(2)
Intrwbslcal Ins1111allon of o l h w drugS(1) TUR-El
TUR-EI(~)
Hyperthermia
-
5-Fluorouracil, intra-arterial (liver) -
-
No No Yes bladder No Yes liver
No No
TABLE3. Comparison of patients with and without recurrence undergoing intravesical BCG instillation 58 Pts. Without 17 pts. With Recurrence
Disease recurred in 17 of the 75 patients (22.7%).Individual data for times to recurrence are shown in table 1, with followup for nonrecurrent cases ranging from 8 to 73 months (average 47.2). There were 13 men and 4 women with, and 54 men and 4 women without recurrence (male-to-female ratios 3.3:l and 13.5:1, respectively, not significant). Of the 17 patients 16 underwent additional surgery, including transurethral resection of bladder tumors in 14 and total cystectomy in 2. A second course of BCG instillations according to the same protocol was given to 12 of the former 14 patients (see figure). Disease recurred again in 4 patients, who underwent transurethral resection of bladder tumors with another course of BCG instillations. There were no further recurrences in 10 patients (83.3%),while 2 failed to respond to additional treatment. Details of the treatment schedules for each individual with recurrence are shown in table 2. The recurrence and no recurrence groups are compared in table 3. No significant differences in average age, sex ratio, and interval between tumor diagnosis and initial BCG treatment were noted. While prior treatments did not significantly differ between the 2 groups, comparison revealed a pronounced tendency for an association with elevated risk of recurrence (4 of 17 versus
Tumor damlh
-
80 80
8
Alive (84) Alive (68) Alive (53) Alive (33) Alive (79) Alive (44) Alive (66)
5-Fluorouracil Rrarubicint
-
RESULTS
TUR-El(14)
-
80
ing computer software, with p <0.05 considered statistically significant.
I
-
Prognosis (mos.)
Alive (50) Alive (56) Dead (50)' Alive (8) Dead (16) Alive (64) Alive (76) Alive (63) Alive (30)
-
0
Tumor
Recurrence
65.5 (3&85) Av. pt. age (range) 65.8 (33-84) 13:4 54:4 Sex ratio (M:F) 15.2 (0.5-114.0) Av. mos. from diagnosis to treat21.1 (0.5-125.5) ment before BCG (range) No. before treatment (5%): 4 (6.9) Systemic chemotherapy 4 (23.5) 4 (6.9) Intravesical instillation* 4 (23.5) (11.8) 0 (0.0) 2 Hyperthennia 56 (96.6) Transurethral resection of blad15 (88.2) der tumor 2 (3.4) Total nephroureteredomy 3 (17.6) 1 (5.9) 0 (0.0) Partial cystectomy 0.6 (0-6) Av. recurrent episodes before 1.5 (0-9) BCG (range) No. history of tuberculosis (%) 0 (0.0) 3 (5.2) No. side effects (5%): Bladder imtation 6 (35.3) 30 (51.7) (11.8) 9 (15.5) Fever (38C or more) 2 Contracted bladderhberculosis 1 (5.9) 1 (1.7) There were no significant differences. * Doxorubicin, mitomycin C plus cytosine arabinoside, cytosine arabinoside or epirubicin.
4 of 58, p = 0.0507) for patients receiving other intravesical chemotherapeutic agents, as well as for those on other systemic chemical pretreatment regimens. There was no significant correlation between history of recurrences or tuberculosis and likelihood of recurrence. Side effects were noted equally in both groups (table 3). Grading and staging of initial lesions, as well as number of tumors at diagnosis immediately before BCG therapy are summarized in table 4. No significant variation between the groups was noted for tumor grade or stage. However, the no recurrence group had significantly fewer tumors before BCG treatment. Comparison of tuberculin reactions revealed an increase after 6 and 12 treatments in the majority of cases in both groups (data not shown).
Total cy!lactomY
TUR-EI(2)
I
Course of recurrent caws after intravesical instillation of BCG. TUR-Bt,transurethral resection of bladder tumors.
DISCUSSION
Our study provides clear evidence that repeated courses of intravesical BCG provide an effective and safe approach to control initially recurrent superficial bladder cancer. In addition, and most importantly, we found that prior chemotherapy may exert a negative influence on the success rate. No
970
BACILLUS CALMETTE-GUERIN FOR INITIALLY RESISTANT SUPERFICIAL BLADDER CANCER
TABLE4. Histopathological comparison between patients with and without recurrence No. Without Recurrence
Grade 1 2 3 Stage: Ta Tla Tlb No. tumors? 1 2-5 6 9 10 or More * p c0.05.
