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Prophylactic Maltose Tetrapalmitate and Bacillus Calmette-Guerin Immunotherapy of Recurrent Superficial Bladder Tumors: Preliminary Report
0022-534 7/88/1403-0498$02.00/0 Vol. 140, September
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
Printed in U.S.A.
PROPHYLACTIC MALTOSE TETRAPALMITATE AND BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY OF RECURRENT SUPERFICIAL BLADDER TUMORS: PRELIMINARY REPORT EL-HOUSSEINY I. IBRAHIEM,* MOHAMED A. GHONEIM, VIJAI NIGAM, CARLOS BRAILOVSKY AND MOSTAFA M. ELHILALI From the Urology and Nephrology Center, Mansoura University, Mansoura, Egypt, and Royal Victoria Hospital, McGill University, Montreal and Centre Hospitaliere Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
ABSTRACT
We divided randomly into 3 groups 47 patients with recurrent superficial transitional cell carcinoma of the bladder: group 1-15 controls who underwent transurethral resection only, group 2-17 patients who underwent transurethral resection and bacillus Calmette-Guerin therapy, and group 3-15 patients treated by transurethral resection and maltose tetrapalmitate. Mean followup was 22.93 months for the controls, 28.0 months for group 2 and 24.4 months for group 3. The recurrence rate per 100 patient-months was 11.34 in the controls, 7.4 in group 2 and 7.19 in group 3, and the recurrence index per month was 0.113, 0.070 and 0.072, respectively. The recurrence rate and recurrence index per month were significantly decreased in the treated groups compared to the controls (p less than 0.005). There was no significant difference between the bacillus CalmetteGuerin and maltose tetrapalmitate groups. Invasive carcinoma developed in 60 per cent of the controls, 29.4 per cent of group 2 and 20 per cent of group 3. Invasive carcinoma required cystectomy or definitive radiotherapy. Bacillus Calmette-Guerin caused irritation of the bladder mucosa, while maltose tetrapalmitate did not have any side effects. (J. Urol., 140: 498-500, 1988) Intracavitary therapy of bladder cancer has attracted particular interest during recent years. The easy accessibility of the bladder permits delivery of a high local concentration of the therapeutic agents and allows for an objective evaluation of the efficacy. Morales and associates presented their initial experience with the use of bacillus Calmette-Guerin (BCG) in the treatment and prophylaxis of recurrent bladder neoplasms. 1 They used the combined intravesical and subcutaneous routes for BCG therapy in bladder patients. The intravesical route alone was evaluated by us experimentally on an orthotopic bladder tumor animal model. 2 During the last 8 years a new class of immunoadjuvant, synthetic glycolipids, has emerged whose structure resembles that of bacterial lipid A, a well known immunoadjuvant. 3 Unlike lipid A, the synthetic glycolipids are devoid of endotoxicity, since they lack phosphate residues and phosphanolamine. 4 Among the several glycolipids synthesized, maltose tetrapalmitate (MTP) was the most effective agent against several tumors, 4 and it was found to be an immunopotentiator as judged by its mitogenicity for spleen lymphocytes and augmentation of humoral immune response to sheep red blood cells. 5 • 6 Acute and chronic toxicity experiments with MTP in rats showed no apparent side effects of toxic clinical manifestations. MTP was equal or superior to BCG, Clostridium parvum, pyran copolymer and levamisole in its antitumor activity against Dunning prostatic carcinoma, 5 and it protected animals against tumor recurrence when given before and after a tumor operation. In a comparative study of intravesical MTP and BCG treatment of transplantable bladder cancer, we found that MTP offered a greater benefit to bladder tumor-bearing hosts than BCG. Intravesical BCG alone was as effective as BCG given by systemic and intravesical routes in terms of reduction of tumor size or decrease in incidence of metastases. 6 We studied the effects of MTP on the incidence of recurrent superficial bladder tumors after transurethral resection, and Accepted for publication December 21, 1987. * Requests for reprints: Urology and Nephrology Center, Mansoura University, Mansoura, Egypt_
compared oral plus intravesical MTP and intravesical BCG on the incidence of recurrent superficial bladder tumor. MATERIAL AND METHODS
