0073_results of a phase 1 & 2 clinical trial fractionated hyperthermia.pdf

8/14/2019 0073_RESULTS OF A PHASE 1 & 2 CLINICAL TRIAL FRACTIONATED HYPERTHERMIA.pdf

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F r o m : HYPERTHERMIAEdited by Haim I. Bicherand Duane F. Bruley(Plenum Publishing Corporation, 1982)

RESULTS OF A PHASE I/II CLINICAL TRIAL OF FRAC~IONATED H YP~I N O 3 M B I N A T I O N W I T H L O W D O S E I O N I Z I N G R A D I A T I O N

H a i m I . B i c h e r M . D . P h . D . F r e d W . H e t z e l P h . D .a n d T a l j i t S . S a n d h u , P h . D .D e p a r t m e n t o f T h e r a p e u t i c R a d i o l o g y , H e n r y F o r d H o s p i t a l ,D e t r o i t , M i c h i g a n 4 8 2 0 2

T h i s p a p e r a d d r e s s e s , i n p a r t , t h e c u r r e n t s t a t u s o f h y p e r -t h e r m i a a s a n e w . c l i n c a l m o d a l i t y a n d r e p o r t s t h e r e s u l t s . o f al a r g e , p r o s p e c t i v e c l i n i c a l t r i a l e m p l o y i n g m i c r o w a v e h y p e r t h e ~ n i ai n c o m b i n a t i o n w i t h l o w d o s e s o f i o n i z i n g r a d i a t i o n . I n t h eprotocol employed, each treated area received 8 hy~ treat-m e n t s o f 1 . 5 h o u r c o m b i n e d w i t h 1 6 0 0 r a d o v e r a t o t a l p e r i o d o f 5~eks. Patients wer e heated with microw aves of 915 or 300 ~e m p l o y i n g e x t e r n a l a p p l i c a t o r s o r i n t e r n a l i n t r a c a v i t a r y a n t e n n a s .The results of this fractionation scheme are ~aging s ince in1 2 1 f i e l d s - t h a t w ~ r e t r e a t e d c o m p l e t e l y a c c o r d i n g t o p r o t o c o l a n dw ~ r e a v a i l a b l e f o r f o l l o w - u p f o r a t l e a s t 2 m o n t h s , c o m p l e t er e s p o n s e s w ~ r e o b s e r v e d i n 6 5 % o f a l l c a s e s , p a r t i a l r e s p o n s e i n3 0 % a n d n o r e s p o n s e i n o n l y 5 % . I t i s a l s o i m p o r t a n t t o n o t e t h a tt e x i c i t y w a s m i n i m a l t h r o u g h o u t t h e s t u d y . ~

T h e u s e o f h y p e r t h e r m i a a s a c l i n i c a l m o d a l i t y b ~ s t a k e n g r e a ts t r i d e s i n t h e , p a s t f e w y e a r s a s m o r e i n v e s t i g a t o r s r e a l i z e d t h ei m p o r t a n c e o f c o m p l e t e t e s ~ _ r a t u r e a n d t r e a t m e n t d o c u m e n t a t i o n .R e c e n t s t u d i e s ( 1 - 7 ) i n v o l v i n g a c o m b i n a t i o n o f h y p e r t h e r m i aa n d x - i r r a d i a t i o n h a v e m a d e a s e r i o u s e f f o r t t o m e a s u r e a n d d o c u -m e n t t h e h y p e r t h e r m i a t r e a t m e n t s m o r e a c c u r a t e l y ~ I n . m o s t c a s e sa c c ~ p a r i s o n w i t h r a d i a t i o n a l o n e c o n t r o l s i s m a d e . K i m e t a l .( 5 ) h a v e t r e a t e d 5 0 r p a t i e n t s w i t h a v a r i e t y o f c u t a n ~ g u s t u m o r s .

87


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R E S U LT S O F A PHASE 1 /11 CLINICAL T RIAL 89radiation alone and the rest with the ccmbination.

The radiation schedule resulted in 46% c~nplete response whichwas enhanced to 85% ccmplete response when ccmbined with hyperthermia,the remaining 15% showed partial response. It should be noted thatin the treatment schedule, when radiation was combined with hyper-thermia, heat was applied inrnediately after the second daily fraction.The authors did not observe any abnormal reactions in areas thatwere treated with combined therapy.I n a p r e l i m i n a r y p u b l i c a t i o n ( 2 ) w e r e p o r t e d a n e f f e c t i v ef r a c t i o n a t i o n r e g i m e u s i n g 4 5 C r e g i o n a l h y p e r t h e r m i a c ~ n b i n e d w i t hi c ~ d o s e ( 1 6 0 0 r a d s ) x - i r r a d i a t i o n , y i e l d i n g a n o v e r a l l t o t a lr e s p o n s e r a t e o f 6 5 % . T h e s e r e s u l t s a r e n o w e x p a r ~ e d t o i n c l u d e a ne n l a r g e d , s e r i e s a s w e l l a s i n t r o d u c i n g a n i n t r a c a v i t a r y d e v i c e f o rt h e t r e a t m e n t o f d e e p s e a t e d t ~ n o r s .T h e a b o v e m e n t i o n e d c l i n i c a l s t u d i e s a r e b o t h i n t e r e s t i n g a n de n c o u r a g i n g . I n a d d i t i o n , r e c e n t p h y s i o l o g i c a l e v i d e n c e s h o w s ad i f f e r e n t i a l " b r e a k i n g p o i n t " i n b l o o d f l c ~ i n t ~ m ~ r s a s o c m p a r e dt o n o r m a l t i s s u e s w h i c h r e s u l t s i n d r a m a t i c s h i f t s ~ n i n t r a t u m o rp H ( 8 ) . T h e s e o b s e r v a t i o n s m a y , i n p a r t , e x p l a i n t h e r e s u l t s o ft h e c l i n i c a l t r i a l w e a r e r e p o r t i n g h e r e .

