Journal of Photochemistry and Photobiology, B: B/o/ogy, 6 (1990) 175-181
175
P H O T O D Y N A M I C T H E R A P Y IN L U N G A N D GASTROINTESTINAL CANCERS* STRASHIMIR KARANOV~ Department of Surgery and Endoscopy, National Oncological Centre, Bulgarian Medical Academy, 6, Plovdivsko Pole St., 1156 Sofia (Bulgaria) DIMITAR KOSTADINOV Research Institute of Pulmonary Diseases, Bulgarian Medical Academy, Sofia (Bulgaria) MARIA SHOPOVA Institute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia (Bulgaria) PANAYOT KURTEV National Oncological Centre, Bulgarian Medical Academy, Sofia (Bulgaria) (Received October 5, 1989; accepted December 3, 1989)
K e y w o r d s . H a e m a t o p o r p h y r i n , p h o t o d y n a m i c t h e r a p y , lung, o e s o p h a g e a l a n d c o l o n c a n c e r s , laser.
Summary Twelve c e n t r a l b r o n c h i a l c a r c i n o m a p a t i e n t s a n d t w o g a s t r o i n t e s t i n a l (GI) t r a c t ( o e s o p h a g e a l a n d colonic) e a r l y - s t a g e c a n c e r p a t i e n t s w e r e t r e a t e d with p h o t o d y n a m i c t h e r a p y (PDT). H a e m a t o p o r p h y r i n (HP/5, J a c o p o Monico, Italy) at a d o s e of 5 m g k g -1 b o d y w e i g h t w a s u s e d as p h o t o s e n s i t i z e r . L a s e r light at 6 2 8 . 2 - 6 3 0 n m g e n e r a t e d b y t w o different l a s e r s y s t e m s (gold v a p o u r l a s e r (I.P. Optics, Sofia, Bulgaria) in l u n g c a n c e r c a s e s a n d a n a r g o n dye l a s e r s y s t e m ( S p e c t r a Physics, M o u n t a i n View, U.S.A.) in GI t r a c t c a n c e r s ) w a s used. L u n g c a n c e r s w e r e i r r a d i a t e d 48 h a f t e r d r u g a d m i n i s t r a t i o n a n d GI t r a c t c a n c e r s w e r e i r r a d i a t e d 72 h a f t e r infusion of the p h o t o s e n s i t i z e r . B o t h t u r n o u t sites w e r e t r e a t e d with a t o t a l e n e r g y d o s e in the r a n g e 3 5 0 - 6 0 0 J c m -2. Efficiency o f P D T in l u n g c a n c e r w a s e v a l u a t e d b y X-rays a n d endoscopic and functional respiratory tests for bronchial de-obstruction. C o m p l e t e r e m i s s i o n a f t e r P D T o f GI t r a c t c a n c e r s w a s c o n s i d e r e d to b e t u m o u r e r a d i c a t i o n (histologically a n d cytologically p r o v e d ) a n d a t u m o u r free interval of at l e a s t 12 m o n t h s .
*Paper presented at the Congress on Photodynamie Therapy of Tumours, Sofia, Bulgaria, October, 1989. *Author to whom correspondence should be addressed.
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176 1. I n t r o d u c t i o n P i o n e e r i n g d e v e l o p m e n t s in p h o t o d y n a m i c t h e r a p y (PDT) o f e n d o b r o n chial a n d g a s t r o i n t e s t i n a l (GI) t u m o u r s have revealed n e w p r o s p e c t s in the t r e a t m e n t o f t h e s e c a n c e r sites [ 1 - 4 ]. Preliminary studies in Bulgaria o n the potential o f the p h o t o d y n a m i c m e t h o d o f t h e r a p y for skin, e n d o m e t r i a l a n d b r o n c h i a l m a l i g n a n c i e s have d e m o n s t r a t e d v e r y g o o d results. Our aims were to follow the i m m e d i a t e p h o t o e f f e c t o n lung c a r c i n o m a a n d the late t h e r a p e u t i c action on GI t r a c t c a n c e r s a n d to test a gold v a p o u r laser d e s i g n e d for this p u r p o s e in Bulgaria. The results were c o m p a r e d with t h o s e o b t a i n e d u s i n g Nd:YAG laser t h e r a p y o f identical t u m o u r sites at the s a m e clinical stage.