Patients. We studied 47 patients with recurrent superficial bladder tumors. Inclusion criteria were transitional cell cancer of the bladder documented histologically in the past, patient free of disease after a previous transurethral resection (that is they should have at least 1 negative cystoscopy study), at least 1 untreated recurrence after transurethral resection, no urinary tract infection, no evidence of malnutrition, patient available for followup, no additional treatment received, that is no chemotherapy or radiotherapy, and patient matched as much as possible in the 3 randomized groups according to sex, age, smoking habits, farmer occupation, bilharzial infestation, surgeon who performed transurethral resection, tumor grade and number of tumors. A full history and physical examination data sheet were completed for each patient. The 47 patients (triplet matched) were divided randomly into 3 groups. Group 1 included 15 controls who received no treatment except for transurethral resection. Group 2 included 15 patients who received 35 mg. MTP dissolved in 50 ml. saline (35C) instilled into the bladder with a 50 ml. syringe and a 16F urethral Nelaton catheter. The patient was instructed to keep the drug inside the bladder for at least 2 hours. To facilitate this procedure the patient was instructed to evacuate the bladder completely and to stop drinking fluids for 6 hours before treatment. The drug was administered intravesically 2 days before the resection, every week after resection for 4 weeks and then every 2 weeks for 1 month. The treatment was continued every month for 4 months and then every 2 months for 1 year. Oral MTP (60 mg.) was started 2 days before transurethral resection and continued for 1 month. The dose then was reduced to 30 mg. per day orally for 1 year. In group 3, 17 patients received 120 mg. BCG (Montreal Armand Frappier strain) in 50 ml. saline intravesically 2 days before transurethral resection, weekly for 6 weeks,
498
499
MALTOSE TETHAPAJLMITATE AND BACILLUS CALMETTE-GUERIN FOR BLADDER TUi,IORS TABLE
l. Patient distribution
Male ptsJfemale pts. Age (yrs.): 30-40 41-50 51-60 61-70 71-80 Grade: 1
Control
BCG
MTP
12/3
14/3
12/3
1 6
1 5 6
2
4 3 1 7 7 1
2 3
4 1
4 4 3 2
8 8
8 6
1
TABLE 2
Stage Pt. Groups Control BCG MTP No. pts.
Total No. Pts.
Ta
Tl
10
5
9
6
8 9
15 17 15
25
22
47
and then at 3 months, 6 months and 1 year according to the protocol described by Lamm and associates. 11 Followup. For every visit after treatment was begun the patients were evaluated by full history data, including urological and nonurological symptoms, performance status and specific questions to detect any gastwintestinal or neurological side effects, and clinical examination, including body weight, general appearance and specific examination. Investigations included urinalysis, culture and sensitivity, urine cytology to detect malignant cells as early as possible, cystoscopy 1 month after transurethral resection to be sure that the resection was complete and no tumors were left, and then 2 months after resection (followup cystoscopy was done every 2 months for 1 year and then every 3 months for 1 year), complete blood count, renal and liver function studies every 2 months, random biopsies from the bladder if cytology results were positive and cystoscopy was negative, and excretory urography every 6 months for 2 years. Immunotherapeutic agents. BCG, Montreal strain TMC 1012,* was supplied as lyophilized preparation in 60 mg. ampules containing 8 x 106 living attenuated bacilli per mg. and it was administered by the intravesical route. MTP was prepared in our laboratory, and it was given orally and intravesically. The parameters used to evaluate the effects of treatment were the recurrence index, defined as the number of recurrent tumors per month, the recurrence rate, defined as the number of recurrences, that is positive cystoscopy studies per followup multiplied by 100, the mean interval to recurrence, defined as the number of months for recurrence to develop patientmonths of followup/total number of recurrences during this period) and development of advanced tumors. Statistical analysis. The data were analyzed Student's t test and the chi-square test with Yates' continuity correlation for statistical differences in frequencies of 2 x 2 table. 7
