© 1990 S. Karger AG, Basel 0042-1138/90/0453-0137S2.75/0
Urol Int 1990;45:137-141
Intravesical Bacillus Calmette-Guerin Prophylactic Treatment for Superficial Bladder Tumors: Results of a Controlled Prospective Study Michael D. Melekos Department of Urology, University of Patras School of Medicine, Rio, Patras, Greece
Keywords. Bladder cancer • Superficial bladder tumors • BCG therapy Abstract. A controlled prospective study in 100 patients evaluated the efficacy of intravesical bacillus CalmetteGuérin (BCG) administration as prophylactic treatment on tumor recurrence and tumor progression rate after endoscopic resection of superficial transitional cell carcinoma of the bladder. There were 27 recurrences in 22 of 67 evaluable patients (33%) who received BCG, compared to 27 recurrences in 19 of 33 control patients (58%) (p < 0.05). The mean follow-up periods for the tumor-free patients in the BCG and control groups were 29 and 30 months, respectively, while the mean times to tumor recurrences for the above groups were 13.36 ± 6 and 9.94 ± 5 months, respectively (p < 0.05). The recurrence rates per 100 patient months for the BCG and control patients were 1.69 and 4.41 recurrences, respectively (p < 0.05), while 7 patients of the BCG group showed recurrent tumors of higher stage or grade, compared to 13 of the controls (p < 0.05). This study confirms that Pasteur strain BCG is safe and efficacious in the prevention of superficial bladder tumor recurrence and tumor progression.
One of the major problems the clinician faces after the initial transurethral resection (TUR) of the superfi cial bladder cancer, which represents 70-80% of all blad der malignancies [1], is the high incidence of subsequent tumors that occur in 40-80% of the patients [2-5], An additional problem is the approximately 20% progres sion rate in tumor stage and grade of the recurrent dis ease [2, 5, 6]. Adjuvant prophylactic intracavitary chemotherapy with several different agents following TUR has been advocated to improve the above situation. Among these agents, bacillus Calmette-Gu6rin (BCG) has proved to be efficacious in multiple clinical trials in the reduction of tumor recurrence rates [7-17], but the optimal treatment dose and schedule have not been established. On the other hand, the characterization of patients and their type of tumors as well as follow-up periods vary to a great extent.
The experience in the present prospective controlled study with 100 patients suffering from superficial blad der carcinoma and randomized to initial TUR alone or to adjuvant intravesical BCG after TUR, followed by a quarterly maintenance dose in the prophylaxis of tumor recurrence, provides additional useful data to aid physi cians who manage patients with intravesical BCG instil lation.
Material and Methods One hundred patients with superficial bladder carcinoma (Ta and T| in stage) who were available for follow-up have been enrolled in an ongoing prospective controlled study. Before randomization of patients existing tumors were completely resected. After histologic confirmation of the diagnosis, patients were divided randomly on a 2:1 basis into two groups, the first including those treated with TUR of the tumors alone, and the second those who received intravesical BCG therapy following the initial TUR. The study included patients with primary or recurrent carcinoma following a previous TUR (av
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Introduction
138
Meiekos
Immunotherapy BCG immunotherapy consisted of 2 ampoules containing 150 mg (1 ampoule = 75 mg) Pasteur strain viable vaccine (immune BCG Pasteur F*, with manufacturer specifications of approxi mately 6 ± 4 X 108 CFU/ampoule) suspended in 50 ml sterile saline, which were given intravesically and held for 2 h. Instillations were initiated within 2-3 weeks after the last TUR and given weekly for 8 consecutive weeks. Evaluation Both patient groups were followed at regular 3-month intervals with cystoscopic, histologic and cytologic examinations. At these intervals and during follow-up period which lasted at least 24 months for all patients, BCG group patients received a maintenance dose (2 ampoules) of intravesical BCG 3-5 days after each follow-up evaluation when the latter revealed no evidence of tumor. Patients in this group were also monitored for BCG toxicity. Treatment and control patients were skin-tested with purified protein derivative (PPD), which was repeated only in the BCG group patients 3-4 months after the initiation of BCG treatment (table 1).
Results Completion of at least 24 posttreatment months of follow-up with absence of endoscopic, histologic and cytologic evidence of cancer was defined as a success, whereas failure as a recurrence of tumor(s) in any of these three investigations at the immediate posttreat ment examinations or at a late date during follow-up. Table 2 summarizes the overall results. There were 27 tumor recurrences in 22 of 67 evalu able patients (33%) who were treated with TUR and BCG and followed for a total 1,593 months, compared to 27 recurrences in 19 of 33 control patients (58%) fol lowed for a total 612 months. Thus, the recurrence rate per 100 patient months with BCG was 1.69 (or 0.2/12
Table 1. Patient and tumor characteristics Groups
Control BCG Totals
Mean age years
Number of patients
Sex male
female
33 67 100
28 (85) 57 (85) 85
5(15) 10(15) 15
68.36±8.78 67.64 ±8.47 67.88 ±8.54
Apart from the mean age, the figures represent numbers with the percentage given in parentheses.
