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British Journal of Urology (1990), 66,35-39 01990 British Journal of Urology
Clinical Study of Prognostic Factors of Superficial Bladder Cancer Treated withi lntiravesical Bacillus Calmette- Guerin T. SHINKA, A. HIRANO, Y. UEKADO and T. OHKAWA Department of Urology, WakayamaMedical College, Wakayama,Japan
Summary-lntravesical instillation of Tokyo 172 strain Bacillus Calmette-Gu6rin (BCG) was performed in 96 patients with initial superficial bladlder cancer (Ta and T1) after transurethral resection (TUR) of tumour as a prophylaxis against tumouir recurrence. The recurrence rate of tumours was estimated by the person-years method, comparing it with that of historical controls. There were statistically significant decreases in recurrent tumours following BCG therapy. To clarify the efficacy of intravesical BCG therapy, t h e prognostic significance of several factors was evaluated in patients with bladder cancer treated with TUR and instillation of BCG. The prophylactic effects were statistically better for those with multiple tumours, grade 3 lesions or Ta lesions than for control patients. No correlation between purified protein derivative (PPD) responsiveness and favourable results could be observed. Our results suggest that intravesical BCG instillation can alter the biological behaviour that affects the recurrence of superficial bladder cancer, especially for multiple, high grade or Ta tumours.
The reported recurrence rate of superficial bladder cancer after transurethral resection ranges from 30% when the original tumour is solitary and of low grade to more than 90% when there are multiple high grade tumours (Soloway, 1988). In addition, most tumours recur within 2 years after TUR (Utz and De Weerd, 1978). In recent years, intravesical Bacillus Calmette-GuCrin therapy for superficial bladder cancer, introduced by Morales et al. (19761, has attracted attention as one of the most effective adjuvant treatments for preventing its recurrence (Haaff et a[., 1985). We reported the effectiveness of intravesical BCG therapy, using Tokyo 172 strain BCG, in preventing the recurrence of superficial bladder cancer after TUR (Shinka etal., 1989). In the present study, the results of intravesical BCG therapy, performed in 96 patients with initial superficial bladder cancer (stage Ta, T1) to prevent recurrence after TUR, were compared with those Accepted for publication 19 October 1989
35
in the control groups, evaluating various factors involved in the efficacy of this therapy and discussing indications and selection of patient.
Patients and Methods The study group consisted of 96 patients with primary superficial transitional cell carcinoma of the bladder who underwent TUR followed by intravesical BCG instillation as adjuvant therapy. The control group comprised 102 patients with superficialtransitional cell carcinoma of the bladder who underwent TUR as initial treatment, of whom 74 weire treated by intravesical chemotherapy (29 with dloxorubicinhydrochloride, 17with mitomycin ancitabine hydroC and 28 with mitomycin C chloride) after TUR (other drug instillation group) and the remaining 28 by TUR alone (non-instillation group). The characteristics of the 96 patients treated by intravesical BCG therapy and the 102 in the control groups are shown in Table 1. The bladder was emptied by catheterisation and
+
36
BRITISH JOURNAL OF UROLOGY
80 mg of Tokyo 172 strain BCG (5-12 x lo7 colony Results forming units/mg, Nihon BCG Co., Japan) susNo significant difference was observed in each pended in 40ml saline were injected into the variate distribution by x2 test between the 96 bladder 7 days after TUR. The patients were patients receiving BCG treatment and the 102 instructed to retain the drug for 2 h. In principle, controls, showing no bias of patients (Table 1). BCG therapy was performed once weekly for 6 The recurrence rate during the 2-year period weeks. The patients were then followed up by after TUR and BCG treatment in 96 patients was urinary cytology and cystoscopy every 3 months. The purified protein derivative skin test was compared with that in each control group (Table 2). The simple recurrence rate was significantly lower performed before and after the 6-week course of in the BCG group (21/96 patients, 22%) than in intravesical BCG. either the drug instillation group (34%) or the nonThe simple recurrence rate and the recurrence instillation group (46%). The number of recurrate by the person-years method (Schoenberg and rences/total patient-months was also significantly Myers, 1977) during the 2-year period after BCG lower in the BCG group (0.019) than in the drug therapy were calculated. The results were compared instillation group (0.030) or in the non-instillation with those in the control groups. Significant group (0.043), with OE ratios of 0.619 and 0.446 differences in the simple recurrence rate were respectively. evaluated by x2 test. In the person-years method, To evaluate various factors associated with the the ratio of the observed actual value to expected efficacy of BCG therapy, the recurrence rate value (O/E) was calculated using the following according to tumour multiplicity, grade or stage equation and significant differences were evaluated was compared between the BCG group and each using the Poisson distribution table : control group (Table 3). The recurrence rate of O/E=(the number of recurrences after BCG multiple tumours was higher than that of solitary tumours in each group. In the BCG group, the therapy)/ recurrence rate of solitary tumours was similar to {(the recurrence rate in the control) x (total patient-months after BCG that in one control group, but the rate of multiple tumours was significantlylower than in both control therapy)).
