© 1991 S. Karger AG, Basel 0302—2838/91/0201—0019$2.75/0
Eur Urol 1991;20:19-25
Intravesical Chemotherapy (Mitomycin C) versus Immunotherapy (Bacillus Calmette-Guérin) in Superficial Bladder Cancer E. Rintala, K. Jauhiainen, O. Alfthan, E. Hansson, H. Juusela, K. Kanerva, H. Korhonen, J. Permi, M. Sotarauta, T. Vaalasti, J. Viitanen, R. Usenius Finnbladder Group, Urological Clinic, Helsinki University Central Hospital, Helsinki, Finland
1606037
Key Words. Intravesical therapy • Superficial bladder cancer • Mitomycin C • Bacillus Calmette-Guérin Abstract. Both intravesical mitomycin C (MMC) and bacillus Calmette-Guérin (BCG; Pasteur strain F) were effective in the present prospective randomized multicenter study consisting of 91 patients with frequently recurrent superficial (Ta-Ti) bladder cancer. The result was in favour of BCG, as shown by the measurements with complete response (CR), disease-free interval and recurrence rate. CR of 58% with MMC and 40% with BCG were reached in 22 instillation series on carcinoma in situ of 18 patients. Due to side effects, MMC instillations were discontinued in 8.6%, and BCG instillations in 19.6%, respectively. After the 2-year follow-up also 1 case of pulmonary tuberculosis occurred in the BCG group.
Intravesical chemoprophylaxis following transure thral resection (TUR) of superficial (Ta-Ti) bladder can cer has gained a wide use. A limited number of local cytostatics has proved to be safe in use, also reduces recurrence rate and is beneficial for delaying and pre venting progression. Some intravesical agents have shown to be cytotoxic on residual carcinoma and carci noma in situ (Tis), although these indications need more experience before solid recommendations can be given. During the last two decades, the main interest has focused on antibiotic cytostatics, among which mitomy cin C (MMC) is one of the most effective and safe agents [1-9]. Many authors have claimed that intravesical immu notherapy with bacillus Calmette-Guérin (BCG) is supe rior to other forms of intravesical treatments [10-14], Randomized studies comparing BCG with MMC were not published when the present study was designed and initiated in 1984.
Material and Methods The prospective multicenter study enrolled 109 patients in 1984-87: 18 with T]S grade 1-3 and 91 patients with frequently recurrent Ta-Ti papillary transitional cell cancer grade 1-3. Inclu sion criteria for TiS required histologically verified malignancy and/or three consecutive malignant cytological findings (Papanico laou class V). In the present study, however, all patients with Tis had a histological confirmation. Ta-Ti cancers with a minimum of two episodes of recurrence during the preceding 1.5 years were accepted. Recurrence rate (RR = number of recurrence times/100 follow-up months) and the recurrence index (Rl/m = number of recurrent tumors/month) were calculated as from the first reappearance of bladder cancer [15-17], Classification of tumors was performed according to the rules of the WHO of 1973, and UICC of 1978 [18, 19]. The upper urinary tract was excluded as a source of malignant cytology by ureteral cytology, intravenous and retrograde pyelogra phy when needed. Urethral or prostatic involvement was excluded by urethroscopy and biopsies. Patients were randomly allocated to receive either local MMC or BCG. 7 persons were transferred from the BCG to the MMC group due to negative PPD skin tests. The two treatment groups were identical in randomization characteristics (table 1). All visible le sions were treated by TUR. Instillations of both groups were started 2 weeks later, repeated weekly during the first month, and once a Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
Introduction
Rintala/Jauhiainen/Alfthan/Hansson/Juusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
Table 1. Randomization characteristics
Number of patients Male Female Age, years
MMC
BCG
58 41 17 67
51 39
12 68
Stage and Grade Tb
12
6
8
4
4
2
Primary Secondary Gl G2 G3
2
1
4
2
6
3 45 34
46 31 15 0 16.6 0.50
Ta-T, Gl G2 G3 RR before prophylaxis Rl/m before prophylaxis
10 1 26.0 0.62
Male/female = 2.8.
Table 2. Tis: Distribution and results in 22 instillation series of 17 patients Pa tients
Primary T,s Secondary Tis Grade 1
MMC (n - 12)
BCG (n = 10)
CR
SD
PD
CR
SD
2 2
3
1
0
2
0 2 1
0 1 2
2
2
1
1
5
3
0
2
2
0
2
0 1 4 4 1
0 0 0 0 0
7/58% 5
0
3 First-line Second-line
14 8 3 7 12 17 5
3 7 0
Total
22
2
2
1 1
2 2 2
4/40% 3
however, able to determine if it is a sign of therapeutic effect or not.) Progression includes muscle invasion and métastasés. CR, PD, disease-free interval (DFI), RR and Rl/m were used in determining the efficacy of the prophylaxis of Ta-T i cancer [4, 15, 16]. Each patient served as his own control when two latter end points were used. The result of TUR alone, i.e., RR and Rl/m before ran domization, has been compared with RR and Rl/m during instillation prophylaxis. The differences between RR and Rl/m during and before the instillation period are indicators of recurrence-preventive efficacy [4,15]. The minimum follow-up period for estimation of efficacy was 6 months, anyhow, side effects were recorded from the beginning to the end. Patients were transferred to the second-line instillation in case of stable disease over a period of 6 months, or due to severe side effects. Mean follow-up time was 28 months (range 6-69) both in therapy of Tis and in prophylaxis of Ta-Ti cancer. The 24-month protocol was not completed by 18 patients, 11 of them were in the MMC group, and 7 in the BCG group. Two patients died from progression of the cancer, and 5 others from an unrelated disease. One patient was in poor general condition, 1 had continuously stable disease, 5 patients suffered from side effects, and 3 refused therapy. Additionally, there was 1 practical error. The following statistical methods were used: Results were ana lyzed by a standard statistical software program (BMDP). %2 test and the test of linear trend were used in the analysis of cross tabulations. Student’s t test was used in the comparison of means of two nor mally distributed variables between treatment groups. Analysis of covariance was used in the comparison of means between treatment groups when controlling pretreatment prognostic factors. Product limit survival analysis was used in the comparison of disease-free curves and sufficient response curves between treatment groups, p < 0.05 was considered statistically significant.