patient months) versus 4.41 (or 0.53/12 patient months), a difference statistically significant (%2 test with Yates correction, p < 0.01) (table 2). The mean follow-up peri ods for tumor-free patients in the BCG and control groups were 28.86 ± 3.74 and 30.21 ± 2.75 months, respectively. The mean intervals to tumor recurrences for BCG patients and the controls were 13.36 ± 6.05 and 9.94 ± 5 months, respectively (Student t test, twosided, DF = 39, p < 0.05) (table 2). Of the 67 BCG patients, 90% were tumor-free after 9 months of follow-up, but this percentage decreased to 84, 72 and 67% after 12, 18 and 24 months of follow-up, respectively. On the other hand, of the 33 controls, 70% were tumor-free after 9 months of follow-up, but this percentage declined to 58, 48 and 42% after 12, 18 and 24 months of follow-up, respectively. Of the 22 BCG failures, 7 showed progression of disease by stage (4 patients) and grade (3 patients), whereas, of the 19 fail ures among the control patients, 8 had disease that had progressed to a higher stage and 5 to a higher grade. Three patients, 2 in the BCG and 1 in the control group, developed tumor occurrences in the prostatic urethra. Two of these patients (1 in each group) had concomitant bladder or/and prostatic urethral carcinoma in situ, while in the 3rd of the BCG group the bladder was free of carcinoma. Additionally, in 1 patient who received BCG a distal ureteric transitional cell cancer appeared, al though no tumor recurrences were present in the bladder during follow-up. Interestingly, in 1 patient of those treated with BCG a nonbladder primary malignancy (carcinoma of the lungs) was demonstrated 9 months after BCG course of therapy. Of the 40 patients (60%) in the BCG group who had negative PPD skin tests before treatment, in 26 the skin
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
erage time to first TUR was 9 months), presenting with either single or multiple tumors. No patient had received previous chemotherapy or radiotherapy. All patients underwent multiple random biopsies close and far from the tumors at TUR. Carcinoma in situ was present in 3 patients, all in the BCG group. Patients underwent one or more TURs at the beginning of the study, depending on the T stage of the cancer, and the last TUR was followed by endoscopic, histologic and cytologic examinations of the voided urine or/and bladder washing samples within 3-4 weeks after the patients were discharged from the hospital. Subjects who had positive cytologic or residual tumors when examined (n = 5) underwent another TUR. When patients entered the study, none of them had evidence of residual cancer as judged by endoscopy, biopsy and cytology. Clinical data of all sub jects are presented in table 1. Both groups were remarkably compa rable in respect of mean age. sex ratio, tumor stage and grade and distribution of primary, recurrent and multiple tumors (t test, p > 0.05) (table 1).
Intravesical BCG Prophylactic Treatment for Superficial Bladder Tumors
139
PPD skin test before treatment
Tumor(s) primary
21 (64) 44 (66) 65
recurrent
12(36) 23 (34) 35
grade
multiple stage tumors present ------------------before study Ta T, 7(21) 14(21) 21
16 (48) 27 (40) 43
17(52) 40 (60) 57
I
II
III
positive
negative
11 (33) 24 (36) 35
19 (58) 34(51) 53
3(9) 903) 12
14 (42) 27 (40) 41
19 (58) 40 (60) 59
Table 2. Summary of results Outcome
Control group (n = 33)
14(42) Tumor free patients 19 (58) Patients with tumor recurrences 9.94 ±5 Mean interval to tumor recurrences, months 30.21 ±2.75 Mean follow-up of tumor-free patients, months 4.41 Recurrences rate/100 patient months 8(24) Tumor progression in stage Tumor progression in grade 5(15) BCG treatment results and correlation with PPD skin test responses Conversion to positive Patients with recurrences Patients free of tumor No conversion (negative) Patients with recurrences Patients free of tumor Previously sensitized Patients with recurrences Patients free of tumor Totals Patients with recurrences Patients free of tumor
BCG group (n = 67) 45 (67) - | 22 (33) J 13.36 ±6.05 28.86 ± 3.74 1.69 4(6) 3(4) J 26 5(19) 21 (81) 14 8 (57) 6(43) 27 9(33) 18 (67) 67 22 (33) 45 (67)
Statistical evaluation
X2 test
with Yates correction, p < 0.05
Student t test, two-sided, DF = 39, p < 0.05 Student t test, p > 0.05 X2 test with Yates correction, p < 0.01 X2
test, DF - 3, p < 0.01
X2 test, DF = 2. p < 0.05
test results converted to positive after the 8-week course of intravesical BCG therapy with only 5 (19%) suffering recurrent tumors. Patients whose skin tests were positive before BCG (40%) or patients who failed to convert fol lowing BCG administration had a 33 and 57% incidence of tumor recurrence, respectively, a difference statisti cally significant (standard y} test, DF = 2, p < 0.05) (table 2).
