Journal of Photochemistry and Photobiology, B: Biology, 6 (1990) 149-155
149
PHOTODYNAMIC THERAPY IN THE TREATMENT OF MALIGNANT TUMOURS: AN ANALYSIS OF 540 CASES* JUN-HENG LI and ZHONG-HE GUO
Great Wall Hospital of China, Beijing (China) MAO-LIN JIN
Beijing Cancer Institute, Belling (China) FU-YUN ZHAO
Beijing Medical University, Stomatological Hospital, Beijing (China) WEI-MING CAI
Cancer Hospital, Chinese Academy of Medical Sciences, Beijing (China) MEN-LIN GAO
PUMC Hospital, Beijing (China) MING-YAN SHU
Beijing Obstetrics and Gynaecology Hospital, Beijing (China) JIN ZOU
Tong Ren Hospital, Beijing (China) (Received October 5, 1989; accepted December 18, 1989)
Keywords. Haematoporphyrin derivative, photodynamic therapy, cancer, malignant tumours, laser.
Summary Malignant tumours (540 cases), including tumours of the lung, oesophagus, cardia, stomach, rectum, bladder, other urinary genital organs, face and mouth, eyes, ear, nose and throat (ENT), head and neck, breast and skin, were treated using photodynamic therapy (PDT) between 1982 and 1985 in Beijing. All of the cases were identified pathologically and the patients received haematoporphyrin derivative (HPD) (5 mg k g - 1) intravenously 4 8 - 7 2 h prior to PDT. An argon-pumped dye laser emitting at 630 nm was used for the treatment. The results were as follows: complete response (CR) was obtained in 227 cases (42.1%), partial response (PR) was obtained in 114 cases (21.1%), mild response (MR) was obtained in 120 cases (22.2%) and 79 cases (14.6%) showed no response (NR). The effectiveness of PDT in the different organs was compared. HPD fluorescence was examined in 409 *Paper presented at the Congress on Photodynamic Therapy of Tumours, Sofia, Bulgaria, October, 1989.
Elsevier Sequoia/Printed in The Netherlands
150 cases of malignant tumours: 344 lesions (84.1%) revealed red fluorescence (positive reaction), 32 gave an equivocal response and 33 gave a negative reaction. Positive fluorescence was seen in all types of malignant t um our in our study. Indications and limitations of PDT for the different organs are discussed and compared.
1. I n t r o d u c t i o n The clinical treatment of malignant tumours using photodynamic therapy (PDT) has been applied in Beijing since 1980; however, research on the clinical application of PDT in China was started after the establishment of a special PDT study group (the Beijing cooperative hospital experimental laser group) in 1982 [1, 2]. In this paper, we r e por t on 540 cases of malignant tumours which received PDT and 409 cases of malignant tumours which were examined for haematoporphyrin derivative (HPD) fluorescence in the period 1 9 8 2 - 1 9 8 5 . 2. M a t e r i a l s a n d m e t h o d s
2.1. Patients 409 cases were examined for HPD fluorescence and 540 cases (393 male, 147 female) received PDT. All cases were identified by histological examination before the HPD laser fluorescence test and treatment. In the PDT group, 124 patients (23.0%) were aged between 41 and 50 years and 364 patients (67.4%) were over 51 years. The various types of t um our examined and treated are summarized in Tables 1 and 2. The pathologic types of t um our included squamous cell carcinoma, undifferentiated carcinoma, adenocarcinoma, basal cell carcinoma, colloid carcinoma, papillary carcinoma, osteoblastic sarcoma, m y o s a r c o m a and rhabdomyosarcoma. Most of the patients were inoperable. 2.2. H a e m a t o p o r p h y r i n d e r i v a t i v e (HPD) HPD was supplied by the Beijing Institute of Medicine Industry. Skin tests were p er f or m e d before administration of HPD to ensure that no anaphylactic reaction occurred. If no evidence of hypersensitivity was observed, HPD (5 mg kg-1 body weight) was diluted with 250 ml normal saline and injected by intravenous drip 4 8 - 7 2 h prior to laser treatment. The patients were p r o tected from exposure to sunlight for 1 month after injection of HPD to avoid sunburn. 2.3. Light source An argon ion laser (emission at 4 8 8 - 5 1 4 . 5 nm) was used for the fluorescence tests in most cases. A black lamp (365 nm) and an H e - C d laser (441.6 nm) were also used.
