0022-534 7/91/453-0498$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1991 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 145, 498-501, March 1991
Printed in U.S.A.
ORAL OR INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS IN BLADDER CARCINOMA CARLOS ARTURO LEVI D' ANCONA, NELSON RODRIGUES NETTO, JR., JOAQUIM ALMEIDA CLARO AND OSAMU IKARI From the Division of Urology, University of Campinas Medical Center, UNICAMP, Sao Paulo, Brazil
ABSTRACT
A total of 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pTl transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to 3 treatment groups: control group-transurethral resection discontinued within the study, oral bacillus CalmetteGuerin (BCG) group-transurethral resection of bladder tumor plus BCG (Moreau*) and intravesical BCG group-transurethral resection of bladder tumor plus BCG. Of 9 patients in the control group 8 (89%) experienced tumor recurrence during a mean followup of 20 months. Of the 28 patients in the oral BCG group 11 (39.3%) had recurrence during a mean followup of 36 months. Of the 34 patients in the intravesical group 6 (18%) had recurrence in a 24-month mean followup. The incidence of complications was higher in the intravesical (41.2%) than in the oral BCG group (28.5%). These results show that intravesical BCG is a more effective immunotherapy; however, oral BCG can be used in patients who do not accept intravesical BCG administration. KEY WORDS:
carcinoma, transitional cell; bladder; mycobacterium bovis
Superficial transitional cell bladder carcinoma is a common condition with a recurrence rate ranging from 62.5 to 85%. 1- 3 Since transurethral resection remains the initial treatment for these tumors, the high recurrence rates and the relative accessibility of these tumors make intravesical adjuvant therapy an appealing concept. In 1976 Morales et al demonstrated that intravesical bacillus Calmette-Guerin (BCG) plus intradermal administration favorably modified the pattern of recurrence in the majority of patients with bladder cancer, without inducing long-lasting adverse effects. 4 Different methods of administrating the BCG can be used, including intravesical, intralesional, oral and intradermal. There are several types of BCG vaccines prepared from different BCG strains, which have been used in different studies and it is not yet clear whether all of these strains are similarly effective. 5 Therefore, we performed a prospective and randomized study to compare intravesical and oral administration of BCG (Moreau strain) to a control group. PATIENTS AND METHODS
From January 1981 to December 1988, 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumors. There were 60 men 28 to 81 years old (median age 66 years) and 11 women 25 to 83 years old (median age 62 years). For staging purposes all patients underwent cystoscopy, selective site bladder mucosa biopsies, bimanual palpation and resection of all visible tumors. Preoperative excretory urograms were obtained to exclude patients with evidence of upper tract disease. A pre-treatment skin test with purified protein derivative was performed initially and repeated 1 year later. A positive purified protein derivative skin test was defined as an area of induration at least 1 cm. in diameter 72 hours after inoculation. Patients with a positive reaction were considered as immunologically competent. All patients had stage pTa or pTl transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The histological criteria used define pTl tumor as being invasive with pushing borders and Accepted for publication August 6, 1990. * Institute Butantan, Sao Paulo, Brazil.
irregularities of the lamina propria. The Koss grading system was used to classify cellular differentiation. 6 Tumor profiles are shown in table 1. Carcinoma in situ was defined as a nonpapillary, intraepithelial, poorly differentiated neoplasm and was diagnosed by biopsy. Multifocal tumors were defined as those involving more than 3 sites. The 71 consecutive patients were randomized by the sealed envelope method into 3 groups according to the treatment protocol: control group (9 patients)-transurethral resection of bladder tumor, oral BCG group (28 patients)-transurethral resection of bladder tumor, plus 1 gm. BCG (Moreau) weekly for 1 year in immunologically competent patients or 1 gm. BCG (Moreau-RJ) 3 times a week for 1 year in immunologically incompetent patients and intravesical BCG group (34 patients)-transurethral resection of bladder tumor plus 1 gm. BCG monthly for 1 year. Those patients without evidence of tumors within a 1-year period continued BCG every 3 months for 1 more year. In cases of recurrence the protocol was started again with monthly instillations. The BCG suspended in 100 ml. saline solution was instilled by catheterization in the bladder and all patients were instructed to retain the BCG for 1 to 2 hours. The Moreau strain of BCG has a viability of 2 x 109 organisms per 100 mg. All patients were followed with urinary cytology and cystoscopy plus random bladder biopsies, including the prostatic urethra in men, every 3 months for 1 year and every 6 months the second year if there was no evidence of tumor recurrence. The date of the last visit was recorded as the last date of followup. Tumor recurrence was defined as evidence of papillary tumor or carcinoma in situ on cystoscopy, or positive urinary cytology. Recurrent tumors were resected transurethrally and studied in routine fashion. Tumor recurrence rates were compared with the chi-square partition test. RESULTS
Patients treated with BCG for superficial bladder tumors who presented with persistent or recurrent tumors at posttherapy followup were considered as treatment failures. The
498
BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS IN BLADDER CARCINOMA TABLE 1.