Adverse reactions to BCG treatment generally were mild and brief. These were: irritative vesical symptoms (lasting 1-3 days) in 84 % of the cases, fever with or with out chills in 27%, macroscopic hematuria in 21%, influenza-like syndrome in 10%, tiredness and weakness in 9%, nausea and vomiting, as well as urinary tract infec tion and malaise in 7% each, flank pain, epididymorchitis and polyarthralgia in 1 patient each.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Apart from those representing time spans, figures show number of patients with the percentage given in parentheses.
Meiekos
140
In this prospective trial, the observation of the control group has confirmed the high recurrence rate of superfi cial bladder tumors, with at least 20% chance of progres sion of the recurrent cancer [18-20], This study has also confirmed previous reports indicating that intravesical BCG therapy alters favorably the pattern of tumor recur rence in a significant percentage of patients with superfi cial bladder carcinoma [7-17], Sixty-seven percent of the patients in the BCG group were free of tumor recur rences for a mean follow-up of approximately 29 months, compared to only 42% of the control patients for almost the same follow-up period. Likewise, the mean times to tumor recurrences and the rates of tumor recurrences per 100 patient months were 13.36 versus 9.94 months and 1.69 versus 4.41 recurrences, respec tively (p < 0.05). If the aim of the adjuvant prophylactic intracavitary BCG therapy is to prevent recurrences, these two last parameters may perhaps be considered among the most important end points. Regarding the tumor progression, the superiority of the BCG group between these two groups in diminishing the progression rate into a higher stage and grade of the disease was evi dent (p < 0.05) (table 2). The experience here and that of others has shown that the relatively prolonged BCG instillations in general were self-limiting even by the elderly population in cluded herein [9, 12, 13]. Quarterly maintenance treat ment was administered on the assumption that this would enhance the antitumor activity of BCG despite the relatively recent reports which claim that mainte nance therapy has no apparent benefit in terms of recur rence [15, 21], Recent reports have raised anxiety regarding a re markable incidence of cancer in other sites than the blad der amongst patients receiving BCG treatment [22], Al though BCG therapy on a patient with primary carci noma is expected to eliminate this tumor, animal and human studies of BCG use for treatment of several malignancies have shown in some instances a rapid development and spread of these malignancies when BCG was administered apparently before the tumors were well established, while second primary malignan cies were seen to develop and progress with variable speed [8, 22-26]. Khanna et al. [22] suggest that the tem poral relationship between the starting point of tumor development and the starting point of BCG treatment could be crucial in determining whether BCG will eradi cate or exacerbate the tumor. In the present series a
metachronous carcinoma of the lungs was developed in 1 patient 9 months after the completion of BCG therapy, while a distal ureteric papillary carcinoma appeared in another patient and a progression of the disease was demonstrated in some others after the end of BCG treat ment. However, it can not be concluded that BCG was the incriminating factor for these phenomena. Transitional cell carcinoma of the bladder has been shown to be an antigenic tumor [27], while BCG is known to produce immunostimulation [28], Intracavi tary BCG treatment is well suited for patients with superficial bladder cancer, since they are more or less immunologically competent [27], have a limited tumor load and their bladders permit close proximity between the BCG living organisms and tumor cells [7, 9, 14, 29], In this study, the observation of tumor occurrence in the prostatic urethra (which is bathed insufficiently by the drug) and distal ureter (where normally no bathing at all occurs), while the bladder remained free of tumor after BCG administration, and the reports that intracavitary BCG instillation alone is as effective as intravesical and intradermal BCG in reducing the recurrence rate of blad der cancer, strengthens the perception that direct contact and local reaction are important for successful treat ment. Regarding PPD skin test response, it has been shown in the present trial that a statistically significant correla tion (p < 0.05) exists between a delayed hypersensitivity response to PPD and BCG therapy results (table 2), that is an immune response to BCG antigens is a favorable prognostic indicator. This correlation strongly indicates the role of systemic immunologic mechanisms of BCG administration. The experience gained in this study confirms that Pasteur strain BCG for intravesical instillations is safe and efficacious in the prophylactic treatment of superfi cial transitional cell carcinoma of the urinary bladder.