Table 1 Distribution of Pre-treatment Characteristics of 96 BCG Patients and 102 Controls Controls
No. of patients Sex Male Female Mean age (years) Multiplicity Solitary Multiple Tumour grade G1
G2 G3 Tumour stage Ta TI associated with Tis Follow-up (months)
BCG instillation group (%I
Other drug instillation group Non-instillation group
(%)
(%I
96
74
28
82 (85.4) 14 (14.6) 66.3 26-9 1
65 (87.8) 9 (12.2) 64.1 19-84
25 (89.3) 3 (10.7) 64.1 41-92
42 (43.7) 54 (56.3)
36 (48.6) 38 (51.4)
13 (46.4) 15 (53.6)
45 (46.9) 35 (36.4) 16 (16.7)
33 (44.6) 28 (37.8) 13 (17.6)
18 (64.3) 6 (21.4) 4 (14.3)
47 (49.0) 49 (51.0)
34 (45.9) 40 (54.1)
16 (57.1) 12 (42.9)
10 13.9 1 .I-24
4 18.8 0.4-24
2 19.2 0.5-24
PROGNOSTIC FACTORS OF SUPERFICIAL BLADDER CANCEiR TREATED WITH INTRAVESICAL BCG
37
Table 2 Recurrence R a t e i n 96 Patients in the 2 Years folllowing BlCG Th er ap y a n d Comparison with 102 Controls No. with recurrent turnours
No. ofpatients
Simple recurrence rate BCG patients 96 21 Controls Other drug instillation group 74 26 Non-instillation group 28 13 BCG group versus other drug group BCG group versus non-instillation groulp ~~
21.9 35.1 46.4
P
British Journal of Urology (1990), 66,35-39 01990 British Journal of Urology
Clinical Study of Prognostic Factors of Superficial Bladder Cancer Treated withi lntiravesical Bacillus Calmette- Guerin T. SHINKA, A. HIRANO, Y. UEKADO and T. OHKAWA Department of Urology, WakayamaMedical College, Wakayama,Japan
Summary-lntravesical instillation of Tokyo 172 strain Bacillus Calmette-Gu6rin (BCG) was performed in 96 patients with initial superficial bladlder cancer (Ta and T1) after transurethral resection (TUR) of tumour as a prophylaxis against tumouir recurrence. The recurrence rate of tumours was estimated by the person-years method, comparing it with that of historical controls. There were statistically significant decreases in recurrent tumours following BCG therapy. To clarify the efficacy of intravesical BCG therapy, t h e prognostic significance of several factors was evaluated in patients with bladder cancer treated with TUR and instillation of BCG. The prophylactic effects were statistically better for those with multiple tumours, grade 3 lesions or Ta lesions than for control patients. No correlation between purified protein derivative (PPD) responsiveness and favourable results could be observed. Our results suggest that intravesical BCG instillation can alter the biological behaviour that affects the recurrence of superficial bladder cancer, especially for multiple, high grade or Ta tumours.
The reported recurrence rate of superficial bladder cancer after transurethral resection ranges from 30% when the original tumour is solitary and of low grade to more than 90% when there are multiple high grade tumours (Soloway, 1988). In addition, most tumours recur within 2 years after TUR (Utz and De Weerd, 1978). In recent years, intravesical Bacillus Calmette-GuCrin therapy for superficial bladder cancer, introduced by Morales et al. (19761, has attracted attention as one of the most effective adjuvant treatments for preventing its recurrence (Haaff et a[., 1985). We reported the effectiveness of intravesical BCG therapy, using Tokyo 172 strain BCG, in preventing the recurrence of superficial bladder cancer after TUR (Shinka etal., 1989). In the present study, the results of intravesical BCG therapy, performed in 96 patients with initial superficial bladder cancer (stage Ta, T1) to prevent recurrence after TUR, were compared with those Accepted for publication 19 October 1989
35
in the control groups, evaluating various factors involved in the efficacy of this therapy and discussing indications and selection of patient.