examination showed that the granuloma was an exaggerated immune reaction. Twelve patients in the BCG group suffered from irritation of the bladder mucosa. On the other hand, intravesical MTP caused bladder irritation in only 1 patient. The mean followup was 22.93 months for the controls, and 24.4 for the MTP and 28.0 for the BCG groups (table 4). The mean interval to recurrence was 7.19 months in the controls, 15.11 in the BCG group and 17.16 in the MTP group. This value was significantly higher in the treated groups than in the controls (p <0.005). No significant difference was found between the BCG and MTP groups (table 5). The recurrence rate per 100 patient-months in the control group treated by transurethral resection only was 11.34 during a followup of 344 patient-months. The BCG group was followed for 426 patient-months and the recurrence rate per 100 patientmonths was 7.4. The MTP group was followed for 334 patientmonths and the recurrence rate was 6.84. The recurrence index per month was 0.113 for the controls, and 0.070 for the BCG and 0.072 for the MTP groups. Statistically, the recurrence rate and recurrence index per month were significantly reduced in the treated groups compared to the controls (p <0.005). The percentage of patients who actually had recurrent tumors was 86. 7 in the control group during a mean of 22.93 months of followup, 88.3 after 28.0 months in the BCG group and only 60 after 24.27 months in the MTP group. The pattern of recurrence in the treated groups was different from the controls. The number of recurrent tumors was few and the tumors were tiny in most of the treated patients. On the other hand, the recurrences in the controls were polycentric and larger. Nine control patients (60 per cent) had muscle invasive bladder cancer. Of these patients 2 had some squamous differentiation during recurrence, while the others had nothing special. All of these tumors were well differentiated (grades I and II). In the BCG group 5 patients (29.4 per cent) had muscle invasive bladder cancer (2 poorly differentiated grade III and 3 grade II tumors), while 3 patients (20 per cent) in the MTP treated group had muscle invasion (1 had grade III disease, 1 had some squamous differentiation during recurrence and 1 had metastases in the pelvic lymph nodes). The latter 2 tumors were grade II. The common feature in all patients with invasive or progressive tumors was the multiplicity pattern of recurrence, sometimes beyond the scope of resection. TABLE
3. Side effects and toxicity ECG (17 pts.)
Cystitis symptoms Granuloma formation
TABLE
MTP (15 pts.)
12 3
4. Followup in months Mean± Standard Deviation
Range
22.93 ± 15.04 24.47 ± 13.95 28.00 ± 13.66
6-49 10-55 3-54
Control MTP ECG
RESULTS
There were 47 patients studied, with a male-to-female ratio of 5:1. Patient age ranged from 30 to 76 years, with a mean age of 55 years. The age and sex distribution were nearly matched among the triplets in the 3 groups. The distribution of patients according to grade also was similar (table 1). The distribution of patients according to stage is given in table 2. Granulomatous reaction in the bladder that was misdiagnosed as recurrence by cystoscopy occurred in 3 of 17 patients in the BCG and 3 of 15 in the MTP group (table 3). Histological * L'institute Microbiologie et Hygiene de Montreal Armand Frappier, Montreal, Quebec, Canada.
TABLE 5.
Effects of treatment on the recurrence rate Control
No. pts. randomized Total pt.-mos. followup Total No. recurrences during followup Recurrence rate/100 pt.-mos. Recurrence index/mo. Mean time of recurrence
15 344 39 11.34 0.11 7.19
ECG 17 426 30 7.40 0.071 15.11
MTP 15 334 24 7.19 0.070 17.16
500
IBRAHIEM AND ASSOCIATES
DISCUSSION
REFERENCES
In patients with recurrent superficial transitional cell carcinoma of the bladder there is a theoretical advantage in the use of intravesical immunoadjuvant therapy. To have optimum effect these immunoadjuvants should come into intimate contact with the tumor, the tumor burden should be limited and the host should be immune competent. Although the potential beneficial effects of nonspecific immunostimulants on the host immune system have been known since 1950, only in the last decade have intensive investigations been performed with BCG for cancer therapy. To date BCG immunotherapy for recurrent superficial cancer represents the most successful form of immunotherapy in man. 8 - 12 lntravesical BCG therapy has been reported to reduce the tumor recurrence rate from approximately 60 to about 10 to 20 per cent when used for prophylaxis, 3 •13 and it induced regression of established superficial tumor in approximately two-thirds of the patients. 8 • 14 These results are superior to those achieved with endoscopic resection alone. 2• 15 Experimentally, we studied the effects of many commonly used immunoadjuvants and compared the results to MTP. 13 We found that MTP and BCG are the most effective. Also, MTP did not show any toxic effect. 