References 1 Lum, B.L.: Intravesical chemotherapy of superficial bladder can cer; in Torti, Urologie cancer: chemotherapeutic principles and management, pp. 3-36 (Spinger, New York 1983). 2 Zincke, H.: Das Blasenkarzinom. Verhandlungsbericht der Deutschen Gesellschaft für Urologie (Spinger, New York 1979). 3 Pavone-Malacuso, M.: Diagnosis and treatment of superficial bladder tumors (Farmitalia Carlo Erba, Milano 1982). 4 Dresner, S.M.; Haaff, E.O.; Ratliff, T.L.; et al.: Bacillus Calmette-Guörin intravesical therapy for superficial bladder cancer. Urology Ground Rounds, pp. 1-9, October 1984.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Discussion
Intravesical BCG Prophylactic Treatment for Superficial Bladder Tumors
20 Lutzeyer, W.; Rübben, H.; Dahm, H.: Prognostic parameters in superficial cancer: an analysis of 315 cases. J. Urol. 127: 250252 (1982). 21 Badalament, R.A.; Herr, H.W.; Wong, G. Y.; et al.: A prospective randomized trial of maitenance versus nonmaintenance intrave sical bacillus Calmette-Guérin therapy of superficial bladder cancer. J. clin. Oncol. 5: 441-449 (1987). 22 Khanna, O.P.; Chon, R.H.; Son, D.L.; et al.: Does bacillus Cal mette-Guérin immunotherapy accelerate growth and cause met astatic spread of second primary malignancy? Urology 31: 459468 (1988). 23 Pang, A.S.D.; Morales, A.: Immunotherapy of a murine bladder cancer with high dose BCG immunizations. J. Urol. 127: 1006— 1009 (1982). 24 Pinsky, C.M.; Camacho, F.J.; Kerr, et al.: Intravesical adminis tration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospec tive, randomized trial. Cancer Treat. Rep. 69: 47-53 (1985). 25 Catalona, W.J.; Hudson, M.A.; Gillen, D.P.; et al.: Risks and benefits of repeated courses of intravesical bacillus CalmetteGuérin therapy for superficial bladder cancer. J. Urol. 137: 220224 (1987). 26 Herr, H.W.; Whitmore, W.F., Jr.: Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tu mor: incidence, possible pathogenesis and management. J. Urol. 138: 292-294 (1987). 27 Catalona, W.J.; Chretien, P.B.: Correlation among host immu nocompétence and tumor stage, tumor grade and vascular per meation in transitional cell carcinoma. J. Urol. 110: 526-528 (1973). 28 El-Demitry, M.I.M.; Smith, G.; Ritchie, A.W.S.; et al.: Local immune responses after intravesical BCG treatment for carci noma in situ. Br. J. Urol. 60: 543-548 (1987). 29 Zbar, B.: Rapp, H.J.: Immunotherapy of guinea pig cancer with BCG. Cancer 34: 1532-1536(1974).
Received: April 13, 1989 Accepted: July 6, 1989 Michael D. Melekos, MD Assistant Professor of Urology Agios Georgios Rio 60 Iroon Polytechniou Street 265 00 Rio, Patras (Greece)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
5 Soloway, M.S.: Selecting initial therapy for bladder cancer. Can cer, suppl. 60, pp. 502-513 (1987). 6 Herr, H.W.; Laudone, V.P.; Whitmore, W.F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol. 138: 1363-1368 (1987). 7 Morales, A.; Eidinger, D.; Bruce, A.W.: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumor. J. Urol. 116: 180-183 (1976). 8 Lamm, D.L.; Thor, D.E.; Harris, S.C.; et al.: Bacillus CalmetteGuérin immunotherapy of superficial bladder cancer. J. Urol. 124: 38-42 (1980). 9 Brosman, S.A.: Experience with bacillus Calmette-Guérin in patients with superficial bladder carcinoma. J. Urol. 128: 27-30 (1982). 10 Herr, H.W.; Pinsky, C.M.; Whitmore, W.F., Jr.; et al.: Experi ence with intravesical bacillus Calmette-Guérin therapy of su perficial bladder tumors. Urology 25: 119-123 (1985). 11 Lamm, D.L.: Bacillus Calmette-Guérin immunotherapy for bladder cancer. J. Urol. 134: 40-47 (1985). 12 Haaff, E.O.; Dresner, S.M.; Ratliff, T.L.; et al.: Two courses of intravesical bacillus Calmette-Guérin for transitional cell carci noma of the bladder. J. Urol. 136: 820-824 (1986). 13 Kelley, D.R.; Haaff, E.O.; Becich, M.; et al.: Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guérin. J. Urol. 135: 268-271 (1986). 14 Schellhammer, P.F.; Ladaga, L.E.; Fillion, M.B.: Bacillus Cal mette-Guérin for superficial transitional cell carcinoma of the bladder. J. Urol. 135: 261-264 (1986). 15 Hudson, M.A.; Ratliff, T.L.; Gillen, D.R.; et al.: Single course versus maintenance bacillus Calmette-Guérin therapy for super ficial bladder tumors: a prospective randomized trial. J. Urol. 138: 295-298 (1987). 16 Khanna, O.P.; Son, D.L.; Mazer, H.; et al.: Superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or Adriamycin: follow-up report. Urology 31: 287-293 (1988). 17 Soloway, M.S.; Perry, A.: Bacillus Calmette-Guérin for treat ment of superficial transitional cell carcinoma of the bladder in patients who have failed Thiotepa and/or Mitomycin C. J. Urol. 137: 871-873 (1987). 18 Barnes. R.; Hadley, H.; Dick, A.: et al.: Changes in grade and stage of recurrent bladder tumors. J. Urol. 118: 177-178 (1977). 19 Gilbert, H.A.; Logan. L.; Kogan, A.R.; et al.: The natural history of papillary transitional cell carcinoma of the bladder and its treatment in an unselected population on the basis of histologic grading. J. Urol. 119: 488-492 (1978).