T h e e x a c t p r o t o c o l f o l l o w e d h a s b e e n r e p o r t e d i n d e t a i l e l s e -w h e r e ( 2 ) ( a l s o R T O G p r o t o c o l # 7 8 - 0 6 A ) . B r i e f l y , t r e a t m e n t c ~ n -s i s t e d o f 4 f r a c t i o n s o f h y p e r t h e r m i a a l o n e f o l l o w e d a f t e r a ( m ew e e k r e s t b y 4 a d d i t i o n a l f r a c t i o n s o f h y p e r t h e r m i a t h i s t i m e i m -m e d i a t e l y f o l l o w i n g r a d i a t i o n . A l l t r e a t m e n t s w e r e s e p a r a t e d b y7 2 h o u r s f o l l o w i n g a M o n d a y - T h u r s d a y o r T u e s d a y - F r i d a y p a t t e r n .E a c h h y p e r t h e r m i a t r e a t m e n t w a s f o r 1 % h o u r s a t t h e p r e s c r i b e dt e m p e r a t u r e ( 4 5 o c a l o n e ; 4 2 o c w i t h r a d i a t i o n ) a n d e a c h r a d i a t i o nd o s e w a s 4 0 0 r a d . T h e r e f o r e , t r e a t m e n t c o n s i s t e d o f a t o t a l o f8 h y p e r t h e r m i a t r e a t m e n t s a n d 1 6 0 0 r a d o v e r a t o t a l p e r i o d o f 5w ~ e k s .C c ~ p l e t e t h e r m c m e t r y w a s p e r f o r m e d d u r i n g e v e r y p a t i e n t r e a t m e n t e m p l o y i n g m i c r o t h e r m o c o u p l e s ( 1 0 0 p ) . T h e m i c r o t h e r m o -c o u p l e s w ~ r e i m p l a n t e d i n t h e t % ~ n o r ( w h e n e v e r p o s s i b l e ) a n d i ns u r r o u n d i n g o r o v e r l y i n g n o r m a l t i s s u e s . T h r o u g h o u t t r e a t m e n t ,t e m p e r a t u r e r e a d i n g s w e r e t a k e n a t 5 m i n u t e i n t e r v a l s u n d e r " p o w e r -o f f " c o n d i t i o n s t o e l i m i n a t e a n y p o s s i b l e i n t e r f e r e n c e a r t i f a c t s .H e a t i n g w a s a c c e m p l i s h e d u s i n g e i t h e r 9 1 5 o r 3 0 0 M H z m i c r o w a v e sd e l i v e r e d w i t h p a r t i a l l y d i e l e c t r i c l o a d e d e x t e r n a l b e a m a p p l i c a t o r so r i n t r a c a v i t a r y a n t e n n a s . I n a l l c a s e s a i r c o o l i n g w a s a p p l i e de i t h e r t o t h e s k i n ( e x t e r n a l a p p l i c a t o r s ) o r t o t h e j a c k e t o f t h ea n t e n n a t o m i n i m i z e n o r m a l t i s s u e h e a t i n g ( a n d h e n c e d a m a g e ) . W i t h


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88 HAIM I. BICHER ET AL.I m p r o v e d r e s u l t s a r e r e p o r t e d f o r b o t h t h e r a d i o s e n s i t i v e ( i . e .m y c o s i s f u n g o i d e s ) a n d r a d i o r e s i s t a n ~ ( i . e . m e l a n c m a ) t u m o r s w i t ht h e c c r a b i n e d h y p e r t h e r m i a a n d r a d i a t i o n t r e a h n e n t a s c c ~ p a r e d t oe i t h e r o f t h e s e m o d a l i t i e s u s e d a l o n e . T h e s e a u t h o r s r e p o r t c c m p l e t ed i s a p p e a r a n c e o f m u l t i p l e r e c u r r e n t m e l a n c m a n o d u l e s w i t h o u t u n u s u a ln o r m a l s k i n r e a c t i o n s . H o w e v e r , c o m b i n a t i o n t h e r a p y d i d p r o d u c ee n h a n c e d s k i n r e a c t i o n s i n p a t i e n t s w h o s e t r e a t e d a r e a s i n c l u d e de i t h e r a ~ s k i n g r a f t o r h e a v i l y s c a r r e d s k i n f r e m e x t e n s i v e s u r g e r y .

H o r n b a c k e t a l . ( 3 ) ~ t r e a t e d 7 2 p a t i e n t s w i t h a d v a n c e d c a n c e ru s i n g t h e c c m b i n e d t h e r a p y . O f t h e p a t i e n t s t r e a t e d w i t h h y p e r -t h e r m i a p r i o r t o r a d i a t i o n t h e r a p y , 5 3 % e x p e r i e n c e d c c r a p l e t e r e -m i s s i o n o f s y m p t c m s w h i l e ~ i n t h e g r o u p o f ~ p a t i e n t s t r e a t e d w i t hh e a t f o l l o w i n g r a d i o t h e r a p y , 9 2 % s h o w e d c o m p l e t e r e m i s s i o n . A g a i nt h e r e w a s n o s e t p r o t o c o l a n d t h e r a d i a t i o n d o s e s v a r i e d f r e m 5 0 0- t o 6 0 0 r a d p e r - d a y w i t h t o t a l d o s e s f r c m 3 0 0 0 t o 6 5 0 0 r a d s . H e a tt r e a t m e n t s w e r e - g i v e n u s i n g 4 3 3 . 9 2 , M H z m i c r o w a v e s . A l t h o u g h t h ea u t h o r s m e n t i o n h a v i n g a t t e m p t e d t o m e a s u r e t L ~ o r t e m p e r a t u r e d u r i n gt h e s e t r e a t m e n t s , t h e r e i s n o m e n t i o n o f t ~ a o r t e m p e r a t u r e s a c h i e v e di n t h e p a t i e n t s .M a n n i n g e t a l . ( 6 ) r e p o r t e d a v e r y l i m i t e d s t u d y c o m b i n i n gl o c a l i z e d h e a t a n d r a d i a t i o n . T h e r e s p o n s e r a t e f o r h e a t - r a d i a t i o n