6 We used MTP for the first time in a comparative study with BCG to reduce and prevent recurrent superficial bladder tumors. The recurrence rate per 100 patient-months and the recurrence index per month were significantly decreased in groups treated by MTP and BCG. MTP proved to be as effective as BCG without any side effects. In our study invasive bladder cancer occurred in 60 per cent of the control patients, and 29.4 per cent of the BCG and 20 per cent of the MTP treated patients. This finding emphasized the importance of immunotherapy in reducing the aggression and burden of recurrent superficial tumors. Lamm and associates described in detail the complications of BCG intravesical therapy reported in the literature. 16 Cystitis occurred in 91 per cent of our patients. Irritative bladder symptoms, such as dysuria and frequency, were reported in 70 per cent of the patients treated with BCG and in only 1 treated with MTP. The symptoms were directly related to the therapy. Recently, Haaff and associates used a second 6-week course of BCG in patients who failed to respond to the first protocol regimen of BCG. 17 Of the 29 patients treated for prophylaxis against tumor recurrence 20 (60 per cent) remained free of tumor after a single 6-week course, while 6 of 9 (67 per cent) were free of disease after a second treatment course. A 90 per cent cumulative response rate was observed in the prophylaxis category (mean followup 12.8 ± 1.3 months). This second course regimen should be tried for MTP as well. In conclusion, our study, although preliminary, shows promising results for intravesical therapy with MTP in the prevention of recurrent bladder tumor in the high risk population. MTP proved to be as effective as the well known BCG. The superiority of MTP in causing no side effects in the treated patients encouraged us to continue our study with this new agent.
1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 2. Ibrahiem, E. H. I., Nigam, V. N., Brailovsky, C. A., Madarnas, P. and Elhilali, M.: Orthotopic implantation of primary N-[4-(5nitro-2-furyl)-2-thiazolyl] formamide-induced bladder cancer in bladder submucosa: an animal model for bladder cancer study. Cancer Res., 43: 617, 1983. 3. Skidmore, B. J., Chiller, J., Morrison, D. and Weigle, W.: Immunologic properties of bacterial polysaccharides (LPS): correlation between the mitogenic, adjuvant and immunogenic activities. J. Immunol., 114: 770, 1975. 4. Nigam, V. N., Brailovsky, C. A. and Chopra, C.: Maltose tetrapalmitate, a non toxic immunopotentiator with antitumor activity. Cancer Res., 38: 3315, 1978. 5. El-Kappany, H., Chopra, C., Nigam, V. N., Brailovsky, C. A. and Elhilali, M.: The antitumor activity of maltose tetrapalmitate compared with other immunoadjuvants and its effects after tumour surgery. Brit. J. Cancer, 42: 703, 1980. 6. Elhilali, M., Ibrahiem, E. H. I., Nigam, V. N., Brailovsky, C. A. and Madarnas, P.: A comparative study of the intravesical MTP and BCG treatment of transplantable bladder cancer. J. Urol., 129: 1265, 1983. 7. Matthews, D. E. and Farewell, V. T.: Using and Understanding Medical Statistics. New York: S. Karger, 1985. 8. Bloomberg, S. D., Brosman, S. A., Hausman, M. S., Cohen, A. and Battenberg, J. D.: The effects of BCG on the dog bladder. Invest. Urol., 12: 423, 1975. 9. Camacho, F., Pinsky, C. M., Kerr, D., Whitmore, W. and Oettgen, H.: Treatment of superficial bladder cancer with intravesical BCG. Proc. Amer. Ass. Cancer Res. Amer. Soc. Clin. Oncol., 21: 359, abstract C-160, 1980. 10. Herr, H. W., Pinsky, C. M., Whitmore, W. F., Jr., Oettgen, H. F. and Melamed, M. R.: Effects of intravesical bacillus CalmetteGuerin (BCG) on carcinoma in situ of the bladder. Cancer, 51: 1323, 1983. 11. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 12. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer, 48: 82, 1981. 13. Ibraheim, E. H., El Kappany, H., Nigam, V. N., Brailovsky, C. A., Madarnas, P. and Elhilali, M. M.: Adjuvant immunotherapy of N-[ 4(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced bladder tumors. Anticancer Res., 4: 209, 1984. 14. Lamm, D. L., Stogdill, V. D. and Thor, D. E.: BCG immunotherapy in superficial transitional cell carcinoma of the urinary bladder. Proc. Amer. Ass. Cancer Res. Amer. Soc. Clin. Oncol., 21: 372, abstract C-208, 1980. 15. Zbar, B. and Rapp, H. J.: Immunotherapy of guinea pig cancer with BCG. Cancer, 34: 1532, 1974. 16. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 17. Haaff, E. 0., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136: 820, 1986.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
Printed in U.S.A.