PD
3/30%
month for a 2-year period (fig. 1). The treatment could be prolonged over 2 years if necessary. The dose of MMC was 20-40 mg when estimated by the AUC method [3, 4, 20], The volume of phosphate buffer of pH 7.4 depended on the capacity of the bladder [20, 21 ]. In the second instillation arm, 6 X 10* CFU immune BCG Pasteur strain F (75 mg) in 50 ml aq. dest. was used. Cytology and cystos copy were checked every 3 months. TUR and biopsies were per formed if needed (fig. 1). The end points of the trial concerning TiS were complete response (CR) and progressive disease (PD). CR does not allow sus pected areas without benign biopsy nor suspicious or malignant (Pa panicolaou class IV or V) cytology [1, 3, 15]. (Cytology resembling class III can sometimes be problematic, the cytologist is usually,
Results
Therapy of T,s A total of 22 evaluable periods of intravesical therapy is presented in table 2. Seventeen of them are first-line, and 5 second-line instillations. CR was 58% in the MMC group (n = 12) without progression. In the BCG group (n = 10), CR was 40%. Three progressions occurred with BCG. Concerning the grade of TIS, CR was 3/3 without pro gressions in mild dysplasia of grade 1, in moderate dysplasia/Tis of grade 2, CR was 3/7 and PD 1/7 in TIS of grade 3, CR was 5/12 and PD 2/12, respectively. Prophylaxis ofTa-Ti Cancer After the follow-up period of 6 months, CR was 70% with MMC and 88% with BCG. Figures were 67 and 90% after a 12-month follow-up and 79 and 97% at 2 years’ evaluation, respectively. There was one progres sion in both prophylactic groups after the follow-up time of 12 months, and one more progression in the MMC group at 2 years’ evaluation. One progression of grade 1 Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
20
MMC versus BCG in Superficial Bladder Cancer
21
M-*-
JPt
□R
n
n
3
6
i
n
u
[]
n
(3
[]
9
12
15
18
21
24 mos
□
B—► -%
0
1
R randomization M mitomycin C (20-40 mg) + buffer for 2 hours B BCG Pasteur F (6x10fl CFU/75 mg) in 50 ml 0 9 %NaCI for 2 hours
Fig. 2. Ta-T i: Disease-free interval, MMC versus BCG.
cancer occurred in both instillation groups. DFI curves demonstrated that BCG confers a significantly better recurrence-preventive effect in comparison with MMC (fig. 2). The initial grade (Gl versus G2 + G3) had some predictive inclination, but not a significant correlation to the occurrence of recurrences (fig. 3). Both MMC and BCG had a clear recurrence-pre ventive efficiency as demonstrated by RR and Rl/m in tables 3 and 4. Efficacy of BCG was significantly supe rior to MMC.
i
Fig. 3. Ta-TV Disease-free interval, grade 1 versus grade 2 and 3.
Efficacy of MMC and BCG, as the superiority of the latter agent, is illustrated in the clusters of figures 4 and 5. Individual patients below the 0-line benefited from prophylaxis, whereas patients above it did not. Who could benefit from prophylaxis? Instillation pro phylaxis seems to be of great use for patients with fre quent recurrence times (high value of RR in figure 6) and multiple tumors (high value of Rl/m in figure 7) after TUR alone, as demonstrated in regression analysis of figures 6 and 7. In contrast, instillation prophylaxis in Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
Fig. 1. Schedule of instilla tions and follow-up.
□ cystoscopy, biopsy, urinary cytology (TUR of vis'ible lesions) instillation
Rintala/J auhiainen/Alfthan/Hansson/J uusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
Table 3. Ta-Ti: Recurrence rate MMC
BCG
RR before prophlaxis RR during prophylaxis RR difference
16.6 7.7 -9.0
Total number of patients
41
44
MMC
BCG
26.0 2.7 -23.3 p = 0.0012
Table 4. Ta-Ti: Recurrence index
Rl/m before prophylaxis Rl/m during prophylaxis Rl/m difference
0.50 0.14 -0.36
Total number of patients
38
0.62 0.04 -0.58 p = 0.0001 40
Table 5. Collected results of BCG in intravesical therapy
Prophylaxis of recurrences Therapy of residual tumors Therapy of TiS
Number of patients
CR, %
596 194 289
75 58
68
24 publications in 1976-88.
patients with few, single tumors seems not to be rational. (They are placed on the left of the horizontal axis and high on the vertical axis in figures 6 and 7.) Side Effects Due to side effects of MMC, instillations had to be discontinued in 8.6% (2 cases because of chemical cysti tis,, 3 due to contact dermatitis/eczema). In the BCG group, treatment was discontinued in 19.6% (9 cases of immunocystitis, 1 of allergy). One patient became ill with pulmonary tuberculosis after 2-year instillations. Three malignancies of another kind were found in both groups during follow-up (MMC: 1 case of adenocarci noma coli, 1 hepatocellular carcinoma and 1 case of epi dermoid pulmonar carcinoma. BCG: 1 case of adenocar cinoma ventriculi and 2 adenocarcinoma coli).