c c ~ b i n a t i o n . . w a s 8 0 - 9 0 % c c ~ p a r e d w i t h 5 0 % r e s p o n s e r a t e f o r h e a ta l o n e a n d r a d i a t i o n a l o n e g r o u p s ~ T h e a u t h o r s s u g g e s t a b e n e f i c i a lt h e r a p e u t i c r a t i o a n d m i n i m a l s i d e e f f e c t s f r c m t h e c ~ n b i n e d t r e a t -A n o t h e r l i m i t e d s t u d y ( 7 ) t r e a t e d t w o g r o u p s o f p a t i e n t s , w i t hr a d i o t h e r a p y a l o n e , h . y p e r t h e r m i a a l o n e , - a n d c o m b i n e d t r e a t m e n t .O n e - g r o u p . o f p a t i e n t s r e c e i v e d 2 0 0 - 6 0 0 r a d f r a c t i o n s , 2 - 5 t i m e sp e r w e e k t o a t o t a l o f 1 8 0 0 - 2 4 0 0 r a d i n 5 - 1 4 f r a c t i o n s . T h eo t h e r g r o u p o f p a t i e n t s r e c e i v e d t h e c e m b i n e d t h e r m o r a d i o t b ~ r a p yt r e a t m e n t s - o n l y , r a d i a t i o n f r a c t i o n s o f 2 0 0 - 6 0 0 r a d , 2 - 5 t i m e s aw ~ k t o a ~ t o t a l o f 2 0 0 0 - 4 8 0 0 r a d i n 6 - 2 0 f r a c t i o n s . H y p e x T 4 h e r m ~ ct r e a t m e n t s f o r . b o t h g r o u p s w a s 4 2 - 4 4 C , 2 - 3 t i m e s p e r w ~ e k t o am a x i m u m o f t e n s e s s i o n s i n - f o u r w e e k s . H y p e r t h e r m i a t r e a t m e n t s

w ~ r e g i v e n u s i n g e i t h e r 2 4 5 0 o r 9 1 5 M H z m i c r o w a v e s . T h e f i r s tg r o u p o f 8 p a t i e n t s , s i x p a t i e n t s e x p e r i e n c e d c c ~ p l e t e r e g r e s s i o no f l e s i o n s t r e a t e d w i t h r a d i a t i o n p l u s h y p e r t h e r m i a w i t h i n o n em o n t h o f t h e r a p y . N o n e o f t h e t u m o r s t r e a t e d w i t h h y p e r t h e r m i aa l o n e r e g r e s s e d , c o m p l e t e l y . I n t h e s e c o n d g r o u p o f p a t i e n t s 7 3 %s h o w e d t u m o r r e g r e s s i o n . M e l a n c m a r e g r e s s e d c o m p l e t e l y i n 2 / 4c a s e s . N o a d v e r s e s i d e e f f e c t s w ~ r e o b s e r v e d o n n o r m a l t i s s u eA n o t h e r i n t e r e s t i n g s t u d y w a s r e p o r t e d b y A r c a n g e l i e t a l .( i ) . I n - . f i f t e e n p a t i e n t s w i t h m u l t i p l e n e c k n o d e m e t a s t a s e s f r o mh e a d a n d n e c k t r e a t e d w i t h e i t h e r r a d i a t i o n a l o n e o r i n c o m b i n a t i o nw i ~ h h - ~ e r t h e r m i a . A t o t a l o f 3 3 n e c k n o d e s w ~ r e t r e a t e d , 1 2 w i t h


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RE S ULT S OF A P H A S E 1 / 11 C L I NI CA L T R I AL 89r a d i a t i o n a l o n e a n d t h e r e s t w i t h t h e c ~ n b i o ~ t i o n .

T h e r a d i a t i o n s c h e d u l e r e s u l t e d i n 4 6 % c c ~ p l e t e r e s p o n s e w h i c hw a s e n h a n c e d t o 8 5 % c c ~ p l e t e r e s p o n s e w h e n c c m b i n e d w i t h h y p e r t h e r m i a ,t h e r e m a i n i n g 1 5 % s h o w e d p a r t i a l r e s p o n s e . I t s h o u l d b e n o t e d t h a ti n t h e t r e a t m e n t s c h e d u l e , w h e n r a d i a t i o n w a s c c r n b i n e d w i t h h y p e r -t h e r m i a , h e a t w a s a p p l i e d i n m e d i a t e l y a f t e r t h e s e c o n d d a i l y f r a c t i o n .T h e a u t h o r s d i d n o t o b s e r v e a n y a b n o r m a l r e a c t i o n s i n a r e a s t h a tI n a p r e l i m i n a r y p u b l i c a t i o n ( 2 ) w ~ r e p o r t e d a n e f f e c t i v ef r a c t i o n a t i o n r e g i m e u s i n g 4 5 C r e g i o n a l h y p e r t h e r m i a c ~ n b i n e d w i t hl o w d o s e ( 1 6 0 0 r a d s ) x - i r r a d i a t i o n , y i e l d i n g a n o v e r a l l t o t a lr e s p o n s e r a t e o f 6 5 % . T h e s e r e s u l t s a r e n o w e x p a n d e d t o i n c l u d e a ne n l a r g e d s e r i e s a s w e l l a s i n t r o d u c i n g a n i n t r a c a v i t a r y d e v i c e f o rt h e t r e a t m e n t o f d e e p s e a t e d t u m o r s .T h e a b o v e m e n t i o n e d c l i n i c a l s t u d i e s a r e b o t h i n t e r e s t i n g a n de n c o u r a g i n g . I n a d d i t i o n , r e c e n t p h y s i o l o g i c a l e v i d e n c e s h o w s ad i f f e r e n t i a l " b r e a k i n g p o i n t " i n b l o o d f l o w i n t ~ o r s a s o c ~ p a r e dt o n o r m a l t i s s u e s w h i c h r e s u l t s i n d r a m a t i c s h i f t s i n i n t r a t ~ n o rp H ( 8 ) . T h e s e o b s e r v a t i o n s m a y , i n p a r t , e x p l a i n t h e r e s u l t s o ft h e c l i n i c a l t r i a l w e a r e r e p o r t i n g h e r e .