141
Urol Int 1990;45:137-141
Intravesical Bacillus Calmette-Guerin Prophylactic Treatment for Superficial Bladder Tumors: Results of a Controlled Prospective Study Michael D. Melekos Department of Urology, University of Patras School of Medicine, Rio, Patras, Greece
Keywords. Bladder cancer • Superficial bladder tumors • BCG therapy Abstract. A controlled prospective study in 100 patients evaluated the efficacy of intravesical bacillus CalmetteGuérin (BCG) administration as prophylactic treatment on tumor recurrence and tumor progression rate after endoscopic resection of superficial transitional cell carcinoma of the bladder. There were 27 recurrences in 22 of 67 evaluable patients (33%) who received BCG, compared to 27 recurrences in 19 of 33 control patients (58%) (p < 0.05). The mean follow-up periods for the tumor-free patients in the BCG and control groups were 29 and 30 months, respectively, while the mean times to tumor recurrences for the above groups were 13.36 ± 6 and 9.94 ± 5 months, respectively (p < 0.05). The recurrence rates per 100 patient months for the BCG and control patients were 1.69 and 4.41 recurrences, respectively (p < 0.05), while 7 patients of the BCG group showed recurrent tumors of higher stage or grade, compared to 13 of the controls (p < 0.05). This study confirms that Pasteur strain BCG is safe and efficacious in the prevention of superficial bladder tumor recurrence and tumor progression.
One of the major problems the clinician faces after the initial transurethral resection (TUR) of the superfi cial bladder cancer, which represents 70-80% of all blad der malignancies [1], is the high incidence of subsequent tumors that occur in 40-80% of the patients [2-5], An additional problem is the approximately 20% progres sion rate in tumor stage and grade of the recurrent dis ease [2, 5, 6]. Adjuvant prophylactic intracavitary chemotherapy with several different agents following TUR has been advocated to improve the above situation. Among these agents, bacillus Calmette-Gu6rin (BCG) has proved to be efficacious in multiple clinical trials in the reduction of tumor recurrence rates [7-17], but the optimal treatment dose and schedule have not been established. On the other hand, the characterization of patients and their type of tumors as well as follow-up periods vary to a great extent.
The experience in the present prospective controlled study with 100 patients suffering from superficial blad der carcinoma and randomized to initial TUR alone or to adjuvant intravesical BCG after TUR, followed by a quarterly maintenance dose in the prophylaxis of tumor recurrence, provides additional useful data to aid physi cians who manage patients with intravesical BCG instil lation.
Material and Methods One hundred patients with superficial bladder carcinoma (Ta and T| in stage) who were available for follow-up have been enrolled in an ongoing prospective controlled study. Before randomization of patients existing tumors were completely resected. After histologic confirmation of the diagnosis, patients were divided randomly on a 2:1 basis into two groups, the first including those treated with TUR of the tumors alone, and the second those who received intravesical BCG therapy following the initial TUR. The study included patients with primary or recurrent carcinoma following a previous TUR (av
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Introduction
138
Meiekos
Immunotherapy BCG immunotherapy consisted of 2 ampoules containing 150 mg (1 ampoule = 75 mg) Pasteur strain viable vaccine (immune BCG Pasteur F*, with manufacturer specifications of approxi mately 6 ± 4 X 108 CFU/ampoule) suspended in 50 ml sterile saline, which were given intravesically and held for 2 h. Instillations were initiated within 2-3 weeks after the last TUR and given weekly for 8 consecutive weeks. Evaluation Both patient groups were followed at regular 3-month intervals with cystoscopic, histologic and cytologic examinations. At these intervals and during follow-up period which lasted at least 24 months for all patients, BCG group patients received a maintenance dose (2 ampoules) of intravesical BCG 3-5 days after each follow-up evaluation when the latter revealed no evidence of tumor. Patients in this group were also monitored for BCG toxicity. Treatment and control patients were skin-tested with purified protein derivative (PPD), which was repeated only in the BCG group patients 3-4 months after the initiation of BCG treatment (table 1).
Results Completion of at least 24 posttreatment months of follow-up with absence of endoscopic, histologic and cytologic evidence of cancer was defined as a success, whereas failure as a recurrence of tumor(s) in any of these three investigations at the immediate posttreat ment examinations or at a late date during follow-up. Table 2 summarizes the overall results. There were 27 tumor recurrences in 22 of 67 evalu able patients (33%) who were treated with TUR and BCG and followed for a total 1,593 months, compared to 27 recurrences in 19 of 33 control patients (58%) fol lowed for a total 612 months. Thus, the recurrence rate per 100 patient months with BCG was 1.69 (or 0.2/12
Table 1. Patient and tumor characteristics Groups
Control BCG Totals
Mean age years
Number of patients
Sex male
female
33 67 100
28 (85) 57 (85) 85
5(15) 10(15) 15
68.36±8.78 67.64 ±8.47 67.88 ±8.54
Apart from the mean age, the figures represent numbers with the percentage given in parentheses.