2. M a t e r i a l s a n d m e t h o d s 2.1. S e l e c t i o n o f p a t i e n t s All patients t r e a t e d b y PDT p o s s e s s e d c o n t r a - i n d i c a t i o n s to o t h e r radical m e a n s o f t r e a t m e n t or possible m e t h o d s o f t r e a t m e n t h a d b e e n e x h a u s t e d . The c a s e s t r e a t e d were a d v a n c e d - s t a g e s q u a m o u s cell lung c a n c e r (Table 1) and early-stage (stage 0 - I ) GI t r a c t c a n c e r (Table 2). Patients s e l e c t e d did n o t p o s s e s s a n y h i s t o r y o f allergic r e a c t i o n s or s e v e r e d i s o r d e r s o f the cardiovascular, liver a n d s e c r e t o r y functions. T u m o u r s w e r e verified histologically. No o t h e r a n t i t u m o u r t h e r a p y w a s applied d u r i n g PDT. 2.2. P h o t o s e n s i t i z a t i o n H a e m a t o p o r p h y r i n (HP/5, J a c o p o Monico, Venezia Mestre, Italy) vials o f 50 m g - 7 0 ml w e r e used. The c o m p o u n d w a s i n t r o d u c e d b y c o n t i n u o u s infusion 48 h (for lung c a n c e r ) a n d 72 h (GI c a r c i n o m a s ) p r i o r to t r e a t m e n t at a dose o f 5 m g k g - 1 b o d y weight. Patients were p r o t e c t e d f r o m direct sunlight for 15 days following sensitization. On d i s c h a r g e f r o m the hospital TABLE 1 Clinical characteristics of patients with lung cancer treated with PDT Number
Age
Sex
Site of tumour
Clinical stage
1 2 3 4 5 6 7 8 9 10 11 12
62 58 48 66 69 51 66 66 65 59 61 63
Male Male Male Male Male Male Male Male Male Male Male Male
Right upper lobe bronchus Left main bronchus Left main bronchus Right upper lobe bronchus Intermediate trunk Middle lobe bronchus Intermediate trunk Left main bronchus Left main bronchus Right main bronchus Right main bronchus Right main bronchus
II III III II III III III III III III III III
177
o
L o
o
Z
E 0 0 o o o o
r~
0
uu~
o ¸
0
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a0
178 t h e y w e r e g i v e n r e c o m m e n d a t i o n s to k e e p a w a y f r o m d i r e c t s u n l i g h t f o r 1 month. 2.3. L a s e r s o u r c e s F o r PDT of GI t u m o u r s a n a r g o n d y e l a s e r s y s t e m ( S p e c t r a P h y s i c s 3 7 5 03, M o u n t a i n View, CA, U.S.A.) wi t h a w a v e l e n g t h of 6 3 0 n m w a s u s e d . In p h o t o t h e r a p y of l u n g c a n c e r a g o l d v a p o u r l a s e r (I.P. O p t i c s , Sofia, B u l g a r i a ) at 6 2 8 . 2 n m w a s e m p l o y e d . Light w a s t r a n s m i t t e d to t h e t u m o u r t h r o u g h a 4 0 0 t~m q u a r t z fibre (QF-NC, Q u e n t r o n , A u s t r a l i a ) w i t h 45 ° d i v e r g e n c e of t h e light b e a m at t h e tip. F o r Nd:YAG l a s e r t h e r a p y two l a s e r s y s t e m s w e r e u s e d ( M e d i l a s 2, MBB, O t t o b r u n n , F.R.G. a n d M C W 100, M e d i t e c , R h e i n h a r d t T h y z e l G m b H , F.R.G.) at, a w a v e l e n g t h of 1 0 6 4 nm; light w a s t r a n s m i t t e d to t h e t u m o u r t h r o u g h 2.6 a n d 2.1 m m q u a r t z m o n o f i l a m e n t f i b r e s w i t h CO2 c o a x i a l c o o l i n g a n d 10 ° light d i v e r g e n c e at t h e tip. 2.4. E n d o s c o p i c t e c h n i q u e F i b r e - e n d o s c o p e s ( B F 2TR, B F 1T10, G I F Q10, G I F 2 T 1 0 a n d CF 1T10; O l y m p u s O p t i c a l Co., J a p a n ) w e r e u s e d . N e c r o t i c t i s s u e s w e r e r e m o v e d u s i n g rigid b r o n c h o s c o p e s (Karl Storz, F.R.G.). 2.5. P h o t o t h e r a p y PDT a n d ND:YAG l a s e r t r e a t m e n t of l u n g c a r c i n o m a w e r e c a r r i e d o u t u s i n g t h e d o s e s a n d s c h e d u l e s s h o w n in T a b l e s 3 a n d 4. P h o t o t h e r a p y o f GI c a n c e r s is g i v e n in T a b l e 2. 2.5. C ~ i t e r i a o f e v a l u a t i o n In l u n g c a n c e r t h e f o l l o w i n g c r i t e r i a of t h e r a p e u t i c effect w e r e a d o p t e d : c o m p l e t e r e s p o n s e ( t u m o u r m a s s r e d u c t i o n of m o r e t h a n 8 0 % a n d ree s t a b l i s h m e n t of b r o n c h i a l c o n t i n u i t y ) ; p a r t i a l r e s p o n s e ( t u m o u r m a s s reTABLE 3 Conditions of irradiation and results of PDT in lung cancer patients Number
Power output (mW)
Time (mill)
Total energy dose (J cm -2)
Response
Follow-up (months)
1 2 3 4 5 6 7 8 9 10 11 12
180 200 210 180 210 250 200 200 200 200 180 200
20 35 2x20 2 x 15 27 20 2x20 2 x 15 2 x 12 30 22 2 x 15
250 300 520 350 350 300 450 420 400 380 360 350
NR PR CR NR CR CR CR CR NR PR CR CR
4 5 6 4 4 3 2 2 5 3 2 1
NR, no response; PR, partial response; CR, complete response.