T h e e x a c t p r o t o c o l f o l l o w e d h a s b e e n r e p o r t e d i n d e t a i l e l s e -w h e r e ( 2 ) ( a l s o R T O G p r o t o c o l # 7 8 - 0 6 A ) . B r i e f l y , t r e a t m e n t c o n -s i s t e d o f 4 f r a c t i o n s o f h y p e r t h e r m i a a l o n e f o l l o w ~ d a f t e r a ~ n ew e e k r e s t b y 4 a d d i t i o n a l f r a c t i o n s o f h y p e r t h e r m i a t h i s t i m e i m -m e d i a t e l y f o l l o w i n g r a d i a t i o n . A l l t r e a t m e n t s w e r e s e p a r a t e d b y7 2 h o u r s f o l l o w i n g a M o n d a y - T h u r s d a y o r T u e s d a y - F r i d a y p a t t e r n .E a c h h y p e r t h e r m i a t r e a t m e n t w a s f o r 1 h o u r s a t t h e p r e s c r i b e dt e m p e r a t u r e ( 4 5 o c a l o n e ; 4 2 o c w i t h r a d i a t i o n ) a n d e a c h r a d i a t i o nd o s e w a s 4 0 0 r a d . T h e r e f o r e , t r e a t m e n t c o n s i s t e d o f a t o t a l o f8 h y p e r t h e r m i a t r e a t m e n t s a n d 1 6 0 0 r a d o v e r a t o t a l p e r i e d o f 5w ~ e k s .C c ~ p l e t e t h e r m c m e t r y w a s p e r f o r m e d d u r i n g e v e r y p a t i e n tt r e a t m e n t e m p l o y i n g m i c r o t h e r m o c o u p l e s ( 1 0 0 p ) . T h e m i c r o t h e r m o -c o u p l e s w ~ r e i m p l a n t e d i n t h e t u m o r ( w h e n e v e r p o s s i b l e ) a n d i ns u r r o u n d i n g o r o v e r l y i n g n o r m a l t i s s u e s . T h r o u g h o u t t r e a t m e n t ,t e m p e r a t u r e r e a d i n g s w e r e t a k e n a t 5 m i n u t e i n t e r v a l s u n d e r " p o w e r -o f f " c o n d i t i o n s t o e l i m i n a t e a n y p o s s i b l e i n t e r f e r e n c e a r t i f a c t s .H e a t i n g w a s a c c c ~ p l i s h e d u s i n g e i t h e r 9 1 5 o r 3 0 0 M H z m i c r o w a v e sd e l i v e r e d w i t h p a r t i a l l y d i e l e c t r i c l o a d e d e x t e r n a l b e a m a p p l i c a t o r so r i n t r a c a v i t a r y a n t e n n a s . I n a l l c a s e s a i r c o o l i n g w a s a p p l i e de i t h e r t o t h e s k i n ( e x t e r n a l a p p l i c a t o r s ) o r t o t h e j a c k e t o f t h ea n t e n n a t o m i n i m i z e n o r m a l t i s s u e h e a t i n g ( a n ~ h e n c e d a m a g e ) . W i t h


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90 HAIM I BICHER ET AL_he w~iety o f heating equip ment av ailable we hav e been able toheat uniformly exte rnally up to 7 cm in depth as well as internallyheating the head and neck , mediastinum and pelvis (i).Results

A t t h i s t i m e 1 7 8 p a t i e n t s h a v e b e e n t r e a t e d a t o u r c l i n i c w i t ha m u l t i m o d a l i t y r e g i m e i n v o l v i n g h y p e r t h e r m i a a d m i n i s t e r e d i n n ~ l -t i f r a c t i o n f a s h i o n ( 8 h y p e r t h e r m i a t r e a t m e n t s p e r f i e l d ) . S i n c em a n y o f t h e s e p a t i e n t s h a d n ~ / I t i p l e t L ~ n o r s , a t l e a s t 2 5 0 t u m o r sh a v e b e e n t r e a t e d ( o v e r 2 , 0 0 0 t r e a t m e n t s e s s i o n s ) . N o t a l l o f t h e mf i t t e d a l l c r i t e r i a f o r i n c l u s i o n i n t h e s p e c i f i c p r o t o c o l , b u ta r o n g e v a l u a b l e r e s u l t s t h e f o l l w i n g c a n b e c i t e d :1 2 1 f i e l d s ( t ~ o r s ) w e r e t r e a t e d a c c o r d i n g t o o u r 8f r a c t i o n p r o t o o o l w i t h 1 6 0 0 r a d s i n 4 f r a c t i o n s . T h ef i n a l r e s u l t s s h o w a l m o s t n o t ~ x i c i t y , a n d a r a t e o f6 5 % o f t o t a l r e s p o n s e s a n d 3 0 % p a r t i a l r e s p o n s e .F u r t h e r a n a l y s i s o f t h i s s e r i e s i s s h o w n i n T a b l e s I - V I I .