PROPHYLACTIC MALTOSE TETRAPALMITATE AND BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY OF RECURRENT SUPERFICIAL BLADDER TUMORS: PRELIMINARY REPORT EL-HOUSSEINY I. IBRAHIEM,* MOHAMED A. GHONEIM, VIJAI NIGAM, CARLOS BRAILOVSKY AND MOSTAFA M. ELHILALI From the Urology and Nephrology Center, Mansoura University, Mansoura, Egypt, and Royal Victoria Hospital, McGill University, Montreal and Centre Hospitaliere Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
ABSTRACT
We divided randomly into 3 groups 47 patients with recurrent superficial transitional cell carcinoma of the bladder: group 1-15 controls who underwent transurethral resection only, group 2-17 patients who underwent transurethral resection and bacillus Calmette-Guerin therapy, and group 3-15 patients treated by transurethral resection and maltose tetrapalmitate. Mean followup was 22.93 months for the controls, 28.0 months for group 2 and 24.4 months for group 3. The recurrence rate per 100 patient-months was 11.34 in the controls, 7.4 in group 2 and 7.19 in group 3, and the recurrence index per month was 0.113, 0.070 and 0.072, respectively. The recurrence rate and recurrence index per month were significantly decreased in the treated groups compared to the controls (p less than 0.005). There was no significant difference between the bacillus CalmetteGuerin and maltose tetrapalmitate groups. Invasive carcinoma developed in 60 per cent of the controls, 29.4 per cent of group 2 and 20 per cent of group 3. Invasive carcinoma required cystectomy or definitive radiotherapy. Bacillus Calmette-Guerin caused irritation of the bladder mucosa, while maltose tetrapalmitate did not have any side effects. (J. Urol., 140: 498-500, 1988) Intracavitary therapy of bladder cancer has attracted particular interest during recent years. The easy accessibility of the bladder permits delivery of a high local concentration of the therapeutic agents and allows for an objective evaluation of the efficacy. Morales and associates presented their initial experience with the use of bacillus Calmette-Guerin (BCG) in the treatment and prophylaxis of recurrent bladder neoplasms. 1 They used the combined intravesical and subcutaneous routes for BCG therapy in bladder patients. The intravesical route alone was evaluated by us experimentally on an orthotopic bladder tumor animal model. 2 During the last 8 years a new class of immunoadjuvant, synthetic glycolipids, has emerged whose structure resembles that of bacterial lipid A, a well known immunoadjuvant. 3 Unlike lipid A, the synthetic glycolipids are devoid of endotoxicity, since they lack phosphate residues and phosphanolamine. 4 Among the several glycolipids synthesized, maltose tetrapalmitate (MTP) was the most effective agent against several tumors, 4 and it was found to be an immunopotentiator as judged by its mitogenicity for spleen lymphocytes and augmentation of humoral immune response to sheep red blood cells. 5 • 6 Acute and chronic toxicity experiments with MTP in rats showed no apparent side effects of toxic clinical manifestations. MTP was equal or superior to BCG, Clostridium parvum, pyran copolymer and levamisole in its antitumor activity against Dunning prostatic carcinoma, 5 and it protected animals against tumor recurrence when given before and after a tumor operation. In a comparative study of intravesical MTP and BCG treatment of transplantable bladder cancer, we found that MTP offered a greater benefit to bladder tumor-bearing hosts than BCG. Intravesical BCG alone was as effective as BCG given by systemic and intravesical routes in terms of reduction of tumor size or decrease in incidence of metastases. 6 We studied the effects of MTP on the incidence of recurrent superficial bladder tumors after transurethral resection, and Accepted for publication December 21, 1987. * Requests for reprints: Urology and Nephrology Center, Mansoura University, Mansoura, Egypt_
compared oral plus intravesical MTP and intravesical BCG on the incidence of recurrent superficial bladder tumor. MATERIAL AND METHODS
Patients. We studied 47 patients with recurrent superficial bladder tumors. Inclusion criteria were transitional cell cancer of the bladder documented histologically in the past, patient free of disease after a previous transurethral resection (that is they should have at least 1 negative cystoscopy study), at least 1 untreated recurrence after transurethral resection, no urinary tract infection, no evidence of malnutrition, patient available for followup, no additional treatment received, that is no chemotherapy or radiotherapy, and patient matched as much as possible in the 3 randomized groups according to sex, age, smoking habits, farmer occupation, bilharzial infestation, surgeon who performed transurethral resection, tumor grade and number of tumors. A full history and physical examination data sheet were completed for each patient. The 47 patients (triplet matched) were divided randomly into 3 groups. Group 1 included 15 controls who received no treatment except for transurethral resection. Group 2 