179 TABLE 4 Clinical characteristics of patients with lung cancer and results from the treatment with Nd:YAG laser Number
Age
Site of tumour
Sessions (N)
Power (Vv')
Energy dose (J)
Response
1 2 3 4 5 6 7 8 9 10 11 12
68 53 59 56 46 51 59 66 60 64 59 65
Right upper lobe bronchus Left main bronchus Left main bronchus Intermediate trunk Intermediate trunk Middle lobe bronchus Right main bronchus Right main bronchus Right upper lobe bronchus Right main bronchus Left main bronchus Left main bronchus
1 1 1 1 1 3 1 3 2 3 5 1
50-60 55-66 40-70 80 60-70 30-80 70 90 67-80 40-70 45-70 40-55
2351 1418 4293 2962 2643 6464 2200 12726 3400 13258 10420 1278
CR CR PR CR CR PR CR NR PR PR NR NR
CR, complete response; PR, partial response; NR, no response. d u c t i o n of 50°/0-80% a n d p a r t i a l r e - e s t a b l i s h m e n t of b r o n c h i a l c o n t i n u i t y ) ; l a c k of r e s p o n s e ( t u m o u r m a s s r e d u c t i o n of l e s s t h a n 5 0 % a n d p e r s i s t i n g o b s t r u c t i o n ) . E v a l u a t i o n of r e s p o n s e w a s m a d e on t h e b a s i s of e n d o s c o p i c findings, c h e s t X - r a y s b e f o r e a n d a f t e r t r e a t m e n t a n d r e s p i r a t o r y p e r f o r m a n c e ( F o r c e d v e n t i l a t o r y c a p a c i t y (FVC), f o r c e d e x p i r a t o r y v o l u m e p e r s e c o n d (FEV1) a n d FEV1/FVC) p r i o r to a n d f o l l o w i n g t r e a t m e n t as r e c o m m e n d e d in ref. 5. F o r GI c a n c e r s t h e f o l l o w i n g c r i t e r i a w e r e a p p l i e d : c o m p l e t e r e m i s s i o n (tumour eradication with negative histological and cytological findings for 12 m o n t h s a f t e r t r e a t m e n t ) ; p a r t i a l r e m i s s i o n ( t u m o u r e r a d i c a t i o n w i t h n e g a t i v e histological and positive cytological results 6-12 months after treatment); no r e m i s s i o n ( t u m o u r p e r s i s t e n c e ) . 2. 7. F o l l o w - u p C a s e s of l u n g c a r c i n o m a w e r e f o l l o w e d u p f o r 1 - 6 m o n t h s a f t e r t r e a t m e n t . GI t r a c t c a n c e r s w e r e f o l l o w e d u p f o r at l e a s t 12 m o n t h s a f t e r t h e r a p y .
3. R e s u l t s R e s u l t s a r e p r e s e n t e d in T a b l e s 2, 3 a n d 4. As s e e n in T a b l e 3, s e v e n p a t i e n t s ( 5 8 . 3 % ) s h o w e d c o m p l e t e r e s p o n s e a f t e r PDT, t w o p a t i e n t s ( 1 6 . 7 % ) s h o w e d p a r t i a l r e s p o n s e a n d t h r e e p a t i e n t s ( 2 5 . 0 % ) s h o w e d no r e s p o n s e . In t o t a l , p a t i e n t s r e s p o n s i v e to t h i s t y p e o f t r e a t m e n t c o n s t i t u t e d 7 5 . 0 % o f all t r e a t e d c a s e s . P a t i e n t s s u b j e c t e d to Nd:YAG l a s e r t h e r a p y h a d a r e s p o n s e r a t e of 4 1 . 7 % (five c a s e s ) w i t h c o m p l e t e r e s p o n s e , 3 3 . 3 % ( f o u r c a s e s ) w i t h p a r t i a l r e s p o n s e a n d 2 5 . 0 % ( t h r e e p a t i e n t s ) w i t h no r e s p o n s e ( T a b l e 4).