T a b l e I s h o w s a s L m m ~ R r y o f a l l t h e p a t i e n t s t r e a t e d w h i c hc ~ m p l e t e d t h e e n t i r e p r o t o c o l a n d w e r e f o l l o w e d u p a t l e a s t t w om o n t h s . T a b l e I I p r o v i d e s a b r e a k d o w n o f t h e s u m m a r i z e d d a t a b yh i s t o l o g y . F r c m t h i s t a b l e i t i s c l e a r t h a t e v e r y h i s t o l o g i c a lt y p e t r e a t e d d o e s r e s p o n d t o t h i s t h e r a p y .T a b l e I I I r e p o r t s t h e r e s u l t s o f o u r t o x i c i t y s t u d y e m p l o y i n gt h e i n t r a c a v i t a r y m i c r o w a v e a n t e n n a s y s t e m . F o l l o w i n g 2 1 2 ( A l le q u i ~ n e n t w a s s u p p l i e d b y M e d t r a I n c . , 1 3 5 0 W . B e t h u n e , D e t r o i t ,M i c h i g a n , 4 8 2 0 2 . ) t r e a t m e n t s e s s i o n s o f 1 h o u r s e a c h , t h e o n l yo b s e r v e d t o x i c i t y w a s o n e c e n t r a l p n e u m o n i t i s . S i n c e r e s p o n s e i so n l y e v a l u a t e d a f t e r 2 m o n t h s a t t h i s t i m e o n l y 1 4 p a t i e n t s a r ee v a l u a b l e ( T a b l e I V ) . E v e n i n t h e s e p a t i e n t s w i t h d e e p s e a t e dt ~ n o r s ( m e d i a s t i n u m , p e l v i s ) o n l y 1 4 % f a i l e d t o r e s p o n d .

T a b l e s V - V I I e v a l u a t e r e s p o n s e t o t h e c o m b i n e d m o d a l i t y i nd i f f e r e n t a n a t c m i c a l l o c a t i o n s . I n h e a d a n d n e c k r e c u r r e n c e s ,b r e a s t a n d c h e s t w a l l , a n d s k i n t u m o r s o n l y a s m a l l p e r c e n t a g e( 9 % , 1 0 % - a n d 3 % r e s p e c t i v e l y ) f a i l e d t o r e s p o n d t o c c m b i n e d h y p e r -t h e r m i a a n d r a d i a t i o n w h i l e t o t a l r e s p o n s e s v a r i e d f r c m 4 6 % t o 7 6 %y i e l d i n g o u r r e p o r t e d a v e r a g e o f 6 5 . 5 % ( T a b l e I ) .D i s c u s s i o n

A s s e e n i n t h e d e t a i l e d r e s p o n s e b r e a k d o w n s h o w n i n T a b l e I I ,t h e h y p e r t h e r m i a - r a d i a t i o n f r a c t i o n a t i o n r e g i m e c h o s e n s e e m s t ob e a t l e a s t p a r t i a l l y s u c c e s s f u l i n a w i d e v a r i e t y o f t u m o r s . D e -t a i l e d e x a m i n a t i o n o f t h e d a t a s h o w s e s s e n t i a l l y n o t r e a t m e n tt ~ x i c i t y w i t h t h e a n t e n n a a p p l i c a t o r s ( T a b l e I I I ) s i n c e 2 1 2 s e s s i o n s( 3 1 8 h o u r s ) o f t r e a t m e n t r e s u l t e d i n o n l y o n e c a s e o f m i n i m a lt o x i c i t y . D u r i n g t h e s e t r e a t m e n t s ( T a b l e I V ) t u m o r r e s p o n s e w a s


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RE S ULT S OF A P H A S E 1 / 11 C L I NI CA L T R I AL 91

12 1 FieIds Treated:

Total ResponsePart~al ResponseNo Response

Recurrence:

Complications:

TABLE I SUI~u~Y OF RESULTS

(82 patients)79 (65.5~)36 (29.1~)6 (

Local:. 5Harginal:

Skin burns: 2 (completely hehted)Tongue Pharynx

Grand seizure:(completely healed)(neck treatment)(epileptic patient)


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T ~LR R E S U L T S Y H I S T O L O G Y

H I STOLt~ YHal Ignant Helmnoma

Malignant l.ymphomaSquamous CeZl Carcinoma

Adenocsrc~noma

O[her (Transitional CeZl,~asal Cell, Glioms, Sarcoma)

9 9Total7 Pnrtial3 N o R e s p o n s e

g R Tntal25 9 Total

15 PartialI N o R e s p o n s e

60 48 Total

10 Partial2 N o R e s p o n s e

9 5 Total

12 1 79 Total3 6 Pnrt|~l6 No Response

N~ ~um0~ a~ 2 mo~ths ~olio~-up ~nd thereafterTumor decreased in size to heI~ or less at 2 months follo~-~lp

FOLLOW-in (Ho~rr~s)2 I~

2 = 92 8

2 - 9

2 - II


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R E S U LT S OF A PHAS E I II I CL I NICAL T R I AL 93

TABLE III R E S U L T S - I N T R A C A V I T A R Y A N T E N N A - T O X I C I T Y

I4

C o m p l e t e ( L e s s T h a n ) 2 ~ M o n t h F o l l o w U p I 0 A T E a e NC o m p l e t e ( A t L e a s t ) 2 M o n t h F o l l o w U p 8 AT Each

T O T A L

10 0112212 Sessions

T o x i c i t y .- 1 C e n t r a l P n e u m o n l . t i s .

AT = H y p e r t h e r ~ l a T r e a t m e n t o f 1 h o u r s

TABLE IV RES b~T S- INTRACAV~TAR7 ~rrENNA-RESPONSE

14 P TIENTS COI~PLETE - A ~I VE A T 2 M O N T H S8 ~yper thermla Treatments

1 6 0 0 P a d s 2 Neeks ~- 4 FractionsT R 6 1 L o c a l R e c u r r e n c ePR

NR 2


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94 HAIM 1 B ICHE R E T AL

TABLE V RESU LTS-H EAD AN D N ECK PATY EN TS

TotalPatients

N E C K R E C U R R E N C E STotal Partial NoResponse R e s p o n s e R _ _ e ~ p o n s ~

22 10 10R e c u r r e n c e

1

TABLE VI BREAST AND CHEST WALL

Total No.of Fields

T o t a l P a r t i a l o~s Response R e s p o - - n s e

29 19

NO, o fI n c o m p l e t e s

T A B L E V I I S K I N T U O R S

T o t a l N o . T o t a l P a r t i a l N oof Fields Response ~9onse e ~ p ~ s e3 3 2 5


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RE S ULT S OF A P H A S E 1 / 11 C L I NI CA L T R I AL 95seen in all but 2 cases. Site specific analysis (Tables V-VII)also shc~s the relative effectiveness of this therapy regardlessof anatcndcal location.

