~
Cancer Chemother Pharmacol (1992) 30 (Suppl): S 45-S 49
ancer
hemotherapyand harmacology
9 Springer-Verlag 1992
Intravesical instillation of Adriamycin for bladder tumors* Hiroshi Ohe 1, Hiroki Watanabe t, Teruo Mishina 2, Munekado Kojima I, and Shuichi Nakagawa 1 1 Dept. of Urology, Kyoto Prefectural University of Medicine 2 Mishina Urological Office
Summary. I n the p r e s e n t series o f trials, A d r i a m y c i n
Table 1. Regimens for ADM instillation therapy
( A D M ) i n t r a v e s i c a l i n s t i l l a t i o n t h e r a p y was f o u n d to b e effective a g a i n s t t u m o r s o f p a p i l l a r y m o r p h o l o g y m e a s u r i n g < 1 0 m m i n d i a m e t e r that were o f l o w p a t h o l o g i c a l stage a n d l o w h i s t o l o g i c a l grade. T h e rate o f c o m p l e t e d i s a p p e a r a n c e i n c r e a s e d in p r o p o r t i o n ~Lothe c o n c e n t r a t i o n o f A D M a n d the d u r a t i o n o f r e t e n t i o n o f the drug, a l t h o u g h the e f f i c a c y rates w e r e a l m o s t the s a m e i n e a c h t r i a l O n the other h a n d , side effects o n the b l a d d e r w e r e r e d u c e d w h e n the i n s t i l l e d s o l u t i o n w a s l o w e r in c o n c e n t r a t i o n a n d the r e t e n t i o n t i m e was short.
First study (1979): Group 1 ADM, 40 rag/20 ml distilled water 20 cases 3 h, every day for 2 weeks
Introduction
Preliminary study: Group 4 ADM derivatives, 30 mg/50 ml saline solution 3 cases (epirubicin, one case; pirarubicin, two cases) 10 rain, 3 times weekly for 2 weeks
It is w e l l k n o w n that i n t r a v e s i c a l i n s t i l l a t i o n o f A D M is a b l a t i v e a g a i n s t b l a d d e r t u m o r s . H o w e v e r , the r e s u l t a n t side effects i n c r e a s e in p r o p o r t i o n to the t r e a t m e n t ' s effectiveness. I n the p r e s e n t report, a n ideal a b l a t i v e A D M - i n stillation r e g i m e n for the t r e a t m e n t o f b l a d d e r t u m o r s is discussed.
Materials and methods In our department, topical ADM instillation therapy for bladder tumors was first studied in 1979 in group 1, comprising 20 cases (Table 1) [1]. In that study, 40 mg ADM dissolved in 20 ml sterifized distilled water was instilled into the bladder. The drug was retained in the bladder as long as possible, usually for about 3 h. This procedure was performed daily for 2 weeks. Next, the administration of two instillation regimens to groups 2 and 3, respectively, were tested in the second study, which was performed up to the date of this writing. In group 2, 50 mg ADM in 30 ml saline solution was used in 17 cases, and in group 3, 50 mg ADM in 50 ml saline solution was instilled in 34 cases. On these schedules, ADM was * Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16-17 November 1990, Osaka, Japan
Correspondence to: H. Ohe, D e p a ~ e n t of Urology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan
Second study: Group 2 ADM, 50 rag/30 ml saline solution 17 cases Group 3 ADM, 50 rag/50 ml saline solution 34 cases 1 h, 3 times weekly for 3 weeks
retained in the bladder for 1 h. These regimens were repeated 3 times weekly for 3 weeks. In a preliminary study in group 4, a brief instillation period of 10 rain was used for the administration of two ADM derivatives in the treatment of three cases of low-grade and low-stage superficial bladder tumors (epirubicin, one case; pirarubicin, two cases; Table 1). The effects of ADM instillationon bladder tumors were evaluated by cystoscopy and sonography after the final instillation of the drug. For interpretation of the results, "complete disappearance" indicated that disappearance of the bladder tumor was confirmed macroscopically by cystoscopic examination. "Partial disappearance" was defined as a reduction of >50% in the diameter of the bladder tumor in cases of a single tumor or a decrease of >50% in the number of tumors in cases of multiple tumors. "No effect" indicated that the reduction in the size of the tumor amounted to 1 cm
