Upsala J Med Sci 90: 127-132, 1985 Intravesical Ethoglucid (EpodylR) for Weatment of Noninvasive Bladder Cancer (Stage Ta) Anders Larson and Ake Fritjofsson Department of Urology, University Hospital, Uppsala, Sweden ABSTRACT Widespread, we 1 d i f f e r e n t i a t e d ( g r a d e I) b l a d d e r turnours c o n f i n e d t o t h e rnucosa ( s t a g e Ta) were t r e a t e d w i t h r e g u l a r i n t r a v e s i c a l i n s t i l l a t i o n s o f e t h o - g l u c i d ( E p o d y l ) n 24 p a t i e n t s . The t h e r a p e u t i c s c h e d u l e c o u l d b e f o l l o w e d i n a l l b u t one p a t i e n t , i n whom s i d e e f f e c t s n e c e s s i t a t e d c e s s a t i o n o f t r e a t m e n t . Complete r e s p o n s e was o b t a i n e d i n 7 5 76 o f t h e p a t i e n t s , and d u r i n g c o n t i n u e d p r o p h y l a c t i c t h e r a p y 90 5 remained t u m o u r - f r e e . A f t e r t e r m i n a t i o n o f t h e t r e a t - ment,however, new tumours appeared i n 60-80 % o f t h e p a t i e n t s . R I N T R O D U C T I O N S u p e r f i c i a l b l a d d e r tumours ( s t a g e Ta and T l ) have a l w a y s been r e g a r d e d w i t h some d i s t r u s t because o f t h e h i g h r e c u r r e n c e r a t e a f t e r e n d o s c o p i c r e s e c t i o n o r f u l g u r a t i o n . Moreover, tumours d e v e l o p i n g a f t e r r e s e c t i o n have sometimes been o f h i g h e r s t a g e o r grade. C o n s e q u e n t l y , t h e e v o l u t i o n o f a n t i t u m o u r chemother- a p e u t i c d r u g s f o r i n t r a v e s i c a l use a r o u s e d e x p e c t a t i o n s o f more permanent c u r e o f s u p e r f i c i a l b l a d d e r tumours a s an a l t e r n a t i v e t o c o n v e n t i o n a l e n d o s c o p i c r e - s e c t i o n or as p r o p h y l a c t i c a d j u v a n t t o t r a n s u r e t h r a l t r e a t m e n t . D u r i n g t h e p a s t 25 y e a r s s e v e r a l c y t o t o x i c a g e n t s have come i n t o use. Numerous s t u d i e s have been done t o d e t e r m i n e w h i c h p a t i e n t s s h o u l d r e c e i v e chemotherapy, when t o i n i t i a t e t r e a t m e n t , and what a g e n t , dose, t r e a t m e n t s c h e d u l e and d u r a t i o n o f t r e a t m e n t a r e most a p p r o p r i a t e f o r s u p e r f i c i a l b l a d d e r tumours. D e f i n i t i v e an- swers t o t h e s e q u e s t i o n s a r e s t i l l a w a i t e d . T h i o t e p a seems t o have been t h e f i r s t a g e n t u t i l i z e d f o r t h i s purpose. A l - though h i g h l y e f f e c t i v e i n some cases o f h i g h l y d i f f e r e n t i a t e d b l a d d e r tumour, t h i s d r u g has n e v e r a c h i e v e d p o p u l a r i t y , m a i n l y because o f i t s s e r i o u s s i d e e f f e c t s , t h e c h i e f o f w h i c h i s rnyelosuppression due t o a b s o r p t i o n t h r o u g h t h e b l a d d e r rnucosa. R E t h o g l u c i d ( E p o d y l ) , i n t r o d u c e d i n 1971 b y R i d d l e & W a l l a c e ( 9 ) , i s an- o t h e r d r u g used f o r t o p i c a l chemotherapy. I t i s an a l k y l a t i n g a n t i n e o p l a s t i c 127 a g e n t with h i g h e r m o l e c u l a r w e i g h t t h a n t h i o t e p a . Systemic s i d e e f f e c t s a r e un- common, presumably because none or v e r y l i t t l e o f t h e d r u g i s absorbed from t h e b l a d d e r . A l t h o u g h new d r u g s such as a d r i a m y c i n ( D o x o r u b i c i n h y d r o c h l o r i d e ) and m i t o m y c i n C have w e l l e s t a