patient months) versus 4.41 (or 0.53/12 patient months), a difference statistically significant (%2 test with Yates correction, p < 0.01) (table 2). The mean follow-up peri ods for tumor-free patients in the BCG and control groups were 28.86 ± 3.74 and 30.21 ± 2.75 months, respectively. The mean intervals to tumor recurrences for BCG patients and the controls were 13.36 ± 6.05 and 9.94 ± 5 months, respectively (Student t test, twosided, DF = 39, p < 0.05) (table 2). Of the 67 BCG patients, 90% were tumor-free after 9 months of follow-up, but this percentage decreased to 84, 72 and 67% after 12, 18 and 24 months of follow-up, respectively. On the other hand, of the 33 controls, 70% were tumor-free after 9 months of follow-up, but this percentage declined to 58, 48 and 42% after 12, 18 and 24 months of follow-up, respectively. Of the 22 BCG failures, 7 showed progression of disease by stage (4 patients) and grade (3 patients), whereas, of the 19 fail ures among the control patients, 8 had disease that had progressed to a higher stage and 5 to a higher grade. Three patients, 2 in the BCG and 1 in the control group, developed tumor occurrences in the prostatic urethra. Two of these patients (1 in each group) had concomitant bladder or/and prostatic urethral carcinoma in situ, while in the 3rd of the BCG group the bladder was free of carcinoma. Additionally, in 1 patient who received BCG a distal ureteric transitional cell cancer appeared, al though no tumor recurrences were present in the bladder during follow-up. Interestingly, in 1 patient of those treated with BCG a nonbladder primary malignancy (carcinoma of the lungs) was demonstrated 9 months after BCG course of therapy. Of the 40 patients (60%) in the BCG group who had negative PPD skin tests before treatment, in 26 the skin
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
erage time to first TUR was 9 months), presenting with either single or multiple tumors. No patient had received previous chemotherapy or radiotherapy. All patients underwent multiple random biopsies close and far from the tumors at TUR. Carcinoma in situ was present in 3 patients, all in the BCG group. Patients underwent one or more TURs at the beginning of the study, depending on the T stage of the cancer, and the last TUR was followed by endoscopic, histologic and cytologic examinations of the voided urine or/and bladder washing samples within 3-4 weeks after the patients were discharged from the hospital. Subjects who had positive cytologic or residual tumors when examined (n = 5) underwent another TUR. When patients entered the study, none of them had evidence of residual cancer as judged by endoscopy, biopsy and cytology. Clinical data of all sub jects are presented in table 1. Both groups were remarkably compa rable in respect of mean age. sex ratio, tumor stage and grade and distribution of primary, recurrent and multiple tumors (t test, p > 0.05) (table 1).
Intravesical BCG Prophylactic Treatment for Superficial Bladder Tumors
139
PPD skin test before treatment
Tumor(s) primary
21 (64) 44 (66) 65
recurrent
12(36) 23 (34) 35
grade
multiple stage tumors present ------------------before study Ta T, 7(21) 14(21) 21
16 (48) 27 (40) 43
17(52) 40 (60) 57
I
II
III
positive
negative
11 (33) 24 (36) 35
19 (58) 34(51) 53
3(9) 903) 12
14 (42) 27 (40) 41
19 (58) 40 (60) 59
Table 2. Summary of results Outcome
Control group (n = 33)
14(42) Tumor free patients 19 (58) Patients with tumor recurrences 9.94 ±5 Mean interval to tumor recurrences, months 30.21 ±2.75 Mean follow-up of tumor-free patients, months 4.41 Recurrences rate/100 patient months 8(24) Tumor progression in stage Tumor progression in grade 5(15) BCG treatment results and correlation with PPD skin test responses Conversion to positive Patients with recurrences Patients free of tumor No conversion (negative) Patients with recurrences Patients free of tumor Previously sensitized Patients with recurrences Patients free of tumor Totals Patients with recurrences Patients free of tumor
BCG group (n = 67) 45 (67) - | 22 (33) J 13.36 ±6.05 28.86 ± 3.74 1.69 4(6) 3(4) J 26 5(19) 21 (81) 14 8 (57) 6(43) 27 9(33) 18 (67) 67 22 (33) 45 (67)
Statistical evaluation
X2 test
with Yates correction, p < 0.05
Student t test, two-sided, DF = 39, p < 0.05 Student t test, p > 0.05 X2 test with Yates correction, p < 0.01 X2
test, DF - 3, p < 0.01
X2 test, DF = 2. p < 0.05
test results converted to positive after the 8-week course of intravesical BCG therapy with only 5 (19%) suffering recurrent tumors. Patients whose skin tests were positive before BCG (40%) or patients who failed to convert fol lowing BCG administration had a 33 and 57% incidence of tumor recurrence, respectively, a difference statisti cally significant (standard y} test, DF = 2, p < 0.05) (table 2).