included 15 patients who received 35 mg. MTP dissolved in 50 ml. saline (35C) instilled into the bladder with a 50 ml. syringe and a 16F urethral Nelaton catheter. The patient was instructed to keep the drug inside the bladder for at least 2 hours. To facilitate this procedure the patient was instructed to evacuate the bladder completely and to stop drinking fluids for 6 hours before treatment. The drug was administered intravesically 2 days before the resection, every week after resection for 4 weeks and then every 2 weeks for 1 month. The treatment was continued every month for 4 months and then every 2 months for 1 year. Oral MTP (60 mg.) was started 2 days before transurethral resection and continued for 1 month. The dose then was reduced to 30 mg. per day orally for 1 year. In group 3, 17 patients received 120 mg. BCG (Montreal Armand Frappier strain) in 50 ml. saline intravesically 2 days before transurethral resection, weekly for 6 weeks,
498
499
MALTOSE TETHAPAJLMITATE AND BACILLUS CALMETTE-GUERIN FOR BLADDER TUi,IORS TABLE
l. Patient distribution
Male ptsJfemale pts. Age (yrs.): 30-40 41-50 51-60 61-70 71-80 Grade: 1
Control
BCG
MTP
12/3
14/3
12/3
1 6
1 5 6
2
4 3 1 7 7 1
2 3
4 1
4 4 3 2
8 8
8 6
1
TABLE 2
Stage Pt. Groups Control BCG MTP No. pts.
Total No. Pts.
Ta
Tl
10
5
9
6
8 9
15 17 15
25
22
47
and then at 3 months, 6 months and 1 year according to the protocol described by Lamm and associates. 11 Followup. For every visit after treatment was begun the patients were evaluated by full history data, including urological and nonurological symptoms, performance status and specific questions to detect any gastwintestinal or neurological side effects, and clinical examination, including body weight, general appearance and specific examination. Investigations included urinalysis, culture and sensitivity, urine cytology to detect malignant cells as early as possible, cystoscopy 1 month after transurethral resection to be sure that the resection was complete and no tumors were left, and then 2 months after resection (followup cystoscopy was done every 2 months for 1 year and then every 3 months for 1 year), complete blood count, renal and liver function studies every 2 months, random biopsies from the bladder if cytology results were positive and cystoscopy was negative, and excretory urography every 6 months for 2 years. Immunotherapeutic agents. BCG, Montreal strain TMC 1012,* was supplied as lyophilized preparation in 60 mg. ampules containing 8 x 106 living attenuated bacilli per mg. and it was administered by the intravesical route. MTP was prepared in our laboratory, and it was given orally and intravesically. The parameters used to evaluate the effects of treatment were the recurrence index, defined as the number of recurrent tumors per month, the recurrence rate, defined as the number of recurrences, that is positive cystoscopy studies per followup multiplied by 100, the mean interval to recurrence, defined as the number of months for recurrence to develop patientmonths of followup/total number of recurrences during this period) and development of advanced tumors. Statistical analysis. The data were analyzed Student's t test and the chi-square test with Yates' continuity correlation for statistical differences in frequencies of 2 x 2 table. 7
examination showed that the granuloma was an exaggerated immune reaction. Twelve patients in the BCG group suffered from irritation of the bladder mucosa. On the other hand, intravesical MTP caused bladder irritation in only 1 patient. The mean followup was 22.93 months for the controls, and 24.4 for the MTP and 28.0 for the BCG groups (table 4). The mean interval to recurrence was 7.19 months in the controls, 15.11 in the BCG group and 17.16 in the MTP group. This value was significantly higher in the treated groups than in the controls (p <0.005). No significant difference was found between the BCG and MTP groups (table 5). The recurrence rate per 100 patient-months in the control group treated by transurethral resection only was 11.34 during a followup of 344 patient-months. The BCG group was followed for 426 patient-months and the recurrence rate per 100 patientmonths was 7.4. The MTP group was followed for 334 patientmonths and the recurrence rate was 6.84. The recurrence index per month was 0.113 for the controls, and 0.070 for the BCG and 0.072 for the MTP groups. Statistically, the recurrence rate and recurrence index per month were significantly reduced in the treated groups compared to the controls (p <0.005). The percentage of patients who actually had recurrent tumors was 86. 7 in the control group during a mean of 22.93 months of followup, 88.3 after 28.0 months in the BCG group and only 60 after 24.27 months in the MTP group. The pattern of recurrence in the treated groups was different from the controls. The number of recurrent tumors was few and the tumors were tiny in most of the treated patients. On the other hand, the recurrences in the controls were polycentric and larger. Nine control patients (60 per cent) had muscle invasive bladder cancer. Of these patients 2 had some squamous differentiation during recurrence, while the others had nothing special. All of these tumors were well differentiated (grades I and II). In the BCG group 5 patients (29.4 per cent) had muscle invasive bladder cancer (2 poorly differentiated grade III and 3 grade II tumors), while 3 patients (20 per cent) in the MTP treated group had muscle invasion (1 had grade III disease, 1 had some squamous differentiation during recurrence and 1 had metastases in the pelvic lymph nodes). The latter 2 tumors were grade II. The common feature in all patients with invasive or progressive tumors was the multiplicity pattern of recurrence, sometimes beyond the scope of resection. TABLE