No. With Recurrence
16 32 10
5 8 3
16 29 9
2 12 1
23 23 7 6
1
a
2 6
association between side effects of BCG and the predilection for recurrence was evident. The initial positive response rate of 77.3% in our series generally agrees with that in the literature. Our rate was somewhat greater than that reported by Kavoussi et al, who showed that a single 6-week treatment course is less effective than 2,6-week courses,4 and almost exactly the same as the 78% rate described by Sarosdy and Lamm.5 Our results also generally agree with those of Akaza et a1 using the same Tokyo strain.7 The positive response of the majority of initially resistant cases was similar to that of previous findings, with the increase from an initial success rate of 78 to 89% reported by Sarosdy and Lamm5 being directly comparable to our final 90.7% rate. Since some of our patients without recurrence have been followed for 73 months (average almost 4 years), our results also provide strong support for the previous conclusion,2 based on followup for just more than 1 year, that the beneficial response is durable rather than simply being a delay until eventual recurrence. In a 10-year followup study, Herr et a1 found that approximately a third of patients remained free of tumors, and that most recurrence or progression was within the first 5 years.12 Considering the observed efficacy, our data suggest that a maximum of 3 courses of the described protocol can be recommended. With regard to progression of tumors after BCG therapy, which is used as an argument for limitation of the number of courses of intravesical BCG? we found that subsequent tumors occurred no more frequently in patients with increased than with decreased grade or stage of malignancy. In fact, the general trend was for no change (table 1).Progression was also rare in the report of Akaza et al,7 and of the stage T1 lesions investigated by Cookson and Sarosdy only 7% progressed to stage T2.6 Even if there is some risk for more advanced lesions with repeated therapy, this approach may still be preferable to no treatment at all. Of the available measures, BCG treatment appears to offer the best promise. Many of the anticancer drugs that might alternatively be applied are, in fact, carcinogenic.13 Another point that must be considered in this context is the strain of bacteria used. The Tokyo strain used in our study may provide good protection against recurrence and progre~sion.~.ll This area clearly warrants further investigation. Another factor that should be investigated in the future is the possible hazard influence of saline, shown experimentally to promote bladder lesions in rats after treatment with N-butyl-N-(4-hydroxybutyl) nitrosamine14 and its replacement by distilled water. Distilled water has been shown to be a more effective medium for BCG against exfoliated bladder cells in vitro.15 However, it should be remembered that other factors may operate in vivo, as suggested by the improved attachment of BCG to bladder epithelium with saline administration.16 The side effects of BCG experienced in our series agree with those reported previously?, l7 including bladder irritation and a subsequent contracted bladder. Pneumonitis and
hepatitis, which have been reported in only 0.9% of cases,17 were not detected in our series. Similarly, sepsis as described by Rawls et a1 in a large series Of Casess was not found. However, they cautioned that BCG should not be given if there is severe cystitis. None of our patients had such a serious complaint. No relationship between side effects found in our study and the propensity for recurrence could be established. Thus, minor complications may not be a contraindication for continuing treatment. Clearly, this factor will depend on the individual case and requires careful consideration. However, adverse effects of prior chemotherapy were strongly indicated by our results, which must be stressed. The association with recurrence was not significant (p = 0.00507) but appeared similar for intravesical and systemic instillation of agents. A positive link was suggested even with hyperthermia therapy. It is well known that multiple drug resistance can be induced readily in tumors by selection of sublines with resistant properties. Presently, the mechanisms of how exposure to a chemotherapeutic agent influences response to BCG are not clear but our results suggest that further studies in this area are warranted. It should be mentioned that doxorubicin can exert promoting effects on experimental bladder tumors. l4 The most important finding in our study is that multiple courses of BCG are feasible for control of superficial bladder cancer. Furthermore, consideration should be given to this approach before recourse to other therapeutic procedures that might, indeed, exert promotional effects. Another possibility is that BCG should be applied in combination with chemotherapeutic agents, since beneficial effects have already been described for such therapy in experimental animals.18 A recent report by the Finnbladder group suggested that alternating mitomycin C and BCG provides effective control of carcinoma in situ with only few side effects.19 Confirmation of this finding by the ongoing phase 11 study of sequential mitomycin C and BCG for control of bladder lesions as mentioned by Balemans et a1,20and the randomized multicenter trial begun in Scandinavian countries for carcinoma in situ noted by Rintala et al,19 will obviously stimulate more such investigations in this promising area. CONCLUSIONS