10
10
7 (70%) 1 (10%)
2
< 1 cm =>1 em
7 14
3
< 1 cm ~1 cm
4
< 1 cm
Partial disappearance of tumors
No effect
Efficacy rate
2 (20%) 3 (30%)
1 (10%) 6 (60%)
40%
2 (29%) 0
2 (29%) 7 (50%)
3 (43%) 3 (21%)
57% 50%
17 16
3 (18%) 1 (6%)
5 (29%) 12 (75%)
9 (53%) 4 (25%)
47% 81%
3
2 (67%)
1 (33%)
67%
No effect
Efficacy rate
0
90%
Table 4. Tumor number and effect Group
Number of tumors
Cases (n)
Complete disappearance of tumors
Partial disappearance of tumors
1
Single Multiple
9 11
4 (44%) 4 (36%)
3 (33%) 2 (18%)
2 (22%) 5 (45%)
78% 55%
2
Single Multiple
8 9
2 (25%) 0
4 (50%) 5 (56%)
2 (25%) 4 (44%)
75% 56%
3
Single Multiple
21 13
2 (10%) 2 (15%)
9 (43%) 8 (62%)
10 (48%) 3 (23%)
52% 77%
4
Single Multiple
2 1
2 (100%) 0
0 0
group 1, the tumors d i s a p p e a r e d c o m p l e t e l y in 8 o f 20 cases (40%). Partial d i s a p p e a r a n c e was achieved in 5 cases (25%), and the result was rated as no effect in 7 cases (35%). A c c o r d i n g l y , the efficacy rate o f this therapy for b l a d d e r tumors was 65% (13/20). In the s e c o n d study, the rate o f c o m p l e t e t u m o r d i s a p p e a r a n c e was the s a m e in groups 2 and 3, i. e., 11.8%. The partial d i s a p p e a r a n c e rates were 52.9% in group 2 and 50.0% in group 3. N o effect was o b s e r v e d in 35.3% o f cases in group 2 and in 38.2% o f cases in group 3. T h e efficacy rates were 64.7% in group 2 and 61.8% in group 3. In G r o u p 4, c o m p l e t e d i s a p p e a r a n c e was o b s e r v e d in 2 cases (66.7%). T h e s e results were ana-
0 1
100% 0
l y z e d with reference to the size, number, m o r p h o l o g y , grade, and stage o f the b l a d d e r tumors prior to the instillation therapy.
Tumor size and effect. In all treatment groups, the c o m p l e t e d i s a p p e a r a n c e rate was higher for tumors with a d i a m e t e r o f 10 m m in d i a m e ter (Table 3). Tumor number and effect. C o m p l e t e d i s a p p e a r a n c e was achieved in a greater n u m b e r o f cases i n v o l v i n g a single
S 47 Table 5. Tumor morphology and effect Group
Tumor morphology
Cases (n)
Complete disappearance of tumors
1
Papillary, pedunculated Papillary, sessile
12
7
Papillary, pedunculated Papillary, sessile
11
Papillary, pedunculated Papillary, sessile
30
2
3
2
Papillary, pedunculated Papillary, sessile
2 1
2
3
4
6
6
Partial disappearance of tumors
No effect
Efficacy rate
(58%)
2 (17%)
3 (25%)
75%
1 (17%)
3 (50%)
4 (67%)
50%
1
(9%)
7 (64%)
3 (27%)
73%
1 (17%)
2 (33%)
3 (50%)
50%
(7%)
16 (53%)
12 (40%)
60%
(67%)
1 (33%)
0
100%
2 (100%)
0
0
100%
0
0
1
0
Table 6, Tumor grade and effect Group
Tumor grade
Cases (n)
Complete disappearance of tumors
Partial disappearance of tumors
1
GlandG2 _>- G3 Unknown
10 2 8
3 (30%) 0 5 (63%)
4 (40%) 0 1 (13%)
3 (30%) 2 (100%) 2 (25%)
70% 0 75%
2
G1 andG2 G3
15 2
2 (13%) 0
8 (53%) 1 (50%)
5 (33%) 1 (50%)
67% 50%
3
G1 andG2 G3
33 1
4 (12%) 0
16 (48%) 1
4
G1
3
2 (67%)
0
No effect
13 0
Efficacy rate
(39%)
61% 100%
1 (33%)
67%
Table 7. Tumor stage and effect Group
Tumor stage
Cases (n)
Complete disappearance of tumors
1
= T2
13 7
8 0
(62%)
3 2
(23%) (29%)
2 (15%) 5 (71%)
85% 29%
2
Ta T1
6 11
2
(33%)
2 7
(33%) (64%)
2 (33%) 4 (36%)
67% 64%
3
Ta T1
33 1
4 0
16 (47%) 1 (100%)
13 (39%) 0
61% 100%
4
Ta T1
2 1
0
(12%)
2 (100%) 0
Partial disappearance of tumors
0 0
No effect
0 I
Efficacy rate
100% 0
tumor than in those beating multiple tumors in groups 1 and 2 (Table 4).