The fractionation regime ~mployed in this study (regional hy-perthermia plus low dose radiation) should be cempared with thoseemployed in other reported clinical trials.In their study, Kim et al, (5) report 78% overall tumor control

rate after combined therapy as cc~pared with 26% after radiationalone. These investigators utilized t%o heating methods. S~nepatients with t~nors on extremities were heated by inversion hnwaterbath. The re st of the patients wer e treated using RF (27.12MHz) inductive heating . It s ho uld be p o inted o ut that there is agreat deal of variation in both the radiation dose and the hyper-thermia trea~nent duration as well as in the number of f ractions.The radiation dose e~ployed varied f rcm 800 rad in ~ f ractionsfor melancma to 2400 rad in 8 fractions for Kaposis sarccma.Similarly hyperthermia (43.5C) treatments varied from 2 fractionsof 30 mJ_nutes for melancma to 5 fractions of 60 minutes for mycosisfungoides. The hyperthermia treatments follow~d inmediately theradiatio n treatments in all cas es . This data do es no t s ug g es t anyparticular treatment schedule f or a particular t~or. The studydoes, however, demonstrate the improved effectiveness of c~nbinedthermoradiotheapy as cc~pared to hyperthermia or radiation alone.

In the study by Manning et al. (6), of the 40 patients treatedwith hyperthermia, four were treated in ccmbination with radiation.Each had a minimum of 3 nod ules. One nodule received a heat treat-ment o f 43C fo r 40 minutes us ing radio frequency currents . Ano thernodule received radiation alone frcm t%o radium needles to a doseo f 4000 rads in i0 0 ho urs . A third les io n had the s ame do s e p lussimultaneous heat to 43oc for 40 minutes using radium needles asheating electro des . A 30- 40% increas e in res p o ns e was o bs erv edfor the ccmbination therapy.Arcangeli and co-~Drkers (I) employed a rather unique technique

in their protocol. Hyperthermia was induced by 500 MHz microwavesusing a non contact applicator. These investigators used a veryinteresting fractional sch~ne. Described as a multiple dailyfractional (MDF) scheme, it consisted of 200 + 150 + 150 rad/day,4-5 hours interval between fractions, 5 days per w~ek, up to atotal of 4000/7000 rad. All the lesions were irradiated with thesame total dose, whether or not they received hyperthermia. Againa 40 increase in response was seen for the combined modalityt h e r a p y .

Johnson et al. (4) conducted a pilot study to evaluate normalSkin and melancma tumor therma e~ancem~t ratios of 41.5 to 42ChypertJ]e mda wit]~ radiation. The res[~nse of nor]hal skin to the


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96 HAIM I BICHER ET ALt r e a t m e n t w ~ s m e a s u r e d b y e v a l u a t i n g t h e d e g r e e o f e r y t h e m a a c c o r d i n gt o a n ~ _ r i c a l s c o r i n g s y s t ~ n . T u m o r r e s p o n s e w a s a s s e s s e d b ym e a s u r i n g t u m o r d i a m e t e r . A l t h o u g h t h e s t u d y w a s n o t c o n c l u s i v ea b o u t t h e t h e r m a l e n h a n c e m ~ _ n t r a t i o , i t d i d b r i n g t o l i g h t s ~ n e o ft h e p r o b l e m s a s s o c i a t e d w i t h o b t a i n i n g u s e f u l c l i n i c a l d a t a . T h es t u d y i n v o l v e d p a t i e n t s w i t h m u l t i p l e m e t a s t a t i c m e l a n c m a l e s i o n s .A t l e a s t t h r e e l e s i o n s w e r e c h o s e n o n e a c h p a t i e n t . T h e p a t i e n t sw ~ r e d i v i d e d i n t o t h r e e g r o u p s a n d g i v e n o n e , 3 o r 4 f r a c t i o n s , w i t ha m i n i ~ x n o f 7 2 h o ~ r s i n t e r v a l b e t w e e n e a c h f r a c t i o n . R a d i a t i o nd o s e p e r f r a c t i o n f o r d i f f e r e n t l e s i o n s o n a p a t i e n t v a r i e d f r c m5 0 0 t o 9 0 0 r a d . I n s c m e c a s e s s i n g l e f r a c t i o n s o f 1 0 0 0 , 1 2 0 0 o r1 3 0 0 r a d w ~ r e u s e d . O n a l l p a t i e n t s o n e l e s i o n w a s h e a t e d i ~ m e d i -a t e l y f o l l o w i n g r a d i a t i o n t h e r a p y a n d t h e o t h e r t ~ D o r m o r e l e s i o n st r e a t e d w i t h r a d i a t i o n a l o n e w e r e u s e d f o r c c m p a r i s o n . H y p e r t h e r m i at r e a t m e n t s w ~ r e a d m i n i s t e r e d u s i n g 9 1 5 M H z d i r e c t c o n t a c t m i c r o w a v ea p p l i c a t o r s ( 4 ) . D u r a t i o n o f h y p e r t h e r m i a t r e a t m e n t s v a r i e d b e t w e e n1 a n d 2 h o u r s a t 4 1 . 5 - 4 2 . 0 C .