180 Excellent results were a c h i e v e d in GI t r a c t cancers: c o m p l e t e r e m i s s i o n for 12 m o n t h s and c o m p l e t e restitution o f irradiated site m u c o s a (Table 2). Nd:YAG-treated patients m a n i f e s t e d s o m e c o m p l i c a t i o n s : o e s o p h a g e a l c a n c e r r e c u r r e d 8 m o n t h s after therapy, and the patient with c o l o r e c t a l c a r c i n o m a c o m p l a i n e d of a dull persisting perineal pain for 1 m o n t h after therapy. C o m p l i c a t i o n s o c c u r r i n g during PDT included two c a s e s of right-sided pneum o n i a w h i c h subsided after a d e q u a t e t r e a t m e n t and one patient s h o w i n g a p r o f u s e urticarial flush over the w h o l e b o d y with slow r e s p o n s e to antihistamine therapy.
4. D i s c u s s i o n E n d o b r o n c h i a l d e v e l o p m e n t of lung c a r c i n o m a results in obstructive p n e u m o n i t i s and impaired r e s p i r a t o r y functions. Thus t u m o u r r e m o v a l and r e - e s t a b l i s h m e n t of b r o n c h i a l drainage are a d e q u a t e a l t h o u g h palliative measures in i n o p e r a b l e central lung cancer. T h e r e f o r e c o m b i n a t i o n o f PDT with c h e m o t h e r a p y and r a d i o t h e r a p y w h e n e v e r possible will i m p r o v e the survival rate and quality of life of patients in this stage o f the disease. The loss of a n a t o m i c a l orientation due to the g r e a t length o f the t u m o u r g r o w t h is a c o n s i d e r a b l e obstacle in the p e r f o r m a n c e of PDT, thus m a k i n g the m e t h o d inefficient a n d risky. PDT for lung c a n c e r t r e a t m e n t was i n t r o d u c e d in 1 9 8 0 a n d since that time it has b e e n successfully applied, in particular to early-stage lung c a r c i n o m a and superficial lesions [4, 6]. Satisfactory t r e a t m e n t of a d v a n c e d s t a g e s d e p e n d s on the t u m o u r m a s s and a n a t o m i c a l site along the b r o n c h i a l tree [1,51. In the PDT of o e s o p h a g e a l and c o l o r e c t a l c a r c i n o m a , r e p o r t s so far refer p r e d o m i n a n t l y to a d v a n c e d c a n c e r patients w h e r e the m e t h o d is palliative [2, 3, 7, 8]. No data on the c o m p a r i s o n o f results o b t a i n e d u s i n g the two laser m e t h o d s ( a r g o n dye laser a n d Nd:YAG laser) are available. At this point it is t o o early to draw a n y conclusions. Nevertheless we believe that PDT has definite merits b o t h with r e g a r d to i m m e d i a t e and late results of t r e a t m e n t o f malignant t u m o u r s . F u t u r e r a n d o m i z e d trials u s i n g b o t h laser m e t h o d s will p r o b a b l y confirm the potential o f PDT.
References 1 Ch. Konaka, H. Kato and Y. Hayata, Lung cancer treated by photodynamic therapy alone: survival for more than three years, L a s e r s Med. Sci., 2 (1987) 17-19. 2 L. Herrera-Ornelas, N. Petrelli, A. Mittelman, T. Dougherty and D. Boyle, Photodynamic therapy in patients with colorectal cancer, Cancer, 57 (1986) 677-684. 3 R. Thomas, M. Abbott, Pr. Bhathal, P. St. John and G. Morstyn, High-dose photoirradiation of esophageal cancer, Ann. Surg., 206 (1987) 193-199. 4 R. Vincent and T. Dougherty, Photoradiation therapy in the treatment of advanced carcinoma of the trachea and bronchus, in D. R. Doyron and G. G. Gomer (eds.), P o r p h y r i n L o c a l i z a t i o n a n d T r e a t m e n t o f Tumors, Alan R. Liss, New York, 1984, pp. 759-766.
181 5 S. Lain, N. Muler, R. Miller, E. Kostashuk, I. Szasz, J. LeRiche and E. Lee-Chuy, Predicting the response of obstructive endobronchial tumors to photodynamic therapy, Cancer, 58 (1986) 2298-2306. 6 D. yon Hardenberg, Y. Yamaguchi, T. Fujisawa, T. Ogawa and E. de Vivie, Therapeutic i n v i v o and i n v i t r o effects of argon dye laser and hematoporphyrin derivative in lung cancer, Thorac. Cardiovasc. Surgeor~ 36 (1988) 15-19. 7 Y. Ito, H. Sugiura, K. Toriyama, S. Hotta and T. Kasugai, Endoscopic photodynamic therapy of stomach and colon tumors, Gastroenterol. Endosc., 28 (1986) 298-308. 8 J. McCaughan, Jr., T. Nims, J. Guy, W. Hicks, T. W'tlliams and L. Laufman, Photodynamic therapy for esophageal tumors, Arch. Surg., 124 (1989) 74--80.