3. Side effects and toxicity ECG (17 pts.)
Cystitis symptoms Granuloma formation
TABLE
MTP (15 pts.)
12 3
4. Followup in months Mean± Standard Deviation
Range
22.93 ± 15.04 24.47 ± 13.95 28.00 ± 13.66
6-49 10-55 3-54
Control MTP ECG
RESULTS
There were 47 patients studied, with a male-to-female ratio of 5:1. Patient age ranged from 30 to 76 years, with a mean age of 55 years. The age and sex distribution were nearly matched among the triplets in the 3 groups. The distribution of patients according to grade also was similar (table 1). The distribution of patients according to stage is given in table 2. Granulomatous reaction in the bladder that was misdiagnosed as recurrence by cystoscopy occurred in 3 of 17 patients in the BCG and 3 of 15 in the MTP group (table 3). Histological * L'institute Microbiologie et Hygiene de Montreal Armand Frappier, Montreal, Quebec, Canada.
TABLE 5.
Effects of treatment on the recurrence rate Control
No. pts. randomized Total pt.-mos. followup Total No. recurrences during followup Recurrence rate/100 pt.-mos. Recurrence index/mo. Mean time of recurrence
15 344 39 11.34 0.11 7.19
ECG 17 426 30 7.40 0.071 15.11
MTP 15 334 24 7.19 0.070 17.16
500
IBRAHIEM AND ASSOCIATES
DISCUSSION
REFERENCES
In patients with recurrent superficial transitional cell carcinoma of the bladder there is a theoretical advantage in the use of intravesical immunoadjuvant therapy. To have optimum effect these immunoadjuvants should come into intimate contact with the tumor, the tumor burden should be limited and the host should be immune competent. Although the potential beneficial effects of nonspecific immunostimulants on the host immune system have been known since 1950, only in the last decade have intensive investigations been performed with BCG for cancer therapy. To date BCG immunotherapy for recurrent superficial cancer represents the most successful form of immunotherapy in man. 8 - 12 lntravesical BCG therapy has been reported to reduce the tumor recurrence rate from approximately 60 to about 10 to 20 per cent when used for prophylaxis, 3 •13 and it induced regression of established superficial tumor in approximately two-thirds of the patients. 8 • 14 These results are superior to those achieved with endoscopic resection alone. 2• 15 Experimentally, we studied the effects of many commonly used immunoadjuvants and compared the results to MTP. 13 We found that MTP and BCG are the most effective. Also, MTP did not show any toxic effect. 6 We used MTP for the first time in a comparative study with BCG to reduce and prevent recurrent superficial bladder tumors. The recurrence rate per 100 patient-months and the recurrence index per month were significantly decreased in groups treated by MTP and BCG. MTP proved to be as effective as BCG without any side effects. In our study invasive bladder cancer occurred in 60 per cent of the control patients, and 29.4 per cent of the BCG and 20 per cent of the MTP treated patients. This finding emphasized the importance of immunotherapy in reducing the aggression and burden of recurrent superficial tumors. Lamm and associates described in detail the complications of BCG intravesical therapy reported in the literature. 16 Cystitis occurred in 91 per cent of our patients. Irritative bladder symptoms, such as dysuria and frequency, were reported in 70 per cent of the patients treated with BCG and in only 1 treated with MTP. The symptoms were directly related to the therapy. Recently, Haaff and associates used a second 6-week course of BCG in patients who failed to respond to the first protocol regimen of BCG. 17 Of the 29 patients treated for prophylaxis against tumor recurrence 20 (60 per cent) remained free of tumor after a single 6-week course, while 6 of 9 (67 per cent) were free of disease after a second treatment course. A 90 per cent cumulative response rate was observed in the prophylaxis category (mean followup 12.8 ± 1.3 months). This second course regimen should be tried for MTP as well. In conclusion, our study, although preliminary, shows promising results for intravesical therapy with MTP in the prevention of recurrent bladder tumor in the high risk population. MTP proved to be as effective as the well known BCG. The superiority of MTP in causing no side effects in the treated patients encouraged us to continue our study with this new agent.