Stage: pTa pTl Associated pTis Grade: I II III No. tumors: Single Multifocal Previous recurrences Mean mos. followup (range) No. pts. with recurrences (%)* No. recurrences No. recurrences/pt. yr.
Patient profiles Intravesical BCG (34 pts.)
Control (9 pts.)
Oral BCG (28 pts.)
9 1
28 4
3 31 3
5 4
8 18 2
16 16 2
6 3 2 20 (3-86)
19 9 11 36 (3-84)
23 11 12 24 (3-84)
8 (89.0)
11 (39.3)
6 (18.0)
12 0.79
25 0.29
No. pts. Stage: pTA pTl Associated pTis Grade: I II III No. tumors: Single Multifocal
12 0.17
Over-all recurrence according to stratification Control No./Total (%)
Oral BCG No./Total (%)
Intravesical BCG No,/Total (%)
9
28
34
8/9 1/1
11/28 2/4
0/3 6/31 1/3
4/5 4/4
3/8 7/18 1/2
2/16 4/16 0/2
5/6 (83) 3/3 (100)
7/9 (37) 4/9 (44)
symptoms and treatment was discontinued. The remaining 8 patients required no therapy. Gross hematuria was reported in 5 patients (14.7%), and fever and malaise in 5 (14.7%). The remaining 2 patients each had a contracted bladder and miliary BCG infection. The total complication rate observed in 14 cases was 41.2%. In the oral BCG group 5 patients had nausea and vomiting (17.8%) and 3 reported fever (10.7%), totaling 8 patients (28.5%, table 3). DISCUSSION
*Chi-square= 16.17, p
Vol. 145, 498-501, March 1991
Printed in U.S.A.
ORAL OR INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS IN BLADDER CARCINOMA CARLOS ARTURO LEVI D' ANCONA, NELSON RODRIGUES NETTO, JR., JOAQUIM ALMEIDA CLARO AND OSAMU IKARI From the Division of Urology, University of Campinas Medical Center, UNICAMP, Sao Paulo, Brazil
ABSTRACT
A total of 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pTl transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to 3 treatment groups: control group-transurethral resection discontinued within the study, oral bacillus CalmetteGuerin (BCG) group-transurethral resection of bladder tumor plus BCG (Moreau*) and intravesical BCG group-transurethral resection of bladder tumor plus BCG. Of 9 patients in the control group 8 (89%) experienced tumor recurrence during a mean followup of 20 months. Of the 28 patients in the oral BCG group 11 (39.3%) had recurrence during a mean followup of 36 months. Of the 34 patients in the intravesical group 6 (18%) had recurrence in a 24-month mean followup. The incidence of complications was higher in the intravesical (41.2%) than in the oral BCG group (28.5%). These results show that intravesical BCG is a more effective immunotherapy; however, oral BCG can be used in patients who do not accept intravesical BCG administration. KEY WORDS:
carcinoma, transitional cell; bladder; mycobacterium bovis
Superficial transitional cell bladder carcinoma is a common condition with a recurrence rate ranging from 62.5 to 85%. 1- 3 Since transurethral resection remains the initial treatment for these tumors, the high recurrence rates and the relative accessibility of these tumors make intravesical adjuvant therapy an appealing concept. In 1976 Morales et al demonstrated that intravesical bacillus Calmette-Guerin (BCG) plus intradermal administration favorably modified the pattern of recurrence in the majority of patients with bladder cancer, without inducing long-lasting adverse effects. 4 Different methods of administrating the BCG can be used, including intravesical, intralesional, oral and intradermal. There are several types of BCG vaccines prepared from different BCG strains, which have been used in different studies and it is not yet clear whether all of these strains are similarly effective. 5 Therefore, we performed a prospective and randomized study to compare intravesical and oral administration of BCG (Moreau strain) to a control group. PATIENTS AND METHODS
From January 1981 to December 1988, 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumors. There were 60 men 28 to 81 years old (median age 66 years) and 11 women 25 to 83 years old (median age 62 years). For staging purposes all patients underwent cystoscopy, selective site bladder mucosa biopsies, bimanual palpation and resection of all visible tumors. Preoperative excretory urograms were obtained to exclude patients with evidence of upper tract disease. A pre-treatment skin test with purified protein derivative was performed initially and repeated 1 year later. A positive purified protein derivative skin test was defined as an area of induration at least 1 cm. in diameter 72 hours after inoculation. Patients with a positive reaction were considered as immunologically competent. All patients had stage pTa or pTl transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The histological criteria used define pTl tumor as being invasive with pushing borders and Accepted for publication August 6, 1990. * Institute Butantan, Sao Paulo, Brazil.