less of the tumor morphology; however, in group 3 it was higher for sessile tumors than for pedunculated tumors.
Tumor morphology and effect. In the first study (group 1), the efficacy rate was higher for the pedunculated type than for the sessile type, especially in terms of the complete disappearance rate (Table 5). In the second study (groups 2 and 3), this point was not analyzed clearly. In group 2 the complete disappearance rate was almost the same, regard-
Tumor grade and effect. Complete disappearance was marked for low-grade tumors (grades G1 and G2) in all groups (Table 6). Tumor stage and effect. In the first study, all cases of complete tumor disappearance involved lesions staged as
$48 Table 8. Local side effects encountered Group
Discussion
Cases (n)
Frequentand painful urination
Interruption of therapy
1 (40 mg/20 ml)
20
20 (100%)
2 (10%)
2 (50 mg/3Oml)
17
13 (76%)
5 (29%)
3 (50 mg/5Oml)
34
8 (24%)
2 (6%)
4 (30 mg/50 ml)
3
0
0
Cancer Chemother Pharmacol (1992) 30 (Suppl): S 45-S 49
ancer
hemotherapyand harmacology
9 Springer-Verlag 1992
Intravesical instillation of Adriamycin for bladder tumors* Hiroshi Ohe 1, Hiroki Watanabe t, Teruo Mishina 2, Munekado Kojima I, and Shuichi Nakagawa 1 1 Dept. of Urology, Kyoto Prefectural University of Medicine 2 Mishina Urological Office
Summary. I n the p r e s e n t series o f trials, A d r i a m y c i n
Table 1. Regimens for ADM instillation therapy
( A D M ) i n t r a v e s i c a l i n s t i l l a t i o n t h e r a p y was f o u n d to b e effective a g a i n s t t u m o r s o f p a p i l l a r y m o r p h o l o g y m e a s u r i n g < 1 0 m m i n d i a m e t e r that were o f l o w p a t h o l o g i c a l stage a n d l o w h i s t o l o g i c a l grade. T h e rate o f c o m p l e t e d i s a p p e a r a n c e i n c r e a s e d in p r o p o r t i o n ~Lothe c o n c e n t r a t i o n o f A D M a n d the d u r a t i o n o f r e t e n t i o n o f the drug, a l t h o u g h the e f f i c a c y rates w e r e a l m o s t the s a m e i n e a c h t r i a l O n the other h a n d , side effects o n the b l a d d e r w e r e r e d u c e d w h e n the i n s t i l l e d s o l u t i o n w a s l o w e r in c o n c e n t r a t i o n a n d the r e t e n t i o n t i m e was short.
First study (1979): Group 1 ADM, 40 rag/20 ml distilled water 20 cases 3 h, every day for 2 weeks
Introduction
Preliminary study: Group 4 ADM derivatives, 30 mg/50 ml saline solution 3 cases (epirubicin, one case; pirarubicin, two cases) 10 rain, 3 times weekly for 2 weeks
It is w e l l k n o w n that i n t r a v e s i c a l i n s t i l l a t i o n o f A D M is a b l a t i v e a g a i n s t b l a d d e r t u m o r s . H o w e v e r , the r e s u l t a n t side effects i n c r e a s e in p r o p o r t i o n to the t r e a t m e n t ' s effectiveness. I n the p r e s e n t report, a n ideal a b l a t i v e A D M - i n stillation r e g i m e n for the t r e a t m e n t o f b l a d d e r t u m o r s is discussed.