1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 2. Ibrahiem, E. H. I., Nigam, V. N., Brailovsky, C. A., Madarnas, P. and Elhilali, M.: Orthotopic implantation of primary N-[4-(5nitro-2-furyl)-2-thiazolyl] formamide-induced bladder cancer in bladder submucosa: an animal model for bladder cancer study. Cancer Res., 43: 617, 1983. 3. Skidmore, B. J., Chiller, J., Morrison, D. and Weigle, W.: Immunologic properties of bacterial polysaccharides (LPS): correlation between the mitogenic, adjuvant and immunogenic activities. J. Immunol., 114: 770, 1975. 4. Nigam, V. N., Brailovsky, C. A. and Chopra, C.: Maltose tetrapalmitate, a non toxic immunopotentiator with antitumor activity. Cancer Res., 38: 3315, 1978. 5. El-Kappany, H., Chopra, C., Nigam, V. N., Brailovsky, C. A. and Elhilali, M.: The antitumor activity of maltose tetrapalmitate compared with other immunoadjuvants and its effects after tumour surgery. Brit. J. Cancer, 42: 703, 1980. 6. Elhilali, M., Ibrahiem, E. H. I., Nigam, V. N., Brailovsky, C. A. and Madarnas, P.: A comparative study of the intravesical MTP and BCG treatment of transplantable bladder cancer. J. Urol., 129: 1265, 1983. 7. Matthews, D. E. and Farewell, V. T.: Using and Understanding Medical Statistics. New York: S. Karger, 1985. 8. Bloomberg, S. D., Brosman, S. A., Hausman, M. S., Cohen, A. and Battenberg, J. D.: The effects of BCG on the dog bladder. Invest. Urol., 12: 423, 1975. 9. Camacho, F., Pinsky, C. M., Kerr, D., Whitmore, W. and Oettgen, H.: Treatment of superficial bladder cancer with intravesical BCG. Proc. Amer. Ass. Cancer Res. Amer. Soc. Clin. Oncol., 21: 359, abstract C-160, 1980. 10. Herr, H. W., Pinsky, C. M., Whitmore, W. F., Jr., Oettgen, H. F. and Melamed, M. R.: Effects of intravesical bacillus CalmetteGuerin (BCG) on carcinoma in situ of the bladder. Cancer, 51: 1323, 1983. 11. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 12. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer, 48: 82, 1981. 13. Ibraheim, E. H., El Kappany, H., Nigam, V. N., Brailovsky, C. A., Madarnas, P. and Elhilali, M. M.: Adjuvant immunotherapy of N-[ 4(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced bladder tumors. Anticancer Res., 4: 209, 1984. 14. Lamm, D. L., Stogdill, V. D. and Thor, D. E.: BCG immunotherapy in superficial transitional cell carcinoma of the urinary bladder. Proc. Amer. Ass. Cancer Res. Amer. Soc. Clin. Oncol., 21: 372, abstract C-208, 1980. 15. Zbar, B. and Rapp, H. J.: Immunotherapy of guinea pig cancer with BCG. Cancer, 34: 1532, 1974. 16. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 17. Haaff, E. 0., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136: 820, 1986.