irregularities of the lamina propria. The Koss grading system was used to classify cellular differentiation. 6 Tumor profiles are shown in table 1. Carcinoma in situ was defined as a nonpapillary, intraepithelial, poorly differentiated neoplasm and was diagnosed by biopsy. Multifocal tumors were defined as those involving more than 3 sites. The 71 consecutive patients were randomized by the sealed envelope method into 3 groups according to the treatment protocol: control group (9 patients)-transurethral resection of bladder tumor, oral BCG group (28 patients)-transurethral resection of bladder tumor, plus 1 gm. BCG (Moreau) weekly for 1 year in immunologically competent patients or 1 gm. BCG (Moreau-RJ) 3 times a week for 1 year in immunologically incompetent patients and intravesical BCG group (34 patients)-transurethral resection of bladder tumor plus 1 gm. BCG monthly for 1 year. Those patients without evidence of tumors within a 1-year period continued BCG every 3 months for 1 more year. In cases of recurrence the protocol was started again with monthly instillations. The BCG suspended in 100 ml. saline solution was instilled by catheterization in the bladder and all patients were instructed to retain the BCG for 1 to 2 hours. The Moreau strain of BCG has a viability of 2 x 109 organisms per 100 mg. All patients were followed with urinary cytology and cystoscopy plus random bladder biopsies, including the prostatic urethra in men, every 3 months for 1 year and every 6 months the second year if there was no evidence of tumor recurrence. The date of the last visit was recorded as the last date of followup. Tumor recurrence was defined as evidence of papillary tumor or carcinoma in situ on cystoscopy, or positive urinary cytology. Recurrent tumors were resected transurethrally and studied in routine fashion. Tumor recurrence rates were compared with the chi-square partition test. RESULTS
Patients treated with BCG for superficial bladder tumors who presented with persistent or recurrent tumors at posttherapy followup were considered as treatment failures. The
498
BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS IN BLADDER CARCINOMA TABLE 1.
Stage: pTa pTl Associated pTis Grade: I II III No. tumors: Single Multifocal Previous recurrences Mean mos. followup (range) No. pts. with recurrences (%)* No. recurrences No. recurrences/pt. yr.
Patient profiles Intravesical BCG (34 pts.)
Control (9 pts.)
Oral BCG (28 pts.)
9 1
28 4
3 31 3
5 4
8 18 2
16 16 2
6 3 2 20 (3-86)
19 9 11 36 (3-84)
23 11 12 24 (3-84)
8 (89.0)
11 (39.3)
6 (18.0)
12 0.79
25 0.29
No. pts. Stage: pTA pTl Associated pTis Grade: I II III No. tumors: Single Multifocal
12 0.17
Over-all recurrence according to stratification Control No./Total (%)
Oral BCG No./Total (%)
Intravesical BCG No,/Total (%)
9
28
34
8/9 1/1
11/28 2/4
0/3 6/31 1/3
4/5 4/4
3/8 7/18 1/2
2/16 4/16 0/2
5/6 (83) 3/3 (100)
7/9 (37) 4/9 (44)
symptoms and treatment was discontinued. The remaining 8 patients required no therapy. Gross hematuria was reported in 5 patients (14.7%), and fever and malaise in 5 (14.7%). The remaining 2 patients each had a contracted bladder and miliary BCG infection. The total complication rate observed in 14 cases was 41.2%. In the oral BCG group 5 patients had nausea and vomiting (17.8%) and 3 reported fever (10.7%), totaling 8 patients (28.5%, table 3). DISCUSSION
*Chi-square= 16.17, p