Second-Line Instillation One Tis patient with MMC had to be transferred to the second-line BCG due to contact dermatitis, and 3 patients because of stable disease. Two of these 4 pa tients achieved CR, 1 remained at stable disease, and 1 got to PD. The only Tis patient with second-line MMC stayed at stable disease (table 2). Due to failure, 8 pa tients with MMC prophylaxis of Ta-T i cancer were trans ferred to second-line BCG: 3 of them achieved CR, fur ther 3 stayed at stable disease, 1 received PD and 1 had not yet new results after transferring. Ten patients with initial BCG prophylaxis were transferred to second-line MMC, 1 remained at stable disease, 9 had CR with BCG, although they suffered from painful local side effects. All 9 patients were, however, able to continue with secondline MMC and remained in CR.
Discussion
A wide antitumor activity of MMC has been shown as early as in the 1950s, but due to delayed cumulative myelosuppression, its clinical use was restricted in the beginning. Later on, several studies demonstrated clini cal safety of intravesical use as well as good effectiveness especially in the recurrence-prevention of Ta-T i bladder cancer and also in the therapy of Tis [1-9]. Accumulated data convincingly show the efficacy of intravesical BCG (table 5). Of four principal rules for adequate immunotherapy dictated in the 1970s by the group of Zbar et al. [22], three are also valid for adequate intravesical chemotherapy: (1) the tumor burden must be small; (2) direct contact between tumor cells and the drug is essential, and (3) the dose of agent must be ade quate. Hence, both intravesical chemo- and immunotreatment are specially indicated in recurrence-pre vention after complete TUR and in the therapy of TIS. We have used immune BCG Pasteur strain F. The amount of 6 X 108 (75 mg) is relatively small, but in range of effective doses according to Lamm et al. [23], Quick freezing and storage did not influence the prepa ration as shown in the control analyses by the pro ducer. The adult population in Finland is usually PPD skin positive, in the present series the figure is 84.3%. Con sidering the previous national burden of tuberculosis in our country, we did not give viable bacilli to test-nega tive patients. Consistently, 7 test-negative patients were changed from the BCG to the MMC group. Hence, the conversion from a negative to a positive test was not Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
22
MMC versus BCG in Superficial Bladder Cancer
Rl/m difference
RR difference
1
3333 33
0
33 3'-'33 33 33 33^333333
- ne
33 33 33 0 ^33 33 33 33 33 33 3333333F3F33r33~
tÜiWW'
33 33 33 33 33
JU
-10
333333333333
□u□□ □ □□□□
333333333333
□□□□□□□
33 33 33 n ^3 33
□□□□□□□
333333
□□□□□□□□□□
-30
D
ri L
4-
4-
'lT
-1
-
33
□□□ □□
□ □□
-2
-20
33
□
□ □
□□□
□
-3 33
33
-4
-40 MMC (41)
BCG (44)
MMC (38)
BCG (40)
Fig. 4. Ta-Ti: Comparison between prophylactic efficacy of MMC (RR difference) and BCG (t test).
Fig. 5. Ta-T!: Comparison between prophylactic efficacy of MMC (Rl/m difference) and BCG (t test).
Fig. 6. Ta-Ti: Prophylactic efficacy (RR difference) of MMC and BCG, separately, versus TUR alone (regression analysis).
Fig. 7. Ta-Ti: Prophylactic efficacy (Rl/m difference) of MMC and BCG, separately, versus TUR alone (regression analysis). Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
10
23
Rintala/Jauhiainen/Alfthan/Hansson/J uusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
possible in the present series. The prognostic value of test alternations is, however, doubtful. We did not treat the patients with additional intradermal BCG, because the benefit for this is also regarded as suspicious in the literature [1, 2, 5, 10, 12, 24], The present results in the therapy of TiS, CR of 58% with MMC and 40% with BCG, were not encouraging. Figures of PD were 0/12 and 3/10 patients, respectively. A small number of cases allows us only to take notice, not to make any comparisons. Anyhow, we have pre viously obtained CRs of 82 and 80% with MMC and doxorubicin in identical materials of Tis [3], Instillation therapy of grade 1 dysplasis/Tls may be critized. In the present material, CR was achieved by 3/3 patients in grade 1, but by 6/9 in our previous material [3, 7], On the other hand, there was 1 progression of 7 grade 2 Tis, and 2 of 12 grade 3 Tis in the present series. In our previous series, the figures were 2/16 and 3/13, respectively [3, 7], Thus, Tis of grade 2 seems to be a disease with the same malignant potency as TIS of grade 3. The present results confirm the earlier reports [1-14] on recurrence-preventive activity of MMC and BCG. Our result also indicates a significant superiority of BCG to MMC, which disagrees with the Dutch [5, 6] and Ger man [25] reports. We found only these two randomized studies comparing MMC and BCG in the literature, and they did not demonstrate significant differences in effi cacy or in side effects between MMC and BCG. It must, however, be mentioned that 50% of the German and 70% of the Dutch patients had a primary tumor, which had possibly no need for prophylaxis. The Dutch dose, 30 mg of MMC, was comparable with our dose; the dose of BCG was 1.6-fold. The German dose, 20 mg of MMC, was, on the average, smaller, the dose of BCG, however, 4- to 16-fold. In this comparison, our dose of 6 X 108 CFU of BCG Pasteur is big enough and effective. Our result with BCG was superior to the result with a rela tively big dose of MMC. In our material, BCG caused three times more considerable side effects than MMC. There was 1 case of pulmonary tuberculosis, too. Other malignancies occurred in equal extent in both instilla tion groups, 5.2% with MMC and 5.9% with BCG.