Adverse reactions to BCG treatment generally were mild and brief. These were: irritative vesical symptoms (lasting 1-3 days) in 84 % of the cases, fever with or with out chills in 27%, macroscopic hematuria in 21%, influenza-like syndrome in 10%, tiredness and weakness in 9%, nausea and vomiting, as well as urinary tract infec tion and malaise in 7% each, flank pain, epididymorchitis and polyarthralgia in 1 patient each.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Apart from those representing time spans, figures show number of patients with the percentage given in parentheses.
Meiekos
140
In this prospective trial, the observation of the control group has confirmed the high recurrence rate of superfi cial bladder tumors, with at least 20% chance of progres sion of the recurrent cancer [18-20], This study has also confirmed previous reports indicating that intravesical BCG therapy alters favorably the pattern of tumor recur rence in a significant percentage of patients with superfi cial bladder carcinoma [7-17], Sixty-seven percent of the patients in the BCG group were free of tumor recur rences for a mean follow-up of approximately 29 months, compared to only 42% of the control patients for almost the same follow-up period. Likewise, the mean times to tumor recurrences and the rates of tumor recurrences per 100 patient months were 13.36 versus 9.94 months and 1.69 versus 4.41 recurrences, respec tively (p < 0.05). If the aim of the adjuvant prophylactic intracavitary BCG therapy is to prevent recurrences, these two last parameters may perhaps be considered among the most important end points. Regarding the tumor progression, the superiority of the BCG group between these two groups in diminishing the progression rate into a higher stage and grade of the disease was evi dent (p < 0.05) (table 2). The experience here and that of others has shown that the relatively prolonged BCG instillations in general were self-limiting even by the elderly population in cluded herein [9, 12, 13]. Quarterly maintenance treat ment was administered on the assumption that this would enhance the antitumor activity of BCG despite the relatively recent reports which claim that mainte nance therapy has no apparent benefit in terms of recur rence [15, 21], Recent reports have raised anxiety regarding a re markable incidence of cancer in other sites than the blad der amongst patients receiving BCG treatment [22], Al though BCG therapy on a patient with primary carci noma is expected to eliminate this tumor, animal and human studies of BCG use for treatment of several malignancies have shown in some instances a rapid development and spread of these malignancies when BCG was administered apparently before the tumors were well established, while second primary malignan cies were seen to develop and progress with variable speed [8, 22-26]. Khanna et al. [22] suggest that the tem poral relationship between the starting point of tumor development and the starting point of BCG treatment could be crucial in determining whether BCG will eradi cate or exacerbate the tumor. In the present series a
metachronous carcinoma of the lungs was developed in 1 patient 9 months after the completion of BCG therapy, while a distal ureteric papillary carcinoma appeared in another patient and a progression of the disease was demonstrated in some others after the end of BCG treat ment. However, it can not be concluded that BCG was the incriminating factor for these phenomena. Transitional cell carcinoma of the bladder has been shown to be an antigenic tumor [27], while BCG is known to produce immunostimulation [28], Intracavi tary BCG treatment is well suited for patients with superficial bladder cancer, since they are more or less immunologically competent [27], have a limited tumor load and their bladders permit close proximity between the BCG living organisms and tumor cells [7, 9, 14, 29], In this study, the observation of tumor occurrence in the prostatic urethra (which is bathed insufficiently by the drug) and distal ureter (where normally no bathing at all occurs), while the bladder remained free of tumor after BCG administration, and the reports that intracavitary BCG instillation alone is as effective as intravesical and intradermal BCG in reducing the recurrence rate of blad der cancer, strengthens the perception that direct contact and local reaction are important for successful treat ment. Regarding PPD skin test response, it has been shown in the present trial that a statistically significant correla tion (p < 0.05) exists between a delayed hypersensitivity response to PPD and BCG therapy results (table 2), that is an immune response to BCG antigens is a favorable prognostic indicator. This correlation strongly indicates the role of systemic immunologic mechanisms of BCG administration. The experience gained in this study confirms that Pasteur strain BCG for intravesical instillations is safe and efficacious in the prophylactic treatment of superfi cial transitional cell carcinoma of the urinary bladder.