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P H O T O D Y N A M I C T H E R A P Y IN L U N G A N D GASTROINTESTINAL CANCERS* STRASHIMIR KARANOV~ Department of Surgery and Endoscopy, National Oncological Centre, Bulgarian Medical Academy, 6, Plovdivsko Pole St., 1156 Sofia (Bulgaria) DIMITAR KOSTADINOV Research Institute of Pulmonary Diseases, Bulgarian Medical Academy, Sofia (Bulgaria) MARIA SHOPOVA Institute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia (Bulgaria) PANAYOT KURTEV National Oncological Centre, Bulgarian Medical Academy, Sofia (Bulgaria) (Received October 5, 1989; accepted December 3, 1989)
K e y w o r d s . H a e m a t o p o r p h y r i n , p h o t o d y n a m i c t h e r a p y , lung, o e s o p h a g e a l a n d c o l o n c a n c e r s , laser.
Summary Twelve c e n t r a l b r o n c h i a l c a r c i n o m a p a t i e n t s a n d t w o g a s t r o i n t e s t i n a l (GI) t r a c t ( o e s o p h a g e a l a n d colonic) e a r l y - s t a g e c a n c e r p a t i e n t s w e r e t r e a t e d with p h o t o d y n a m i c t h e r a p y (PDT). H a e m a t o p o r p h y r i n (HP/5, J a c o p o Monico, Italy) at a d o s e of 5 m g k g -1 b o d y w e i g h t w a s u s e d as p h o t o s e n s i t i z e r . L a s e r light at 6 2 8 . 2 - 6 3 0 n m g e n e r a t e d b y t w o different l a s e r s y s t e m s (gold v a p o u r l a s e r (I.P. Optics, Sofia, Bulgaria) in l u n g c a n c e r c a s e s a n d a n a r g o n dye l a s e r s y s t e m ( S p e c t r a Physics, M o u n t a i n View, U.S.A.) in GI t r a c t c a n c e r s ) w a s used. L u n g c a n c e r s w e r e i r r a d i a t e d 48 h a f t e r d r u g a d m i n i s t r a t i o n a n d GI t r a c t c a n c e r s w e r e i r r a d i a t e d 72 h a f t e r infusion of the p h o t o s e n s i t i z e r . B o t h t u r n o u t sites w e r e t r e a t e d with a t o t a l e n e r g y d o s e in the r a n g e 3 5 0 - 6 0 0 J c m -2. Efficiency o f P D T in l u n g c a n c e r w a s e v a l u a t e d b y X-rays a n d endoscopic and functional respiratory tests for bronchial de-obstruction. C o m p l e t e r e m i s s i o n a f t e r P D T o f GI t r a c t c a n c e r s w a s c o n s i d e r e d to b e t u m o u r e r a d i c a t i o n (histologically a n d cytologically p r o v e d ) a n d a t u m o u r free interval of at l e a s t 12 m o n t h s .
*Paper presented at the Congress on Photodynamie Therapy of Tumours, Sofia, Bulgaria, October, 1989. *Author to whom correspondence should be addressed.
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176 1. I n t r o d u c t i o n P i o n e e r i n g d e v e l o p m e n t s in p h o t o d y n a m i c t h e r a p y (PDT) o f e n d o b r o n chial a n d g a s t r o i n t e s t i n a l (GI) t u m o u r s have revealed n e w p r o s p e c t s in the t r e a t m e n t o f t h e s e c a n c e r sites [ 1 - 4 ]. Preliminary studies in Bulgaria o n the potential o f the p h o t o d y n a m i c m e t h o d o f t h e r a p y for skin, e n d o m e t r i a l a n d b r o n c h i a l m a l i g n a n c i e s have d e m o n s t r a t e d v e r y g o o d results. Our aims were to follow the i m m e d i a t e p h o t o e f f e c t o n lung c a r c i n o m a a n d the late t h e r a p e u t i c action on GI t r a c t c a n c e r s a n d to test a gold v a p o u r laser d e s i g n e d for this p u r p o s e in Bulgaria. The results were c o m p a r e d with t h o s e o b t a i n e d u s i n g Nd:YAG laser t h e r a p y o f identical t u m o u r sites at the s a m e clinical stage.