Conclusions
(1) MMC and BCG are an alternative to cystectomy in the therapy of Tis of grades 2 and 3, or at least a respite under close control. Further conclusions are not possible without wide randomized studies. Who is will
ing to perform a randomized study consisting of the three arms primary cystectomy versus intravesical ther apy versus no treatment? Wait-and-see policy would be entitled for mild dysplasia of grade 1. (2) Both MMC and BCG have a significant recur rence-preventive efficacy in patients with frequently and multiple recurrent tumors. Prophylactic effect on pro gressions could be deducted when there are less recur rences and recurrent tumors. Instillation prophylaxis of a primary and single (Ta-Ti grade 1-2) cancer is futile. (3) Both MMC (like doxorubicin and epirubicin) and BCG may cause considerable side effects resulting in dis continuation of the therapy. BCG is probably the most effective prophylactic drug for Ta-Ti bladder cancer today, an intravesical alternative (currently most likely MMC) is, however, needed in use. (4) Second-line instillation can be useful, especially for patients suffering from troublesome side effects but also in cases with failure (stable disease) of the first-line instillation.
Acknowledgements The Finnish Cancer Foundation, the Academy of Finland Paolo Foundation and the Research and Science Foundation of Farmos have supported this study.
References 1 Soloway MS: Overview of treatment of superficial bladder can cer. Urology 1985;26(suppl 4): 18-26. 2 Soloway MS: Selecting initial therapy for bladder cancer. Cancer 1987;60:502-513. 3 Jauhiainen K, Sotarauta M, Permi J, Alfthan O: Effect of mito mycin C and doxorubicin instillation on carcinoma in situ of the urinary bladder. Eur Urol 1986;12:32-37. 4 Jauhiainen K, Alfthan O: Mitomycin C and doxorubicin instil lation as recurrence prophylaxis in superficial (Ta-Ti) urinary bladder cancer. Br J Urol 1987;60:54-59. 5 DeBruyne FMJ, van der Meijden APM, Geboers ADH, Franssen MPH, van Leeuwen MJW, Steerenberg PA, de Jonge WH, Ruitenberg JJ: BCG (RIVM) versus mitomycin intravesi cal therapy in superficial bladder cancer: First results of random ized trial. Urology 1988;31(suppl 3):20-25. 6 Van der Meijden APM: Nonspecific immunotherapy with BCGRIVM in superficial bladder cancer; Histological, immunologi cal and therapeutic aspects; thesis (ISBN 90 900 2361 5) Den Haag, 1988. 7 Jauhiainen K, Alfthan O: Die Behandlung von Carcinoma in situ der Harnblase mit lokaler Adriamycininstillation. Aktuel Urol 1984;15:129-133. 8 Jauhiainen K: Detecting mitomycin C in human plasma during intravesical therapy. Int Urol Nephrol 1985;17:155-158. Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
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MMC versus BCG in Superficial Bladder Cancer
18 Mostofi FK, Sobin LH, Torloni H: Histological typing of urinary bladder tumor; in International Histological Classification of Tumors. Geneva, WHO, 1973, No 10. 19 TNM classification of malignant tumors. Geneva, Union Inter nationale Contre le Cancer (UICC), ed 3, 1978, pp 113-117. 20 Eksborg S, Nilsson S-O, Edsmyr F: Intravesical instillation of Adriamycin, A model for standardization of chemotherapy. Eur Urol 1980;6:218-220. 21 Jauhiainen K, Kangas L, Käpylä H, Alfthan O: Intravesical cyto statics: pH-dependence of antitumour activity. Urol Res 1985; 13:19-21. 22 Zbar B, Bernstein ID, Bartlett GL, Hanna MG Jr, Rapp HJ: Immunotherapy of cancer: Regression of intradermal tumors and prevention of growth of lymph node métastasés after intralesional injection of living Mycobacterium bovis. J Natl Cancer Inst r972;49:119-130. 23 Lamm DL, Reichert DF, Harris SC, Lucio RM: Immunotherapy of murine transitional cell carcinoma. J Urol 1982;128:1104— 1108. 24 Torrence RJ, Kavoussi LR, Catalona WJ, Ratliff TL: Prognostic factors in patients treated with intravesical bacillus CalmetteGuérin for superficial bladder cancer. J Urol 1988; 139:941— 944. 25 Ruebben H, Graf-Dobberstein C, Ostwald R, Stauffenberg A, Jaeger N, Deutz FJ, Steffens L, Giani G: Prospective random ized study of adjuvant therapy after complete resection of super ficial bladder cancer; Mitomycin C vs. BCG Connaught vs. TUR alone; in deKemion JB (ed): Immunotherapy of Urological Tumors. Edinburgh, Churchill Livingstone, 1990, pp 27-36.
Erkki Rintala, MD Malmi Hospital Sairaalakatu 3 SF-00700 Helsinki (Finland)
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9 Jauhiainen K, Eksborg S, Kangas L, Perilä M, Alfthan O: The absorption of doxorubicin and mitomycin C in perioperative instillation. Eur Urol 1985;11:269-272. 10 Morales A, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976;116:180-183. 11 DeKemion JB, Huang M-Y, Lindner A, Smith RB, Kaufman JJ: The management of superficial bladder tumors and carcinoma in situ with intravesical bacillus Calmette-Guérin. J Urol 1985; 133:598-601. 12 Lamm DL, Stogdill VL, Stogdill BJ, Crispen RG: Complications of bacillus Calmette-Guérin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272-274. 13 Badalament RA, Herr HW, Wong GY, Gnecco C, Pinsky CM, Whitmore WF Jr, Fair WR, Oettgen HF: A prospective random ized trial of maintenance versus nonmaintenance bacillus Cal mette-Guérin therapy of superficial bladder cancer. J Clin Oncol 1987;5:441-449. 14 Rintala E, Jauhiainen K, Alfthan O, The Finnbladder Group: Immunotherapy (BCG) vs. chemotherapy (MMC) in endovesical treatment of superficial urinary bladder cancer; in Di Silverio F, Steg A (eds): International Workshop in Urology, Roma, Acta Med 1987, pp 223-226. 15 Jauhiainen K, Alfthan O: Methodologies for quantifying the results of intravesical chemotherapy of superficial tumors of the bladder. Med Oncol Tumor Pharmacother 1985;2:249-254. 16 Byar D, Kaihara S, Sylvester R; Freeman L, Hannigan J, Koiso K, Oohashi Y, Tsugawa R: Statistical analysis techniques and sample size determination for clinical trials of treatments for bladder cancer; in Denis L, Niijama T, Prout G Jr, Schröder FH (eds): Developments in Bladder Cancer. New York, Alan R Liss, 1986, voi 221, PP 49-64. 17 Kurth KH, Dalesio O, dePauw M, Ay R, Carpentier P, Mit glieder der EOTC GU-Gruppe: Welche oberflächlichen Übergangzellkarzinome der Harnblase sollten adjuvant chemothera peutisch behandelt werden? Aktuelle Urol 1985;16:87-90.