S k i n e n h a n c ~ m ~ _ n t r a t i o ( S E R ) a n d t h e r m a l e n h a n c e m e n t r a t i o( T E R ) c o u l d b e e v a l u a t e d o n l y f o r a l i m i t e d n u m b e r o f p a t i e n t sb e c a u s e o f l a c k o f f o l l o w u p d a t a . S E R v a l u e s v a r i e d f o r 1 .2 t o1 . 7 w h i l e T E R v a l u e s i n m o s t c a s e s w ~ r e i . 3 . T h i s s t u d y d e m o n -s t r a t e d , h o w e v e r , t h a t s u p e r f i c i a l t i m e r s u p t o 4 c r n i n d i a m e t e ra n d 2 c m i n d e p t h c o u l d b e t r e a t e d w i t h a n a c c u r a c y o f + 0 . 5 Ce i t h e r d u r i n g , o r a f t e r r a d i a t i o n w i t h 9 15 M H z m i c r o w a v e s .

T h e s t u d y r e p o r t e d h e r e a s ~ e l l a s t h e r e s u l t s o f o t h e r i n -v e s t i g a t o r s t e n d t o i n d i c a t e t h e r e l a t i v e e f f e c t i v e n e s s a n d l a c ko f o v e r a l l a d v e r s e e f f e c t s f r c m c o m b i n e d h y p e r t h e r m i a a n d r a d i a t i o n .F u r t h e r p r o s p e c t i v e , s i t e s p e c i f i c t r i a l s a r e n o w p l a n n e d o r i np r o g r e s s t o f u r t h e r e v a l u a t e b o t h t h e s a f e t y a n d e f f e c t i v e n e s s o ff r a c t i o n a t e d h y p e r t h e r m i a a n d r a d i a t i o n . I n a d d i t i o n , t h e p a t i e n t sa l r e a d y t r e a t e d w i l l c o n t i n u e t o b e f o l l o w e d a t 2 m o n t h i n t e r v a l s .

i . A r c a n g e l i , G . , B a r n i , E . , D i v i d a l l i , A . , e t a l . E f f e c t i v e n e s so f m i c r o w a v e h y p e r t h e r m i a c o m b i n e d w i t h i o n i z i n g r a d i a t i o n :clinical results on nec k node metastases. Int. J_~.O n D o l , B i o l . P h _ v s . 1 9 8 0 ; 6 : 1 4 3 - 1 4 8 .2 . B i c h e r , H . I . , S a n d h u , T . S . , H e t z e l , F . W . H y p e r t h e r m i a a n dr a d i a t i o n i n c o m b i n a t i o n : a c l i n i c a l f r a c t i o n a t i o n r e g i m e .I n t . J . R a d i a t . O n c o l . B i o l . P h y s . 1 9 8 0 ; 6 : 8 6 7 - 8 7 0 .3 . H o r n b a c k , N . B . , S h u p e , R . E . , H ~ n a y o n , S . , e t a l . P r e l i m i n a r yc l i n i c a l r e s u l t s o f e ~ n b i n e d 4 3 3 M H z m i c r o w a v e t h e r a p ya n d r a d i a t i o n t h e r a p y o n p a t i e n t s w i t h a d v a n c e d c a n c e r .C a n c e r 1 9 7 7 ; 4 0 : 2 3 5 4 - 2 8 6 3 .4 . J o h n s o n , R . J . R . , S a r ~ l h u , T . S . , H e t z e l , F . W . , e t a l . Ap i l o t s t u d y t o i n v e s t i g a t e t h e t h e r a p e u t i c r a t i o o f 4 1 . 5 -4 2 . 0 C h y p e r t h e r m i a r a d i a t i o n . I n t . J . R a d i a t . O n c o l .


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R E SU L TS O F A P H A SE 1 / II C L IN ICA L TR IA L 97Biol. Phys. 1979; 5: 947-953.5. Kim, J. H., Hahn, E. W., Benjamin, F. J. Treatment of super-ficial cancers by combination hyperthermla and radiationtherapy. Clin. Bul. 1979; 9: 13-16.6. Manning, M. R., Cetas, T., Boone, M. L. M., Miller, R. C.Clinical hyperthermia: results of the phase I clinicaltrial ccmbining localized hyperthermia with or withoutradiation. (Abstr. ) Int. J. Radiat. Oncol. Biol. Ph ys.1979; 5: $2: 173.

7. U. R., Noell, K. T., Woodward, K. T. et al. Microw ave-inducedl o c a l h y p e r t h e r m i a " . i n c o m b i n a t i o n w i t h r a d i o t h e r a p y o fhuman malignant tumors. Cancer 1980; 45: 638 646.8. Bicher, H. I., Hetzel, F. W., Sandhu, T. S., et al. Effectso f h y p e r t h e r m i a o n n o r m a l a n d t u m ~ g r m i c r o e n vi ~ t .Radiolog y 1980; 137: 523-530.


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96 HAIM I. BICHER ET AL.t r e a ~ r a e n t w ~ s m e a s u r e d b y e v a l u a t i n g t h e d e g r e e o f e r y t h e m a a c c o r d i n gt o a n ~ n e r i c a l s c o r i n g s y s t e m . T u m o r r e s p o n s e w a s a s s e s s e d b ym e a s u r i n g t i m ~ D r d i a m e t e r . A l t h o u g h t h e s t u d y w a s n o t c o n c l u s i v ea b o u t t h e t h e r m a l e n h a n c e m e n t r a t i o , i t d i d b r i n g t o l i g h t s o m e o ft h e p r o b l e m s a s s o c i a t e d w i t h o b t a i n i n g u s e f u l c l i n i c a l d a t a . T h es t u d y i n v o l v e d p a t i e n t s w i t h m u l t i p l e m e t a s t a t i c m e l a n c m a l e s i o n s .A t l e a s t t h r e e l e s i o n s ~ e r e c h o s e n o n e a c h p a t i e n t . T h e p a t i e n t sw e r e d i v i d e d i n t o t h r e e g r o u p s a n d g i v e n o n e , 3 o r 4 f r a c t i o n s , w i t ha ~ of 72 hours interval betw~e_n each fraction. Radiationd o s e p e r f r a c t i o n f o r d i f f e r e n t l e s i o n s o n a p a t i e n t v a r i e d f r c m5 0 0 t o 9 0 0 r a d . I n s c m e c a s e s s i n g l e f r a c t i o n s o f i 0 0 0 , 1 2 0 0 o r1 3 0 0 r a d w ~ r e u s e d . ~ n a l l p a t i e n t s o n e l e s i o n w a s h e a t e d i n m e d i -a t e l y f o l l o w i n g r a d i a t i o n t h e r a p y a r ~ t h e o t h e r t w o o r m o r e l e s i o n st r e a t e d w i t h r a d i a t i o n a l o n e w ~ r e u s e d f o r c ~ m ~ r i s o n . H y p e r t h e r m i at r e . a , t m e n t s w ~ r e a d m i n i s t e r e d u s i n g 9 1 5 M H z d i r e c t c o n t a c t m i c r o w a v ea p p l i c a t o r s ( 4 ) . D u r a t i o n o f h y p e r t h e r m i a t r e a t m e n t s v a r i e d b e t w e e n1 a n d 2 h o u r s a t 4 1 . 5 - 4 2 . 0 O c .