b l i s h e d e f f i c a c y a g a i n s t s u p e r F i c i a 1 b l a d d e r c a n c e r , E p o d y l i s s t i l l e x t e n s i v e l y used i n many c e n t r e s , e s p e c i a l l y i n Europe, a s s t a n d a r d t r e a t m e n t o f s u p e r f i c i a l tumours o f t h e b l a d d e r , The aim o f t h i s s t u d y was t o d e t e r m i n e t h e t h e r a p e u t i c e f f e c t o f i n t r a v e s i c - a 1 E p o d y l on s u p e r f i c i a l p a p i l l a r y c a n c e r o f t h e b l a d d e r , w i t h o u t i n v a s i o n i n t o t h e l a m i n a p r o p r i a ( s t a g e Ta) and o f l o w m a l i g n a n c y g r a d e ( g r a d e 1). MATERIAL AND METHODS The s e r i e s c o m p r i s e d 24 p a t i e n t s , 2 1 men (mean age 66, r a n g e 33-85 y e a r s ) and t h r e e women (aged 68, 76 and 8 1 ) . A l l p r e s e n t e d w i t h e x t e n s i v e b l a d d e r tu- mours. I n 1 2 cases t h e s e tumours were r e c u r r e n c e s a f t e r f r e q u e n t t r a n s u r e t h r a l r e s e c t i o n and/or f u l g u r a t i o n f o r p a p i l l o m a . The o t h e r 1 2 p a t i e n t s had n o t p r e - v i o u s l y r e c e i v e d t r e a t w e n t . I n a l l t h e p a t i e n t s s u r g i c a l b i o p s y was t a k e n f o r p a t h o l o g i c c l a s s i f i c a t i o n o f t h e tumour, w h i c h o t h e r w i s e was l e f t i n t a c t . To make t h e s e r i e s as homogeneous a s p o s s i b l e , o n l y p a t i e n t s with tumours c l a s s i f i e d as s t a g e Ta (UICC), g r a d e I (WHO) were i n c l u d e d i n t h e s t u d y . F o r t r e a t m e n t w i t h E p o d y l ( I C I , U K ) , t h e R i d d l e - W a l l a c e ( 9 ) s c h e d u l e was used. A s o l u t i o n o f 1 m l E p o d y l i n 100 m l d i s t i l l e d w a t e r was i n s t i l l e d with a g l a s s s y r i n g e i n t o t h e empty b l a d d e r , and t h e s o l u t i o n was r e t a i n e d for one h o u r . The s c h e d u l e f o r i n s t i l l a t i o n s was a s f o l l o w s : Once weekly for 3 months, t h e n f o r t n i g h t l y f o r 3 months, t h e n m o n t h l y f o r 1 year, t h e n m o n t h l y t o e v e r y t h i r d month. The t r e a t m e n t was g i v e n on an o u t - p a t i e n t b a s i s . C y s t o s c o p i c checks were made e v e r y t h i r d month. RESULTS The r e s u l t s a r e s u r v e y e d i n F i g . 1. Complete r e g r e s s i o n (CR) was o b t a i n e d 128 N C .rl a, u a, ci ci 3 a, ci 0 z 4 m c 4.J c E n M 3 m ci E r n .d a, x a, o v ) a , I ci c i m 3r oc, a c c i o E 0 Z M 0, .ri ci 3 D a, o u c c m a , c i E cic, 3 m 4 129 i n 1 8 o f t h e 24 p a t i e n t s a f t e r 3 t o 6 months o f t h e r a p y . E l e v e n o f t h e 1 8 re- c e i v e d f u r t h e r p r o p h y l a c t i c t r e a t m e n t f o r p e r i o d s r a n g i n g f r o m 1 t o 5 y e a r s , and d u r i n g t h e s e p e r i o d s 10 o f t h e p a t i e n t s remained f r e e f r o m turnour. A f t e r t h e t r e a t m e n t was stopped, however, s i x had r e c u r r e n c e , a l l w i t h i n 1 8 m o n t h s . Four p a t i e n t s have remained t u m o u r - f r e e d u r i n g f o l l o w - u p f o r p e r i o d s o f 3 months t o 6 y e a r s . One p a t i e n t showed r e c u r r e n c e o f tumour w h i l e u n d e r g o i n g p r o p h y l a c t i c t r e a t m e n t . F i v e o f t h e 18 p a t i e n t s w i t h C R were n o t s u b s e q u e n t l y g i v e n p r o p h y l a c t i c t r e a t m e n t . I n f o u r o f them t h e r e was r e c u r r e n c e o f