25
Eur Urol 1991;20:19-25
Intravesical Chemotherapy (Mitomycin C) versus Immunotherapy (Bacillus Calmette-Guérin) in Superficial Bladder Cancer E. Rintala, K. Jauhiainen, O. Alfthan, E. Hansson, H. Juusela, K. Kanerva, H. Korhonen, J. Permi, M. Sotarauta, T. Vaalasti, J. Viitanen, R. Usenius Finnbladder Group, Urological Clinic, Helsinki University Central Hospital, Helsinki, Finland
1606037
Key Words. Intravesical therapy • Superficial bladder cancer • Mitomycin C • Bacillus Calmette-Guérin Abstract. Both intravesical mitomycin C (MMC) and bacillus Calmette-Guérin (BCG; Pasteur strain F) were effective in the present prospective randomized multicenter study consisting of 91 patients with frequently recurrent superficial (Ta-Ti) bladder cancer. The result was in favour of BCG, as shown by the measurements with complete response (CR), disease-free interval and recurrence rate. CR of 58% with MMC and 40% with BCG were reached in 22 instillation series on carcinoma in situ of 18 patients. Due to side effects, MMC instillations were discontinued in 8.6%, and BCG instillations in 19.6%, respectively. After the 2-year follow-up also 1 case of pulmonary tuberculosis occurred in the BCG group.
Intravesical chemoprophylaxis following transure thral resection (TUR) of superficial (Ta-Ti) bladder can cer has gained a wide use. A limited number of local cytostatics has proved to be safe in use, also reduces recurrence rate and is beneficial for delaying and pre venting progression. Some intravesical agents have shown to be cytotoxic on residual carcinoma and carci noma in situ (Tis), although these indications need more experience before solid recommendations can be given. During the last two decades, the main interest has focused on antibiotic cytostatics, among which mitomy cin C (MMC) is one of the most effective and safe agents [1-9]. Many authors have claimed that intravesical immu notherapy with bacillus Calmette-Guérin (BCG) is supe rior to other forms of intravesical treatments [10-14], Randomized studies comparing BCG with MMC were not published when the present study was designed and initiated in 1984.
Material and Methods The prospective multicenter study enrolled 109 patients in 1984-87: 18 with T]S grade 1-3 and 91 patients with frequently recurrent Ta-Ti papillary transitional cell cancer grade 1-3. Inclu sion criteria for TiS required histologically verified malignancy and/or three consecutive malignant cytological findings (Papanico laou class V). In the present study, however, all patients with Tis had a histological confirmation. Ta-Ti cancers with a minimum of two episodes of recurrence during the preceding 1.5 years were accepted. Recurrence rate (RR = number of recurrence times/100 follow-up months) and the recurrence index (Rl/m = number of recurrent tumors/month) were calculated as from the first reappearance of bladder cancer [15-17], Classification of tumors was performed according to the rules of the WHO of 1973, and UICC of 1978 [18, 19]. The upper urinary tract was excluded as a source of malignant cytology by ureteral cytology, intravenous and retrograde pyelogra phy when needed. Urethral or prostatic involvement was excluded by urethroscopy and biopsies. Patients were randomly allocated to receive either local MMC or BCG. 7 persons were transferred from the BCG to the MMC group due to negative PPD skin tests. The two treatment groups were identical in randomization characteristics (table 1). All visible le sions were treated by TUR. Instillations of both groups were started 2 weeks later, repeated weekly during the first month, and once a Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
Introduction
Rintala/Jauhiainen/Alfthan/Hansson/Juusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
Table 1. Randomization characteristics
Number of patients Male Female Age, years
MMC
BCG
58 41 17 67
51 39
12 68
Stage and Grade Tb
12
6
8
4
4
2
Primary Secondary Gl G2 G3
2
1
4
2
6
3 45 34
46 31 15 0 16.6 0.50
Ta-T, Gl G2 G3 RR before prophylaxis Rl/m before prophylaxis
10 1 26.0 0.62
Male/female = 2.8.