Our study reveals firm evidence that repeated courses of BCG associated with surgery provide a reliable approach to control of superficial bladder cancer, with a success rate of more than 90%. Comparison of patients who did and did not have recurrence indicated a significant adverse influence of prior intravesical instillation, which suggests that BCG should be the initial choice in future. REFERENCES
A.,Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116 180, 1976. 2. Haaff, E. O., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: T w o courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136 820, 1986. 3. Catalona, W.J.,Hudson, M. A,, Gillen, D. P., Andriole, G. L. and Ratliff, T. L.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 137: 220, 1987. 4. Kavoussi, L. R., Torrence, R. J., Gillen, D. P., Hudson, M. A., Haaff, E. O., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Results of 6 weekly intravesical bacillus Calmette-Guerin instillations on the treatment of superficial bladder tumors. J. Urol., 139 935, 1988. 5. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142 719, 1989. 6. Cookson, M. S. and Sarosdy, M. F.: Management of stage “1 superficial bladder cancer with intravesical bacillus CalmetteGuerin therapy. J. Urol., 148 797, 1992. 1. Morales,
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7. Akaza, H., Hinotsu, S., Aso, Y., Kakizoe, T. and Koiso, K: Badrugs-a survey. J . Clin. Hosp. Pharm., 1 0 223,1985. cillus Calmette-Guerin treatment of existing papillary bladder 14. Ohtani, M., Fukushima, S., Okamura, T., Sakata, T., Ito, N., cancer and carcinoma in situ of the bladder. Four-year results. Koiso, K and Niijima, T.: Effects of intravesical instillation of The Bladder Cancer BCG Study Group. Cancer, 7 5 552,1995. antitumor chemotherapeutic agents on bladder carcinogenesis in rats treated with N-but~l-N-(4-h~drox~butvl)nitrosamine. 8. Rawls, W. H., Lamm, D. L., Lowe, B. A,, Crawford, E. D., " Sarosdy, M. F., Montie, J. E., Grossman, H. B. and Scardino, Cancer, 54: 1525,1984. P. T.: Fatal sepsis following intravesical bacillus Calmette- 15. Bolkier. M.. Moskovitz. B.. Ginesin. Y. and Levin, D. R.: Effect of distilled 'water and' bacillus Calmette-GuCrin on exfoliated Guerin administration for bladder cancer. J. Urol., 144:1328, bladder tumor cells. Eur. Urol., 1 9 319,1991. 1990. 9. Smith, R. L., Alexander, R. F. and Aranda, C. P.: Pulmonaq 16. Hudson, M. A,, Catalona, W. J., Ritchey, J . K., Aslanzadeh, J., Brown, E. J. and Ratliff, T. L.: Choice of a n optimal diluent for granulomata. A complication of intravesical administration of intravesical bacillus Calmette-Guerin administration. bacillus Calmette-Guerin for superficial bladder carcinoma. J. Urol., 142: 1438,1989. Cancer, 71: 1846,1993. 10. Akaza, H., Kameyama, S., Kakizoe, T., Kojima, H., Koiso, K., 17. L a m . D. L.. Stondill. V. D.. Sto~dill.B. J. and Crispen, R. G.: Complications o? bacillus Calmitte-Guerin immundtherapy in Aso, Y. and Niijima, T.: Ablative and prophylactic effects of 1,278patients with bladder cancer. J . Urol., 135 272,1986. BCG Tokyo 172 strain for intravesical treatment in patients with superficial bladder cancer and carcinoma in situ of the 18. Steinberg, G.D., Brendler, C. B., Squire, R. A. and Isaacs, J . T.: Experimental intravesical therapy for superficial transitional bladder. Bladder Cancer BCG Study Group. Jap. J. Urol., 83: cell carcinoma in a rat bladder tumor model. J. Urol., 145 647, 183, 1992. 1991. 11. Akaza, H., Kameyama, S., Koiso, K., Kakizoe, T., Kojima, H., Umeda, T., Kawabe, K., Fujita, K., Nishimura, Y., Yokoyama, 19.Rintala, E., Jauhiainen, K, Rajala, P., Ruutu, M., Kaasinen, E., Alfthan, 0. and the Finnbladder Group.: Alternating mitomyM., Kawamura, T., Mikata, N., Ishii, Y.,Nakauchi, K, Nito, cin C and bacillus Calmette-Guerin instillation therapy for H., Kinoshita, K., Kishi, H., Hara, T., Aso, Y. and Niijima, T.: carcinoma in situ of the bladder. J. Urol., 154.2050, 1995. Analyses of the effects of intravesical bacillus CalmetteGuerin (Tokyo 172 strain) therapy of superficial bladder can- 20. Balemans, L. T., Vegt, P. D., Steerenberg, P. A., De Boer, E. C., Van Swaaij, A., De Vries, R. E., Van der Meijden, A. P. and cer. Jap. J . Urol., 80 167,1989. Den Otter, W.: Effects of sequential intravesical administra12. Herr, H. W., Wartinger, D. D., Fair, W. R. and Oettgen, H. F.: tion of mitomycin C and bacillus Calmette-Guerin on the imBacillus Calmette-Guerin therapy for superficial bladder canmune response in the guinea pig bladder. Urol. Res., 22: 239, cer: a 10-year followup. J . Urol., 147: 1020, 1992. 1994. 13. Lien, E. J. and Ou, X. C.: Carcinogenicity of some anticancer "
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