tumour a f t e r 3 t o 9 months, w h i l e one has remained t u m o u r - f r e e d u r i n g two y e a r s o f o b s e r v a t i o n . I n 6 o f t h e 24 p a t i e n t s t h e E p o d y l i n s t i l l a t i o n s d i d n o t r e s u l t i n CR. Two o f t h e 18 p a t i e n t s w i t h CR f a i l e d t o a t t e n d for f o l l o w - u p i n v e s t i g a t - i o n . L o c a l s i d e e f f e c t s i n t h e form o f f r e q u e n c y o f m i c t u r i t i o n and d y s u r i a were e x p e r i e n c e d by 1 0 ( 4 0 % ) o f t h e p a t i e n t s , b u t n e c e s s i t a t e d d i s c o n t i n u a t i o n o f t r e a t m e n t o n l y i n one. There were no s y s t e m i c s i d e e f f e c t s . A l l t h e p a t i e n t s w i t h r e c u r r e n c e o f tumour have r e c e i v e d f u r t h e r t r e a t m e n t , w i t h i n t e n s i f i e d t r a n s u r e t h r a l r e s e c t i o n and/or a d d i t i o n a l chemotherapy. DISCUSSION I n t h i s series o f p a t i e n t s , i n t r a v e s i c a l i n s t i l l a t i o n s o f E p o d y l f o r wide- spread, n o n i n v a s i v e ( s t a g e Ta), h i g h l y d i f f e r e n t i a t e d ( g r a d e I ) b l a d d e r c a n c e r i n i t i a l l y gave c o m p l e t e e r a d i c a t i o n o f tumour i n 75 % o f t h e cases. When t h e c u r a t i v e t r e a t m e n t was n o t superseded b y p r o p h y l a c t i c chemotherapy, however, new tumours appeared i n 80 % o f t h e p a t i e n t s w i t h i n 3 t o 9 months. When p r o - p h y l a x i s was g i v e n , 90 X o f t h e p a t i e n t s remained t u m o u r - f r e e d u r i n g t h e t r e a t m e n t p e r i o d . A f t e r t e r m i n a t i o n o f t h e p r o p h y l a x i s , 60 L o f t h e s e p a t i e n t s a l s o sooner or l a t e r showed new tumours. Comparison o f o u r r e s u l t s w i t h t h o s e o f o t h e r i n v e s t i g a t o r s i s n o t easy, s i n c e such s t u d i e s commonly do n o t d e s c r i b e i n d e t a i l how many o f t h e s o - c a l l e d s u p e r f i c i a l tumours were, i n f a c t , i n s t a g e Ta or T 1 , how many were p a p i l l a r y tumours o r p r i m a r y c a r c i n o m a i n s i t u and how many p a t e n t s had been g i v e n Epo- d y l as t r e a t m e n t w i t h c u r a t i v e i n t e n t or a s p r o p h y l a x s f o l l o w i n g t r a n s u r e t h r a l tumour r e s e c t i o n . Moreover, f i g u r e s f o r r e s p o n s e r a t e have sometimes i n c l u d e d b o t h c o m p l e t e and p a r t i a l r e g r e s s i o n o f tumour. I n some s e r i e s r e p o r t e d i n t h e l i t e r a t u r e , however, s u p e r f i c i a l b l a d d e r tumours were managed e s s e n t i a l l y as i n o u r p a t i e n t s , w i t h i n t r a v e s i c a l i n - s t i l l a t i o n s o f E p o d y l g i v e n a s t h e r a p y and n o t s i m p l y as complement t o endo- s c o p i c p r o c e d u r e s . I n comparison w i t h such series, o u r f i g u r e s f o r c o m p l e t e 130 tumour r e g r e s s i o n l l , l 2 ) , e q u a l t h o s e f o r m i t o m y c i n C (41, and a r e c l e a r l y s u p e r i o r t o r e s u l t s w i t h t h i o t e p a (3,7,14) and a d r i a m y c i n ( 2 , 5 ) . e q u a l or exceed t h o s e s t a t e d f o r E p o d y l t r e a t m e n t (1,9,10, Our series comprised o n l y p a t i e n t s w i t h p r e c i s e l y d e f i n e d p a t h o l o g i c s t a g e o f tumour, Ta. This may e x p l a i n t h e more f a v o u r a b l e response r a t e among o u r p a t i e n t s t h a n i n o t h e