Patients and Methods The study group consisted of 96 patients with primary superficial transitional cell carcinoma of the bladder who underwent TUR followed by intravesical BCG instillation as adjuvant therapy. The control group comprised 102 patients with superficialtransitional cell carcinoma of the bladder who underwent TUR as initial treatment, of whom 74 weire treated by intravesical chemotherapy (29 with dloxorubicinhydrochloride, 17with mitomycin ancitabine hydroC and 28 with mitomycin C chloride) after TUR (other drug instillation group) and the remaining 28 by TUR alone (non-instillation group). The characteristics of the 96 patients treated by intravesical BCG therapy and the 102 in the control groups are shown in Table 1. The bladder was emptied by catheterisation and
+
36
BRITISH JOURNAL OF UROLOGY
80 mg of Tokyo 172 strain BCG (5-12 x lo7 colony Results forming units/mg, Nihon BCG Co., Japan) susNo significant difference was observed in each pended in 40ml saline were injected into the variate distribution by x2 test between the 96 bladder 7 days after TUR. The patients were patients receiving BCG treatment and the 102 instructed to retain the drug for 2 h. In principle, controls, showing no bias of patients (Table 1). BCG therapy was performed once weekly for 6 The recurrence rate during the 2-year period weeks. The patients were then followed up by after TUR and BCG treatment in 96 patients was urinary cytology and cystoscopy every 3 months. The purified protein derivative skin test was compared with that in each control group (Table 2). The simple recurrence rate was significantly lower performed before and after the 6-week course of in the BCG group (21/96 patients, 22%) than in intravesical BCG. either the drug instillation group (34%) or the nonThe simple recurrence rate and the recurrence instillation group (46%). The number of recurrate by the person-years method (Schoenberg and rences/total patient-months was also significantly Myers, 1977) during the 2-year period after BCG lower in the BCG group (0.019) than in the drug therapy were calculated. The results were compared instillation group (0.030) or in the non-instillation with those in the control groups. Significant group (0.043), with OE ratios of 0.619 and 0.446 differences in the simple recurrence rate were respectively. evaluated by x2 test. In the person-years method, To evaluate various factors associated with the the ratio of the observed actual value to expected efficacy of BCG therapy, the recurrence rate value (O/E) was calculated using the following according to tumour multiplicity, grade or stage equation and significant differences were evaluated was compared between the BCG group and each using the Poisson distribution table : control group (Table 3). The recurrence rate of O/E=(the number of recurrences after BCG multiple tumours was higher than that of solitary tumours in each group. In the BCG group, the therapy)/ recurrence rate of solitary tumours was similar to {(the recurrence rate in the control) x (total patient-months after BCG that in one control group, but the rate of multiple tumours was significantlylower than in both control therapy)).
Table 1 Distribution of Pre-treatment Characteristics of 96 BCG Patients and 102 Controls Controls
No. of patients Sex Male Female Mean age (years) Multiplicity Solitary Multiple Tumour grade G1
G2 G3 Tumour stage Ta TI associated with Tis Follow-up (months)
BCG instillation group (%I
Other drug instillation group Non-instillation group
(%)
(%I
96
74
28
82 (85.4) 14 (14.6) 66.3 26-9 1
65 (87.8) 9 (12.2) 64.1 19-84
25 (89.3) 3 (10.7) 64.1 41-92
42 (43.7) 54 (56.3)
36 (48.6) 38 (51.4)
13 (46.4) 15 (53.6)
45 (46.9) 35 (36.4) 16 (16.7)
33 (44.6) 28 (37.8) 13 (17.6)
18 (64.3) 6 (21.4) 4 (14.3)
47 (49.0) 49 (51.0)
34 (45.9) 40 (54.1)
16 (57.1) 12 (42.9)
10 13.9 1 .I-24
4 18.8 0.4-24
2 19.2 0.5-24
PROGNOSTIC FACTORS OF SUPERFICIAL BLADDER CANCEiR TREATED WITH INTRAVESICAL BCG
37
Table 2 Recurrence R a t e i n 96 Patients in the 2 Years folllowing BlCG Th er ap y a n d Comparison with 102 Controls No. with recurrent turnours
No. ofpatients
Simple recurrence rate BCG patients 96 21 Controls Other drug instillation group 74 26 Non-instillation group 28 13 BCG group versus other drug group BCG group versus non-instillation groulp ~~
21.9 35.1 46.4
P