2. M a t e r i a l s a n d m e t h o d s 2.1. S e l e c t i o n o f p a t i e n t s All patients t r e a t e d b y PDT p o s s e s s e d c o n t r a - i n d i c a t i o n s to o t h e r radical m e a n s o f t r e a t m e n t or possible m e t h o d s o f t r e a t m e n t h a d b e e n e x h a u s t e d . The c a s e s t r e a t e d were a d v a n c e d - s t a g e s q u a m o u s cell lung c a n c e r (Table 1) and early-stage (stage 0 - I ) GI t r a c t c a n c e r (Table 2). Patients s e l e c t e d did n o t p o s s e s s a n y h i s t o r y o f allergic r e a c t i o n s or s e v e r e d i s o r d e r s o f the cardiovascular, liver a n d s e c r e t o r y functions. T u m o u r s w e r e verified histologically. No o t h e r a n t i t u m o u r t h e r a p y w a s applied d u r i n g PDT. 2.2. P h o t o s e n s i t i z a t i o n H a e m a t o p o r p h y r i n (HP/5, J a c o p o Monico, Venezia Mestre, Italy) vials o f 50 m g - 7 0 ml w e r e used. The c o m p o u n d w a s i n t r o d u c e d b y c o n t i n u o u s infusion 48 h (for lung c a n c e r ) a n d 72 h (GI c a r c i n o m a s ) p r i o r to t r e a t m e n t at a dose o f 5 m g k g - 1 b o d y weight. Patients were p r o t e c t e d f r o m direct sunlight for 15 days following sensitization. On d i s c h a r g e f r o m the hospital TABLE 1 Clinical characteristics of patients with lung cancer treated with PDT Number
Age
Sex
Site of tumour
Clinical stage
1 2 3 4 5 6 7 8 9 10 11 12
62 58 48 66 69 51 66 66 65 59 61 63
Male Male Male Male Male Male Male Male Male Male Male Male
Right upper lobe bronchus Left main bronchus Left main bronchus Right upper lobe bronchus Intermediate trunk Middle lobe bronchus Intermediate trunk Left main bronchus Left main bronchus Right main bronchus Right main bronchus Right main bronchus
II III III II III III III III III III III III
177
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178 t h e y w e r e g i v e n r e c o m m e n d a t i o n s to k e e p a w a y f r o m d i r e c t s u n l i g h t f o r 1 month. 2.3. L a s e r s o u r c e s F o r PDT of GI t u m o u r s a n a r g o n d y e l a s e r s y s t e m ( S p e c t r a P h y s i c s 3 7 5 03, M o u n t a i n View, CA, U.S.A.) wi t h a w a v e l e n g t h of 6 3 0 n m w a s u s e d . In p h o t o t h e r a p y of l u n g c a n c e r a g o l d v a p o u r l a s e r (I.P. O p t i c s , Sofia, B u l g a r i a ) at 6 2 8 . 2 n m w a s e m p l o y e d . Light w a s t r a n s m i t t e d to t h e t u m o u r t h r o u g h a 4 0 0 t~m q u a r t z fibre (QF-NC, Q u e n t r o n , A u s t r a l i a ) w i t h 45 ° d i v e r g e n c e of t h e light b e a m at t h e tip. F o r Nd:YAG l a s e r t h e r a p y two l a s e r s y s t e m s w e r e u s e d ( M e d i l a s 2, MBB, O t t o b r u n n , F.R.G. a n d M C W 100, M e d i t e c , R h e i n h a r d t T h y z e l G m b H , F.R.G.) at, a w a v e l e n g t h of 1 0 6 4 nm; light w a s t r a n s m i t t e d to t h e t u m o u r t h r o u g h 2.6 a n d 2.1 m m q u a r t z m o n o f i l a m e n t f i b r e s w i t h CO2 c o a x i a l c o o l i n g a n d 10 ° light d i v e r g e n c e at t h e tip. 2.4. E n d o s c o p i c t e c h n i q u e F i b r e - e n d o s c o p e s ( B F 2TR, B F 1T10, G I F Q10, G I F 2 T 1 0 a n d CF 1T10; O l y m p u s O p t i c a l Co., J a p a n ) w e r e u s e d . N e c r o t i c t i s s u e s w e r e r e m o v e d u s i n g rigid b r o n c h o s c o p e s (Karl Storz, F.R.G.). 2.5. P h o t o t h e r a p y PDT a n d ND:YAG l a s e r t r e a t m e n t of l u n g c a r c i n o m a w e r e c a r r i e d o u t u s i n g t h e d o s e s a n d s c h e d u l e s s h o w n in T a b l e s 3 a n d 4. P h o t o t h e r a p y o f GI c a n c e r s is g i v e n in T a b l e 2. 2.5. C ~ i t e r i a o f e v a l u a t i o n In l u n g c a n c e r t h e f o l l o w i n g c r i t e r i a of t h e r a p e u t i c effect w e r e a d o p t e d : c o m p l e t e r e s p o n s e ( t u m o u r m a s s r e d u c t i o n of m o r e t h a n 8 0 % a n d ree s t a b l i s h m e n t of b r o n c h i a l c o n t i n u i t y ) ; p a r t i a l r e s p o n s e ( t u m o u r m a s s reTABLE 3 Conditions of irradiation and results of PDT in lung cancer patients Number
Power output (mW)
Time (mill)
Total energy dose (J cm -2)
Response
Follow-up (months)
1 2 3 4 5 6 7 8 9 10 11 12
180 200 210 180 210 250 200 200 200 200 180 200
20 35 2x20 2 x 15 27 20 2x20 2 x 15 2 x 12 30 22 2 x 15
250 300 520 350 350 300 450 420 400 380 360 350
NR PR CR NR CR CR CR CR NR PR CR CR
4 5 6 4 4 3 2 2 5 3 2 1
NR, no response; PR, partial response; CR, complete response.