r s e r i e s , w h i c h i n c l u d e d T i s , a tumour w i t h p r o g n o s i s o f t e n much worse t h a n f o r o t h e r s u p e r f i c i a l tumours. The o b s e r v a t i o n t h a t new tumours so o f t e n arise a f t e r t e r m i n a t i o n o f i n i t i a l t r a n s u r e t h r a l r e s e c t i o n and/or i n t r a v e s i c a l chemotherapy t h a t has e l i m i n a t e d e x i s t i n g tumours s u p p o r t s t h e t h e o r y p o s t u l a t e d by Soloway ( 1 3 ) and o t h e r s , v i z . t h a t t h e l a t e r l e s i o n s a r e n o t " r e c u r r e n c e s " b u t a r e i n d e e d new, p o s s i b l y produced by c a r c i n o g e n s or o t h e r , s t i l l obscure a e t i o l o g i c f a c t o r s . L o c a l s i d e e f f e c t s o c c u r r e d i n 40 5 o f o u r p a t i e n t s , e s p e c i a l l y d u r i n g t h e f i r s t phase o f t r e a t m e n t , when t h e i n s t i l l a t i o n s had t o be f a i r l y f r e q u e n t . B u t o n l y i n one case were t h e s i d e e f f e c t s so s e v e r e a s t o n e c e s s i t a t e d i s c o n - t i n u a t i o n o f t h e t r e a t m e n t . I n t h e o t h e r p a t i e n t s f r e q u e n c y and d y s u r i a were t r a n s i e n t , and a f t e r some a d j u s t m e n t o f dosage and t r e a t m e n t s c h e d u l e t h e i n - s t i l l a t i o n s c o u l d be c o n t i n u e d . Our r e s u l t s i n t h i s r e s p e c t c o n t r a s t f a v o u r a b l y with e a r l i e r r e p o r t e d o b s e r v a t i o n s t h a t E p o d y l t r e a t m e n t had t o b e s t o p p e d be- cause o f s e r i o u s s i d e e f f e c t s i n 5 t o 25 % o f cases ( 8 ) . Much a t t e n t i o n has been g i v e n t o t h e r i s k t h a t tumours may d e v e l o p as a com- p l i c a t i o n o f chemotherapy ( 6 ) . I n o u r s t u d y , however, t h e h i s t o l o g i c appearance o f new tumours a p p e a r i n g d u r i n g or a f t e r t h e p r o p h y l a c t i c t r e a t m e n t d i d n o t d i f f e r f r o m t h a t i n t h e i n i t i a l turnours, a l t h o u g h i n some cases t r e a t m e n t h a d been g i v e n f o r up t o 5 f y e a r s . I n c o n c l u s i o n , o u r s t u d y showed t h a t p a t i e n t s w i t h s u p e r f i c i a l b l a d d e r t u - mours o f s t a g e Ta, g r a d e I a r e s u i t a b l e f o r i n t r a v e s i c a l chemotherapy. Compared w i t h o t h e r c h e m o t h e r a p e u t i c a g e n t s , E p o d y l has p r o v e d f a v o u r a b l e f o r t h i s p u r - pose. The advantages o f E p o d y l a r e i t s documented e f f e c t i v e n e s s , r e l a t i v e l a c k o f s i d e e f f e c t s and f a i r l y l o w c o s t . REFERENCES 1. C o l l e e n , S., Ek, A . , H e l l s t e n , S. & Lindholm, C.-E.: I n t r a c a v i t a r y E p o d y l f o r m u l t i p l e , n o n - i n v a s i v e , h i g h l y d i f f e r e n t i a t e d b l a d d e r tumours. Scand J Urol N e p h r o l 14:43-45,1980. 2. Edsmyr, F., B e r l i n , T . , Boman, J . , Duchek, M . , E s p o s t i , P.L., G u s t a f s s o n , H. W i j k s t r o m , H. & C o l l s t e , L.C.: I n t r a v e s i c a l t h e r a p y w i t h s u p e r f i c i a l b l a d d e r tumours. E u r U r o l 6: 132-136,1980. tumours b y i n s t i l l a t i o n o f t h i o t e p a and 5 - f l u o r a c i l I n v e s t U r o l 2: 381, 1966. 3 . E s q u i v a l , E.L. Mackenzie, A.R. & Whitmore, W.F.: Treatment o f b l a d d e r 131 4. 5. 6 . 7. 8. 9. 10. 11. 12. 13. 14. 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