References 1 Lum, B.L.: Intravesical chemotherapy of superficial bladder can cer; in Torti, Urologie cancer: chemotherapeutic principles and management, pp. 3-36 (Spinger, New York 1983). 2 Zincke, H.: Das Blasenkarzinom. Verhandlungsbericht der Deutschen Gesellschaft für Urologie (Spinger, New York 1979). 3 Pavone-Malacuso, M.: Diagnosis and treatment of superficial bladder tumors (Farmitalia Carlo Erba, Milano 1982). 4 Dresner, S.M.; Haaff, E.O.; Ratliff, T.L.; et al.: Bacillus Calmette-Guörin intravesical therapy for superficial bladder cancer. Urology Ground Rounds, pp. 1-9, October 1984.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
Discussion
Intravesical BCG Prophylactic Treatment for Superficial Bladder Tumors
20 Lutzeyer, W.; Rübben, H.; Dahm, H.: Prognostic parameters in superficial cancer: an analysis of 315 cases. J. Urol. 127: 250252 (1982). 21 Badalament, R.A.; Herr, H.W.; Wong, G. Y.; et al.: A prospective randomized trial of maitenance versus nonmaintenance intrave sical bacillus Calmette-Guérin therapy of superficial bladder cancer. J. clin. Oncol. 5: 441-449 (1987). 22 Khanna, O.P.; Chon, R.H.; Son, D.L.; et al.: Does bacillus Cal mette-Guérin immunotherapy accelerate growth and cause met astatic spread of second primary malignancy? Urology 31: 459468 (1988). 23 Pang, A.S.D.; Morales, A.: Immunotherapy of a murine bladder cancer with high dose BCG immunizations. J. Urol. 127: 1006— 1009 (1982). 24 Pinsky, C.M.; Camacho, F.J.; Kerr, et al.: Intravesical adminis tration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospec tive, randomized trial. Cancer Treat. Rep. 69: 47-53 (1985). 25 Catalona, W.J.; Hudson, M.A.; Gillen, D.P.; et al.: Risks and benefits of repeated courses of intravesical bacillus CalmetteGuérin therapy for superficial bladder cancer. J. Urol. 137: 220224 (1987). 26 Herr, H.W.; Whitmore, W.F., Jr.: Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tu mor: incidence, possible pathogenesis and management. J. Urol. 138: 292-294 (1987). 27 Catalona, W.J.; Chretien, P.B.: Correlation among host immu nocompétence and tumor stage, tumor grade and vascular per meation in transitional cell carcinoma. J. Urol. 110: 526-528 (1973). 28 El-Demitry, M.I.M.; Smith, G.; Ritchie, A.W.S.; et al.: Local immune responses after intravesical BCG treatment for carci noma in situ. Br. J. Urol. 60: 543-548 (1987). 29 Zbar, B.: Rapp, H.J.: Immunotherapy of guinea pig cancer with BCG. Cancer 34: 1532-1536(1974).
Received: April 13, 1989 Accepted: July 6, 1989 Michael D. Melekos, MD Assistant Professor of Urology Agios Georgios Rio 60 Iroon Polytechniou Street 265 00 Rio, Patras (Greece)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/4/2018 3:00:20 AM
5 Soloway, M.S.: Selecting initial therapy for bladder cancer. Can cer, suppl. 60, pp. 502-513 (1987). 6 Herr, H.W.; Laudone, V.P.; Whitmore, W.F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol. 138: 1363-1368 (1987). 7 Morales, A.; Eidinger, D.; Bruce, A.W.: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumor. J. Urol. 116: 180-183 (1976). 8 Lamm, D.L.; Thor, D.E.; Harris, S.C.; et al.: Bacillus CalmetteGuérin immunotherapy of superficial bladder cancer. J. Urol. 124: 38-42 (1980). 9 Brosman, S.A.: Experience with bacillus Calmette-Guérin in patients with superficial bladder carcinoma. J. Urol. 128: 27-30 (1982). 10 Herr, H.W.; Pinsky, C.M.; Whitmore, W.F., Jr.; et al.: Experi ence with intravesical bacillus Calmette-Guérin therapy of su perficial bladder tumors. Urology 25: 119-123 (1985). 11 Lamm, D.L.: Bacillus Calmette-Guérin immunotherapy for bladder cancer. J. Urol. 134: 40-47 (1985). 12 Haaff, E.O.; Dresner, S.M.; Ratliff, T.L.; et al.: Two courses of intravesical bacillus Calmette-Guérin for transitional cell carci noma of the bladder. J. Urol. 136: 820-824 (1986). 13 Kelley, D.R.; Haaff, E.O.; Becich, M.; et al.: Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guérin. J. Urol. 135: 268-271 (1986). 14 Schellhammer, P.F.; Ladaga, L.E.; Fillion, M.B.: Bacillus Cal mette-Guérin for superficial transitional cell carcinoma of the bladder. J. Urol. 135: 261-264 (1986). 15 Hudson, M.A.; Ratliff, T.L.; Gillen, D.R.; et al.: Single course versus maintenance bacillus Calmette-Guérin therapy for super ficial bladder tumors: a prospective randomized trial. J. Urol. 138: 295-298 (1987). 16 Khanna, O.P.; Son, D.L.; Mazer, H.; et al.: Superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or Adriamycin: follow-up report. Urology 31: 287-293 (1988). 17 Soloway, M.S.; Perry, A.: Bacillus Calmette-Guérin for treat ment of superficial transitional cell carcinoma of the bladder in patients who have failed Thiotepa and/or Mitomycin C. J. Urol. 137: 871-873 (1987). 18 Barnes. R.; Hadley, H.; Dick, A.: et al.: Changes in grade and stage of recurrent bladder tumors. J. Urol. 118: 177-178 (1977). 19 Gilbert, H.A.; Logan. L.; Kogan, A.R.; et al.: The natural history of papillary transitional cell carcinoma of the bladder and its treatment in an unselected population on the basis of histologic grading. J. Urol. 119: 488-492 (1978).
141