Table 2. Tis: Distribution and results in 22 instillation series of 17 patients Pa tients
Primary T,s Secondary Tis Grade 1
MMC (n - 12)
BCG (n = 10)
CR
SD
PD
CR
SD
2 2
3
1
0
2
0 2 1
0 1 2
2
2
1
1
5
3
0
2
2
0
2
0 1 4 4 1
0 0 0 0 0
7/58% 5
0
3 First-line Second-line
14 8 3 7 12 17 5
3 7 0
Total
22
2
2
1 1
2 2 2
4/40% 3
however, able to determine if it is a sign of therapeutic effect or not.) Progression includes muscle invasion and métastasés. CR, PD, disease-free interval (DFI), RR and Rl/m were used in determining the efficacy of the prophylaxis of Ta-T i cancer [4, 15, 16]. Each patient served as his own control when two latter end points were used. The result of TUR alone, i.e., RR and Rl/m before ran domization, has been compared with RR and Rl/m during instillation prophylaxis. The differences between RR and Rl/m during and before the instillation period are indicators of recurrence-preventive efficacy [4,15]. The minimum follow-up period for estimation of efficacy was 6 months, anyhow, side effects were recorded from the beginning to the end. Patients were transferred to the second-line instillation in case of stable disease over a period of 6 months, or due to severe side effects. Mean follow-up time was 28 months (range 6-69) both in therapy of Tis and in prophylaxis of Ta-Ti cancer. The 24-month protocol was not completed by 18 patients, 11 of them were in the MMC group, and 7 in the BCG group. Two patients died from progression of the cancer, and 5 others from an unrelated disease. One patient was in poor general condition, 1 had continuously stable disease, 5 patients suffered from side effects, and 3 refused therapy. Additionally, there was 1 practical error. The following statistical methods were used: Results were ana lyzed by a standard statistical software program (BMDP). %2 test and the test of linear trend were used in the analysis of cross tabulations. Student’s t test was used in the comparison of means of two nor mally distributed variables between treatment groups. Analysis of covariance was used in the comparison of means between treatment groups when controlling pretreatment prognostic factors. Product limit survival analysis was used in the comparison of disease-free curves and sufficient response curves between treatment groups, p < 0.05 was considered statistically significant.
PD
3/30%
month for a 2-year period (fig. 1). The treatment could be prolonged over 2 years if necessary. The dose of MMC was 20-40 mg when estimated by the AUC method [3, 4, 20], The volume of phosphate buffer of pH 7.4 depended on the capacity of the bladder [20, 21 ]. In the second instillation arm, 6 X 10* CFU immune BCG Pasteur strain F (75 mg) in 50 ml aq. dest. was used. Cytology and cystos copy were checked every 3 months. TUR and biopsies were per formed if needed (fig. 1). The end points of the trial concerning TiS were complete response (CR) and progressive disease (PD). CR does not allow sus pected areas without benign biopsy nor suspicious or malignant (Pa panicolaou class IV or V) cytology [1, 3, 15]. (Cytology resembling class III can sometimes be problematic, the cytologist is usually,
Results
Therapy of T,s A total of 22 evaluable periods of intravesical therapy is presented in table 2. Seventeen of them are first-line, and 5 second-line instillations. CR was 58% in the MMC group (n = 12) without progression. In the BCG group (n = 10), CR was 40%. Three progressions occurred with BCG. Concerning the grade of TIS, CR was 3/3 without pro gressions in mild dysplasia of grade 1, in moderate dysplasia/Tis of grade 2, CR was 3/7 and PD 1/7 in TIS of grade 3, CR was 5/12 and PD 2/12, respectively. Prophylaxis ofTa-Ti Cancer After the follow-up period of 6 months, CR was 70% with MMC and 88% with BCG. Figures were 67 and 90% after a 12-month follow-up and 79 and 97% at 2 years’ evaluation, respectively. There was one progres sion in both prophylactic groups after the follow-up time of 12 months, and one more progression in the MMC group at 2 years’ evaluation. One progression of grade 1 Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
20
MMC versus BCG in Superficial Bladder Cancer
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R randomization M mitomycin C (20-40 mg) + buffer for 2 hours B BCG Pasteur F (6x10fl CFU/75 mg) in 50 ml 0 9 %NaCI for 2 hours
Fig. 2. Ta-T i: Disease-free interval, MMC versus BCG.
cancer occurred in both instillation groups. DFI curves demonstrated that BCG confers a significantly better recurrence-preventive effect in comparison with MMC (fig. 2). The initial grade (Gl versus G2 + G3) had some predictive inclination, but not a significant correlation to the occurrence of recurrences (fig. 3). Both MMC and BCG had a clear recurrence-pre ventive efficiency as demonstrated by RR and Rl/m in tables 3 and 4. Efficacy of BCG was significantly supe rior to MMC.
i
Fig. 3. Ta-TV Disease-free interval, grade 1 versus grade 2 and 3.
Efficacy of MMC and BCG, as the superiority of the latter agent, is illustrated in the clusters of figures 4 and 5. Individual patients below the 0-line benefited from prophylaxis, whereas patients above it did not. Who could benefit from prophylaxis? Instillation pro phylaxis seems to be of great use for patients with fre quent recurrence times (high value of RR in figure 6) and multiple tumors (high value of Rl/m in figure 7) after TUR alone, as demonstrated in regression analysis of figures 6 and 7. In contrast, instillation prophylaxis in Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
Fig. 1. Schedule of instilla tions and follow-up.
□ cystoscopy, biopsy, urinary cytology (TUR of vis'ible lesions) instillation
Rintala/J auhiainen/Alfthan/Hansson/J uusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
Table 3. Ta-Ti: Recurrence rate MMC
BCG
RR before prophlaxis RR during prophylaxis RR difference
16.6 7.7 -9.0
Total number of patients
41
44
MMC
BCG
26.0 2.7 -23.3 p = 0.0012
Table 4. Ta-Ti: Recurrence index
Rl/m before prophylaxis Rl/m during prophylaxis Rl/m difference
0.50 0.14 -0.36
Total number of patients
38
0.62 0.04 -0.58 p = 0.0001 40
Table 5. Collected results of BCG in intravesical therapy
Prophylaxis of recurrences Therapy of residual tumors Therapy of TiS
Number of patients
CR, %
596 194 289
75 58
68
24 publications in 1976-88.
patients with few, single tumors seems not to be rational. (They are placed on the left of the horizontal axis and high on the vertical axis in figures 6 and 7.) Side Effects Due to side effects of MMC, instillations had to be discontinued in 8.6% (2 cases because of chemical cysti tis,, 3 due to contact dermatitis/eczema). In the BCG group, treatment was discontinued in 19.6% (9 cases of immunocystitis, 1 of allergy). One patient became ill with pulmonary tuberculosis after 2-year instillations. Three malignancies of another kind were found in both groups during follow-up (MMC: 1 case of adenocarci noma coli, 1 hepatocellular carcinoma and 1 case of epi dermoid pulmonar carcinoma. BCG: 1 case of adenocar cinoma ventriculi and 2 adenocarcinoma coli).