179 TABLE 4 Clinical characteristics of patients with lung cancer and results from the treatment with Nd:YAG laser Number
Age
Site of tumour
Sessions (N)
Power (Vv')
Energy dose (J)
Response
1 2 3 4 5 6 7 8 9 10 11 12
68 53 59 56 46 51 59 66 60 64 59 65
Right upper lobe bronchus Left main bronchus Left main bronchus Intermediate trunk Intermediate trunk Middle lobe bronchus Right main bronchus Right main bronchus Right upper lobe bronchus Right main bronchus Left main bronchus Left main bronchus
1 1 1 1 1 3 1 3 2 3 5 1
50-60 55-66 40-70 80 60-70 30-80 70 90 67-80 40-70 45-70 40-55
2351 1418 4293 2962 2643 6464 2200 12726 3400 13258 10420 1278
CR CR PR CR CR PR CR NR PR PR NR NR
CR, complete response; PR, partial response; NR, no response. d u c t i o n of 50°/0-80% a n d p a r t i a l r e - e s t a b l i s h m e n t of b r o n c h i a l c o n t i n u i t y ) ; l a c k of r e s p o n s e ( t u m o u r m a s s r e d u c t i o n of l e s s t h a n 5 0 % a n d p e r s i s t i n g o b s t r u c t i o n ) . E v a l u a t i o n of r e s p o n s e w a s m a d e on t h e b a s i s of e n d o s c o p i c findings, c h e s t X - r a y s b e f o r e a n d a f t e r t r e a t m e n t a n d r e s p i r a t o r y p e r f o r m a n c e ( F o r c e d v e n t i l a t o r y c a p a c i t y (FVC), f o r c e d e x p i r a t o r y v o l u m e p e r s e c o n d (FEV1) a n d FEV1/FVC) p r i o r to a n d f o l l o w i n g t r e a t m e n t as r e c o m m e n d e d in ref. 5. F o r GI c a n c e r s t h e f o l l o w i n g c r i t e r i a w e r e a p p l i e d : c o m p l e t e r e m i s s i o n (tumour eradication with negative histological and cytological findings for 12 m o n t h s a f t e r t r e a t m e n t ) ; p a r t i a l r e m i s s i o n ( t u m o u r e r a d i c a t i o n w i t h n e g a t i v e histological and positive cytological results 6-12 months after treatment); no r e m i s s i o n ( t u m o u r p e r s i s t e n c e ) . 2. 7. F o l l o w - u p C a s e s of l u n g c a r c i n o m a w e r e f o l l o w e d u p f o r 1 - 6 m o n t h s a f t e r t r e a t m e n t . GI t r a c t c a n c e r s w e r e f o l l o w e d u p f o r at l e a s t 12 m o n t h s a f t e r t h e r a p y .
3. R e s u l t s R e s u l t s a r e p r e s e n t e d in T a b l e s 2, 3 a n d 4. As s e e n in T a b l e 3, s e v e n p a t i e n t s ( 5 8 . 3 % ) s h o w e d c o m p l e t e r e s p o n s e a f t e r PDT, t w o p a t i e n t s ( 1 6 . 7 % ) s h o w e d p a r t i a l r e s p o n s e a n d t h r e e p a t i e n t s ( 2 5 . 0 % ) s h o w e d no r e s p o n s e . In t o t a l , p a t i e n t s r e s p o n s i v e to t h i s t y p e o f t r e a t m e n t c o n s t i t u t e d 7 5 . 0 % o f all t r e a t e d c a s e s . P a t i e n t s s u b j e c t e d to Nd:YAG l a s e r t h e r a p y h a d a r e s p o n s e r a t e of 4 1 . 7 % (five c a s e s ) w i t h c o m p l e t e r e s p o n s e , 3 3 . 3 % ( f o u r c a s e s ) w i t h p a r t i a l r e s p o n s e a n d 2 5 . 0 % ( t h r e e p a t i e n t s ) w i t h no r e s p o n s e ( T a b l e 4).