Materials and methods In our department, topical ADM instillation therapy for bladder tumors was first studied in 1979 in group 1, comprising 20 cases (Table 1) [1]. In that study, 40 mg ADM dissolved in 20 ml sterifized distilled water was instilled into the bladder. The drug was retained in the bladder as long as possible, usually for about 3 h. This procedure was performed daily for 2 weeks. Next, the administration of two instillation regimens to groups 2 and 3, respectively, were tested in the second study, which was performed up to the date of this writing. In group 2, 50 mg ADM in 30 ml saline solution was used in 17 cases, and in group 3, 50 mg ADM in 50 ml saline solution was instilled in 34 cases. On these schedules, ADM was * Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16-17 November 1990, Osaka, Japan
Correspondence to: H. Ohe, D e p a ~ e n t of Urology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan
Second study: Group 2 ADM, 50 rag/30 ml saline solution 17 cases Group 3 ADM, 50 rag/50 ml saline solution 34 cases 1 h, 3 times weekly for 3 weeks
retained in the bladder for 1 h. These regimens were repeated 3 times weekly for 3 weeks. In a preliminary study in group 4, a brief instillation period of 10 rain was used for the administration of two ADM derivatives in the treatment of three cases of low-grade and low-stage superficial bladder tumors (epirubicin, one case; pirarubicin, two cases; Table 1). The effects of ADM instillationon bladder tumors were evaluated by cystoscopy and sonography after the final instillation of the drug. For interpretation of the results, "complete disappearance" indicated that disappearance of the bladder tumor was confirmed macroscopically by cystoscopic examination. "Partial disappearance" was defined as a reduction of >50% in the diameter of the bladder tumor in cases of a single tumor or a decrease of >50% in the number of tumors in cases of multiple tumors. "No effect" indicated that the reduction in the size of the tumor amounted to 1 cm
10
10
7 (70%) 1 (10%)
2
< 1 cm =>1 em
7 14
3
< 1 cm ~1 cm
4
< 1 cm
Partial disappearance of tumors
No effect
Efficacy rate
2 (20%) 3 (30%)
1 (10%) 6 (60%)
40%
2 (29%) 0
2 (29%) 7 (50%)
3 (43%) 3 (21%)
57% 50%
17 16
3 (18%) 1 (6%)
5 (29%) 12 (75%)
9 (53%) 4 (25%)
47% 81%
3
2 (67%)
1 (33%)
67%
No effect
Efficacy rate
0
90%
Table 4. Tumor number and effect Group
Number of tumors
Cases (n)
Complete disappearance of tumors
Partial disappearance of tumors
1
Single Multiple
9 11
4 (44%) 4 (36%)
3 (33%) 2 (18%)
2 (22%) 5 (45%)
78% 55%
2
Single Multiple
8 9
2 (25%) 0
4 (50%) 5 (56%)
2 (25%) 4 (44%)
75% 56%
3
Single Multiple
21 13
2 (10%) 2 (15%)
9 (43%) 8 (62%)
10 (48%) 3 (23%)
52% 77%
4
Single Multiple
2 1
2 (100%) 0
0 0
group 1, the tumors d i s a p p e a r e d c o m p l e t e l y in 8 o f 20 cases (40%). Partial d i s a p p e a r a n c e was achieved in 5 cases (25%), and the result was rated as no effect in 7 cases (35%). A c c o r d i n g l y , the efficacy rate o f this therapy for b l a d d e r tumors was 65% (13/20). In the s e c o n d study, the rate o f c o m p l e t e t u m o r d i s a p p e a r a n c e was the s a m e in groups 2 and 3, i. e., 11.8%. The partial d i s a p p e a r a n c e rates were 52.9% in group 2 and 50.0% in group 3. N o effect was o b s e r v e d in 35.3% o f cases in group 2 and in 38.2% o f cases in group 3. T h e efficacy rates were 64.7% in group 2 and 61.8% in group 3. In G r o u p 4, c o m p l e t e d i s a p p e a r a n c e was o b s e r v e d in 2 cases (66.7%). T h e s e results were ana-
0 1
100% 0
l y z e d with reference to the size, number, m o r p h o l o g y , grade, and stage o f the b l a d d e r tumors prior to the instillation therapy.