Second-Line Instillation One Tis patient with MMC had to be transferred to the second-line BCG due to contact dermatitis, and 3 patients because of stable disease. Two of these 4 pa tients achieved CR, 1 remained at stable disease, and 1 got to PD. The only Tis patient with second-line MMC stayed at stable disease (table 2). Due to failure, 8 pa tients with MMC prophylaxis of Ta-T i cancer were trans ferred to second-line BCG: 3 of them achieved CR, fur ther 3 stayed at stable disease, 1 received PD and 1 had not yet new results after transferring. Ten patients with initial BCG prophylaxis were transferred to second-line MMC, 1 remained at stable disease, 9 had CR with BCG, although they suffered from painful local side effects. All 9 patients were, however, able to continue with secondline MMC and remained in CR.
Discussion
A wide antitumor activity of MMC has been shown as early as in the 1950s, but due to delayed cumulative myelosuppression, its clinical use was restricted in the beginning. Later on, several studies demonstrated clini cal safety of intravesical use as well as good effectiveness especially in the recurrence-prevention of Ta-T i bladder cancer and also in the therapy of Tis [1-9]. Accumulated data convincingly show the efficacy of intravesical BCG (table 5). Of four principal rules for adequate immunotherapy dictated in the 1970s by the group of Zbar et al. [22], three are also valid for adequate intravesical chemotherapy: (1) the tumor burden must be small; (2) direct contact between tumor cells and the drug is essential, and (3) the dose of agent must be ade quate. Hence, both intravesical chemo- and immunotreatment are specially indicated in recurrence-pre vention after complete TUR and in the therapy of TIS. We have used immune BCG Pasteur strain F. The amount of 6 X 108 (75 mg) is relatively small, but in range of effective doses according to Lamm et al. [23], Quick freezing and storage did not influence the prepa ration as shown in the control analyses by the pro ducer. The adult population in Finland is usually PPD skin positive, in the present series the figure is 84.3%. Con sidering the previous national burden of tuberculosis in our country, we did not give viable bacilli to test-nega tive patients. Consistently, 7 test-negative patients were changed from the BCG to the MMC group. Hence, the conversion from a negative to a positive test was not Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
22
MMC versus BCG in Superficial Bladder Cancer
Rl/m difference
RR difference
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-40 MMC (41)
BCG (44)
MMC (38)
BCG (40)
Fig. 4. Ta-Ti: Comparison between prophylactic efficacy of MMC (RR difference) and BCG (t test).
Fig. 5. Ta-T!: Comparison between prophylactic efficacy of MMC (Rl/m difference) and BCG (t test).
Fig. 6. Ta-Ti: Prophylactic efficacy (RR difference) of MMC and BCG, separately, versus TUR alone (regression analysis).
Fig. 7. Ta-Ti: Prophylactic efficacy (Rl/m difference) of MMC and BCG, separately, versus TUR alone (regression analysis). Downloaded by: University of Exeter 144.173.6.94 - 5/6/2020 5:50:54 PM
10
23
Rintala/Jauhiainen/Alfthan/Hansson/J uusela/Kanerva/Korhonen/Permi/Sotarauta/Vaalasti/Viitanen/Usenius
possible in the present series. The prognostic value of test alternations is, however, doubtful. We did not treat the patients with additional intradermal BCG, because the benefit for this is also regarded as suspicious in the literature [1, 2, 5, 10, 12, 24], The present results in the therapy of TiS, CR of 58% with MMC and 40% with BCG, were not encouraging. Figures of PD were 0/12 and 3/10 patients, respectively. A small number of cases allows us only to take notice, not to make any comparisons. Anyhow, we have pre viously obtained CRs of 82 and 80% with MMC and doxorubicin in identical materials of Tis [3], Instillation therapy of grade 1 dysplasis/Tls may be critized. In the present material, CR was achieved by 3/3 patients in grade 1, but by 6/9 in our previous material [3, 7], On the other hand, there was 1 progression of 7 grade 2 Tis, and 2 of 12 grade 3 Tis in the present series. In our previous series, the figures were 2/16 and 3/13, respectively [3, 7], Thus, Tis of grade 2 seems to be a disease with the same malignant potency as TIS of grade 3. The present results confirm the earlier reports [1-14] on recurrence-preventive activity of MMC and BCG. Our result also indicates a significant superiority of BCG to MMC, which disagrees with the Dutch [5, 6] and Ger man [25] reports. We found only these two randomized studies comparing MMC and BCG in the literature, and they did not demonstrate significant differences in effi cacy or in side effects between MMC and BCG. It must, however, be mentioned that 50% of the German and 70% of the Dutch patients had a primary tumor, which had possibly no need for prophylaxis. The Dutch dose, 30 mg of MMC, was comparable with our dose; the dose of BCG was 1.6-fold. The German dose, 20 mg of MMC, was, on the average, smaller, the dose of BCG, however, 4- to 16-fold. In this comparison, our dose of 6 X 108 CFU of BCG Pasteur is big enough and effective. Our result with BCG was superior to the result with a rela tively big dose of MMC. In our material, BCG caused three times more considerable side effects than MMC. There was 1 case of pulmonary tuberculosis, too. Other malignancies occurred in equal extent in both instilla tion groups, 5.2% with MMC and 5.9% with BCG.