S k i n e n h a n c e m e n t r a t i o ( S E R ) a n d t h e r m a l e n h a n c e m e n t r a t i o( T E R ) c o u l d b e e v a l u a t e d o n l y f o r a l i m i t e d n u m b e r o f p a t i e n t sb e c a u s e o f l a c k o f f o l l o w u p d a t a . S E R v a l u e s v a r i e d f o r 1 . 2 t o1 . 7 w h i l e T E R v a l u e s i n m o s t c a s e s w e r e i . 3 . T h i s s t u d y d e m o n -s t r a t e d , h ~ w ~ % ~ r , t h a t s u p e r f i c i a l t ~ o r s u p t o 4 c r n i n d i a m e t e ra n d 2 c m i n d e p t h c o u l d b e t r e a t e d w i t h a n a c c u r a c y o f + 0 . 5 Ce i t h e r d u r i n g , o r a f t e r r a d i a t i o n w i t h 9 1 5 M H z m i c r o w a v e s .T h e s t u d y r e p o r t e d h e r e a s w e l l a s t h e r e s u l t s o f o t h e r i n -v e s t i g a t o r s t e n d t o i n d i c a t e t h e r e l a t i v e e f f e c t i v e n e s s a n d l a c ko f o v e r a l l a d v e r s e e f f e c t s f r e m c c m b i n e d h y p e r t h e r m i a a n d r a d i a t i o n .F u r t h e r p r o s p e c t i v e , s i t e s p e c i f i c t r i a l s a r e n o w p l a n n e d o r i np r o g r e s s t o f u r t h e r e v a l u a t e b o t h t h e s a f e t y a n d e f f e c t i v e n e s s o ff r a c t i c ~ a t e d h y p e r t h e r m i a a n d r a d i a t i o n . I n a d d i t i o n , t h e p a t i e n t sa l r e a d y t r e a t e d w i l l c o n t i n u e t o b e f o l l o w ~ d a t 2 m o n t h i n t e r v a l s .

i . A r c a n g e l i , G ~ , B a r n i , E . , D i v i d a l l i , A . , e t a l . E f f e c t i v e n e s so f m i c r o w a v e h y p e r t h e r m i a c o m b i n e d w i t h i o n i z i n g r a d i a t i o n :c l i n i c a l r e s u l t s o n n e c k n o d e m e t a s t a s e s . I n t . J , R a d i a t .O n c o l . B i o l . P h _ v s . 1 9 8 0 ; 6 : 1 4 3 - 1 4 8 .2 . B i c h e r , H . I . , S a n d h u , T . S . , H e t z e l , F . W . H y p e r t h e r m i a a n dr a d i a t i o n i n c o m b i n a t i o n : a c l i n i c a l f r a c t i o n a t i o n r e g i m e .I n t . J . R a d i a t . O n c o l . B i o l . P h y s . 1 9 8 0 ; 6 : 8 6 7 - 8 7 0 .3 . H o r n b a c k , N . B . , S h u p e , R . E . , H ~ n a y o n , S . , e t a l . P r e l i m i n a r yc l i n i c a l r e s u l t s o f c ~ n b i n e d 4 3 3 M H z m i c r o w a v e t h e r a p ya n d r a d i a t i o n t h e r a p y o n p a t i e n t s w i t h a d v a n c e d c a n c e r .C a n c e r 1 9 7 7 ; 4 0 : 2 3 5 4 - 2 8 6 3 .4 . J o h n s o n , R . J . R . , S a n d h u , T . S . , H e t z e l , F . W . , e t a l . Ap i l o t s t u d y t o i n v e s t i g a t e t h e t h e r a p e u t i c r a t i o o f 4 1 . 5 -4 2 . 0 C h y p e r t h e r m i a r a d i a t i o n . I n t . J . R a d i a t . O n c o l .


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R E S U LT S OF A PHAS E I /I t CL I NICAL T R I AL 97Biol. Phys. 1979; 5: 947-953.5. Kim, J. H., Hahn, E. W., BenJamin, F. J. Treatment of super-ficial cancers by ecmbination hyperthermia and radiationtherapy. Clin. Bul. 1979; 9: 13-16.6. Manning, M. R., Cetas, T., Boone, M. L. M., Miller, R. C.Clinical hyperthermia: results of the phase I clinicaltrial canbining localized hyperthermia with or withoutradiation. (Abstr.) Int. J. Radiat. Oncol. Biol. Phys.1979; 5: $2: 173.

7. U. R., Noell, K. T., Woodward, K. T. et al. Microw ave-inducedlocal hyperthermia ~ cc~bination with radiotherapy ofhuman malignant t%~nors. Cancer 1980; 45: 638 646.8. Bicher, H. I., Hetzel, F. W., Sandhu, T. S., et al. Effectso f h y p e r t h e r m i a o n n o r m a l a n d t u m o r m i c r o e n v i ~ t .Radioloqy 1980; 137: 523-530.

0073_results of a phase 1 & 2 clinical trial fractionated hyperthermia.pdf

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