Tumor size and effect. In all treatment groups, the c o m p l e t e d i s a p p e a r a n c e rate was higher for tumors with a d i a m e t e r o f 10 m m in d i a m e ter (Table 3). Tumor number and effect. C o m p l e t e d i s a p p e a r a n c e was achieved in a greater n u m b e r o f cases i n v o l v i n g a single
S 47 Table 5. Tumor morphology and effect Group
Tumor morphology
Cases (n)
Complete disappearance of tumors
1
Papillary, pedunculated Papillary, sessile
12
7
Papillary, pedunculated Papillary, sessile
11
Papillary, pedunculated Papillary, sessile
30
2
3
2
Papillary, pedunculated Papillary, sessile
2 1
2
3
4
6
6
Partial disappearance of tumors
No effect
Efficacy rate
(58%)
2 (17%)
3 (25%)
75%
1 (17%)
3 (50%)
4 (67%)
50%
1
(9%)
7 (64%)
3 (27%)
73%
1 (17%)
2 (33%)
3 (50%)
50%
(7%)
16 (53%)
12 (40%)
60%
(67%)
1 (33%)
0
100%
2 (100%)
0
0
100%
0
0
1
0
Table 6, Tumor grade and effect Group
Tumor grade
Cases (n)
Complete disappearance of tumors
Partial disappearance of tumors
1
GlandG2 _>- G3 Unknown
10 2 8
3 (30%) 0 5 (63%)
4 (40%) 0 1 (13%)
3 (30%) 2 (100%) 2 (25%)
70% 0 75%
2
G1 andG2 G3
15 2
2 (13%) 0
8 (53%) 1 (50%)
5 (33%) 1 (50%)
67% 50%
3
G1 andG2 G3
33 1
4 (12%) 0
16 (48%) 1
4
G1
3
2 (67%)
0
No effect
13 0
Efficacy rate
(39%)
61% 100%
1 (33%)
67%
Table 7. Tumor stage and effect Group
Tumor stage
Cases (n)
Complete disappearance of tumors
1
= T2
13 7
8 0
(62%)
3 2
(23%) (29%)
2 (15%) 5 (71%)
85% 29%
2
Ta T1
6 11
2
(33%)
2 7
(33%) (64%)
2 (33%) 4 (36%)
67% 64%
3
Ta T1
33 1
4 0
16 (47%) 1 (100%)
13 (39%) 0
61% 100%
4
Ta T1
2 1
0
(12%)
2 (100%) 0
Partial disappearance of tumors
0 0
No effect
0 I
Efficacy rate
100% 0
tumor than in those beating multiple tumors in groups 1 and 2 (Table 4).
less of the tumor morphology; however, in group 3 it was higher for sessile tumors than for pedunculated tumors.
Tumor morphology and effect. In the first study (group 1), the efficacy rate was higher for the pedunculated type than for the sessile type, especially in terms of the complete disappearance rate (Table 5). In the second study (groups 2 and 3), this point was not analyzed clearly. In group 2 the complete disappearance rate was almost the same, regard-
Tumor grade and effect. Complete disappearance was marked for low-grade tumors (grades G1 and G2) in all groups (Table 6). Tumor stage and effect. In the first study, all cases of complete tumor disappearance involved lesions staged as
$48 Table 8. Local side effects encountered Group
Discussion
Cases (n)
Frequentand painful urination
Interruption of therapy
1 (40 mg/20 ml)
20
20 (100%)
2 (10%)
2 (50 mg/3Oml)
17
13 (76%)
5 (29%)
3 (50 mg/5Oml)
34
8 (24%)
2 (6%)
4 (30 mg/50 ml)
3
0
0