Conclusions
(1) MMC and BCG are an alternative to cystectomy in the therapy of Tis of grades 2 and 3, or at least a respite under close control. Further conclusions are not possible without wide randomized studies. Who is will
ing to perform a randomized study consisting of the three arms primary cystectomy versus intravesical ther apy versus no treatment? Wait-and-see policy would be entitled for mild dysplasia of grade 1. (2) Both MMC and BCG have a significant recur rence-preventive efficacy in patients with frequently and multiple recurrent tumors. Prophylactic effect on pro gressions could be deducted when there are less recur rences and recurrent tumors. Instillation prophylaxis of a primary and single (Ta-Ti grade 1-2) cancer is futile. (3) Both MMC (like doxorubicin and epirubicin) and BCG may cause considerable side effects resulting in dis continuation of the therapy. BCG is probably the most effective prophylactic drug for Ta-Ti bladder cancer today, an intravesical alternative (currently most likely MMC) is, however, needed in use. (4) Second-line instillation can be useful, especially for patients suffering from troublesome side effects but also in cases with failure (stable disease) of the first-line instillation.
Acknowledgements The Finnish Cancer Foundation, the Academy of Finland Paolo Foundation and the Research and Science Foundation of Farmos have supported this study.
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MMC versus BCG in Superficial Bladder Cancer
18 Mostofi FK, Sobin LH, Torloni H: Histological typing of urinary bladder tumor; in International Histological Classification of Tumors. Geneva, WHO, 1973, No 10. 19 TNM classification of malignant tumors. Geneva, Union Inter nationale Contre le Cancer (UICC), ed 3, 1978, pp 113-117. 20 Eksborg S, Nilsson S-O, Edsmyr F: Intravesical instillation of Adriamycin, A model for standardization of chemotherapy. Eur Urol 1980;6:218-220. 21 Jauhiainen K, Kangas L, Käpylä H, Alfthan O: Intravesical cyto statics: pH-dependence of antitumour activity. Urol Res 1985; 13:19-21. 22 Zbar B, Bernstein ID, Bartlett GL, Hanna MG Jr, Rapp HJ: Immunotherapy of cancer: Regression of intradermal tumors and prevention of growth of lymph node métastasés after intralesional injection of living Mycobacterium bovis. J Natl Cancer Inst r972;49:119-130. 23 Lamm DL, Reichert DF, Harris SC, Lucio RM: Immunotherapy of murine transitional cell carcinoma. J Urol 1982;128:1104— 1108. 24 Torrence RJ, Kavoussi LR, Catalona WJ, Ratliff TL: Prognostic factors in patients treated with intravesical bacillus CalmetteGuérin for superficial bladder cancer. J Urol 1988; 139:941— 944. 25 Ruebben H, Graf-Dobberstein C, Ostwald R, Stauffenberg A, Jaeger N, Deutz FJ, Steffens L, Giani G: Prospective random ized study of adjuvant therapy after complete resection of super ficial bladder cancer; Mitomycin C vs. BCG Connaught vs. TUR alone; in deKemion JB (ed): Immunotherapy of Urological Tumors. Edinburgh, Churchill Livingstone, 1990, pp 27-36.
Erkki Rintala, MD Malmi Hospital Sairaalakatu 3 SF-00700 Helsinki (Finland)
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9 Jauhiainen K, Eksborg S, Kangas L, Perilä M, Alfthan O: The absorption of doxorubicin and mitomycin C in perioperative instillation. Eur Urol 1985;11:269-272. 10 Morales A, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976;116:180-183. 11 DeKemion JB, Huang M-Y, Lindner A, Smith RB, Kaufman JJ: The management of superficial bladder tumors and carcinoma in situ with intravesical bacillus Calmette-Guérin. J Urol 1985; 133:598-601. 12 Lamm DL, Stogdill VL, Stogdill BJ, Crispen RG: Complications of bacillus Calmette-Guérin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272-274. 13 Badalament RA, Herr HW, Wong GY, Gnecco C, Pinsky CM, Whitmore WF Jr, Fair WR, Oettgen HF: A prospective random ized trial of maintenance versus nonmaintenance bacillus Cal mette-Guérin therapy of superficial bladder cancer. J Clin Oncol 1987;5:441-449. 14 Rintala E, Jauhiainen K, Alfthan O, The Finnbladder Group: Immunotherapy (BCG) vs. chemotherapy (MMC) in endovesical treatment of superficial urinary bladder cancer; in Di Silverio F, Steg A (eds): International Workshop in Urology, Roma, Acta Med 1987, pp 223-226. 15 Jauhiainen K, Alfthan O: Methodologies for quantifying the results of intravesical chemotherapy of superficial tumors of the bladder. Med Oncol Tumor Pharmacother 1985;2:249-254. 16 Byar D, Kaihara S, Sylvester R; Freeman L, Hannigan J, Koiso K, Oohashi Y, Tsugawa R: Statistical analysis techniques and sample size determination for clinical trials of treatments for bladder cancer; in Denis L, Niijama T, Prout G Jr, Schröder FH (eds): Developments in Bladder Cancer. New York, Alan R Liss, 1986, voi 221, PP 49-64. 17 Kurth KH, Dalesio O, dePauw M, Ay R, Carpentier P, Mit glieder der EOTC GU-Gruppe: Welche oberflächlichen Übergangzellkarzinome der Harnblase sollten adjuvant chemothera peutisch behandelt werden? Aktuelle Urol 1985;16:87-90.
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