180 Excellent results were a c h i e v e d in GI t r a c t cancers: c o m p l e t e r e m i s s i o n for 12 m o n t h s and c o m p l e t e restitution o f irradiated site m u c o s a (Table 2). Nd:YAG-treated patients m a n i f e s t e d s o m e c o m p l i c a t i o n s : o e s o p h a g e a l c a n c e r r e c u r r e d 8 m o n t h s after therapy, and the patient with c o l o r e c t a l c a r c i n o m a c o m p l a i n e d of a dull persisting perineal pain for 1 m o n t h after therapy. C o m p l i c a t i o n s o c c u r r i n g during PDT included two c a s e s of right-sided pneum o n i a w h i c h subsided after a d e q u a t e t r e a t m e n t and one patient s h o w i n g a p r o f u s e urticarial flush over the w h o l e b o d y with slow r e s p o n s e to antihistamine therapy.
4. D i s c u s s i o n E n d o b r o n c h i a l d e v e l o p m e n t of lung c a r c i n o m a results in obstructive p n e u m o n i t i s and impaired r e s p i r a t o r y functions. Thus t u m o u r r e m o v a l and r e - e s t a b l i s h m e n t of b r o n c h i a l drainage are a d e q u a t e a l t h o u g h palliative measures in i n o p e r a b l e central lung cancer. T h e r e f o r e c o m b i n a t i o n o f PDT with c h e m o t h e r a p y and r a d i o t h e r a p y w h e n e v e r possible will i m p r o v e the survival rate and quality of life of patients in this stage o f the disease. The loss of a n a t o m i c a l orientation due to the g r e a t length o f the t u m o u r g r o w t h is a c o n s i d e r a b l e obstacle in the p e r f o r m a n c e of PDT, thus m a k i n g the m e t h o d inefficient a n d risky. PDT for lung c a n c e r t r e a t m e n t was i n t r o d u c e d in 1 9 8 0 a n d since that time it has b e e n successfully applied, in particular to early-stage lung c a r c i n o m a and superficial lesions [4, 6]. Satisfactory t r e a t m e n t of a d v a n c e d s t a g e s d e p e n d s on the t u m o u r m a s s and a n a t o m i c a l site along the b r o n c h i a l tree [1,51. In the PDT of o e s o p h a g e a l and c o l o r e c t a l c a r c i n o m a , r e p o r t s so far refer p r e d o m i n a n t l y to a d v a n c e d c a n c e r patients w h e r e the m e t h o d is palliative [2, 3, 7, 8]. No data on the c o m p a r i s o n o f results o b t a i n e d u s i n g the two laser m e t h o d s ( a r g o n dye laser a n d Nd:YAG laser) are available. At this point it is t o o early to draw a n y conclusions. Nevertheless we believe that PDT has definite merits b o t h with r e g a r d to i m m e d i a t e and late results of t r e a t m e n t o f malignant t u m o u r s . F u t u r e r a n d o m i z e d trials u s i n g b o t h laser m e t h o d s will p r o b a b l y confirm the potential o f PDT.
References 1 Ch. Konaka, H. Kato and Y. Hayata, Lung cancer treated by photodynamic therapy alone: survival for more than three years, L a s e r s Med. Sci., 2 (1987) 17-19. 2 L. Herrera-Ornelas, N. Petrelli, A. Mittelman, T. Dougherty and D. Boyle, Photodynamic therapy in patients with colorectal cancer, Cancer, 57 (1986) 677-684. 3 R. Thomas, M. Abbott, Pr. Bhathal, P. St. John and G. Morstyn, High-dose photoirradiation of esophageal cancer, Ann. Surg., 206 (1987) 193-199. 4 R. Vincent and T. Dougherty, Photoradiation therapy in the treatment of advanced carcinoma of the trachea and bronchus, in D. R. Doyron and G. G. Gomer (eds.), P o r p h y r i n L o c a l i z a t i o n a n d T r e a t m e n t o f Tumors, Alan R. Liss, New York, 1984, pp. 759-766.
181 5 S. Lain, N. Muler, R. Miller, E. Kostashuk, I. Szasz, J. LeRiche and E. Lee-Chuy, Predicting the response of obstructive endobronchial tumors to photodynamic therapy, Cancer, 58 (1986) 2298-2306. 6 D. yon Hardenberg, Y. Yamaguchi, T. Fujisawa, T. Ogawa and E. de Vivie, Therapeutic i n v i v o and i n v i t r o effects of argon dye laser and hematoporphyrin derivative in lung cancer, Thorac. Cardiovasc. Surgeor~ 36 (1988) 15-19. 7 Y. Ito, H. Sugiura, K. Toriyama, S. Hotta and T. Kasugai, Endoscopic photodynamic therapy of stomach and colon tumors, Gastroenterol. Endosc., 28 (1986) 298-308. 8 J. McCaughan, Jr., T. Nims, J. Guy, W. Hicks, T. W'tlliams and L. Laufman, Photodynamic therapy for esophageal tumors, Arch. Surg., 124 (1989) 74--80.