151 TABLE 1 The results of fluorescence tests on various types of malignant tumours
Location of turnout
Positive
Lung Oesophagus Cardia Stomach Rectum Urinary bladder Other urinary and genital organs Face and oral cavity Eye ENT Head and neck Breast Skin Bone and muscle Brain Total cases (%)
Equivocal
Negative
33 24 41 21 9 3 16
4 6 3 6 1 2 1
3 5
93 12 9 2 9 35 25 12
2 1 1 1 2 2 4
16
344 84.1
32 7.8
Total 40 35 44 28 10 5 18
1
1
1
111 13 10 3 12 38 29 13
33 8.1
409 100
1 1
All types of turnouts gave a positive reaction.
TABLE 2 Therapeutic results of PDT on different types of malignant tumours
Location of turnout
Lung Oesophagus Cardia Stomach Rectum Urinary bladder Other urinary and genital organs Face and oral cavity Eye ENT Head and neck Breast Skin Total cases (%)
Complete remission 9
Partial remission
Mild remission
19 6 21 6 9 4
20 23 15 5
76 10 14 4 7 48
15 11 3 3 3 14
17 2 2 6 3 15
227 42.1
114 21.1
120 22.2
3 2 40 14
4 8
No remission
Total
6 14 9 3 4 2 3
54 43 48 16 13 50 25
11 10 5 1 11
119 33 19 18 14 88
79 14.6
540 100
152 An a r g o n - p u m p e d dye l a s e r delivering a 630 n m b e a m w a s u s e d for t h e r a p y in m o s t cases. T h e l a s e r a p p a r a t u s w a s built b y the Nanjing E l e c t r o n T u b e F a c t o r y , the Beijing Institute o f O p t o - E l e c t r o n i c T e c h n o l o g y a n d the R e s e a r c h Institute of E l e c t r o n i c T e c h n o l o g y o f the C h i n e s e A c a d e m y o f Science. S o m e c a s e s w e r e e x a m i n e d for f l u o r e s c e n c e or t r e a t e d u s i n g a S p e c t r a P h y s i c s 171-09 a r g o n ion l a s e r a n d a S p e c t r a P h y s i c s 3 7 5 B dye laser r e s p e c t i v e l y .
2.4. Fibre optics Quartz optical fibres ( 3 0 0 - 4 0 0 ~ m ) including flat tip type, lens t y p e a n d bulb type, w e r e m a n u f a c t u r e d b y the Chinese Institute of Building Materials a n d the Beijing Institute of Glass T e c h n o l o g y or O n c o l o g y R e s e a r c h a n d D e v e l o p m e n t , Inc., NY, U.S.A.
2.5. Methods 2.5.1. E x a m i n a t i o n of fluorescence Red f l u o r e s c e n c e of H P D in c a n c e r tissue, e x c i t e d b y the a r g o n ion l a s e r or the H e - C d laser, w a s o b s e r v e d t h r o u g h a b r o w n filter. L e s i o n s in canalized o r g a n s w e r e o b s e r v e d t h r o u g h an e n d o s c o p e ; a quartz fibre c o u p l e d to the a r g o n ion l a s e r w a s i n s e r t e d t h r o u g h the e n d o s c o p e c h a n n e l until its tip p r o t r u d e d a b o u t 1 - 1 . 5 c m f r o m the tip of the e n d o s c o p e . The p o w e r densities w e r e 50 m W c m -2 a n d 2 0 - 4 0 m W c m - z for the a r g o n ion l a s e r a n d the H e - C d l a s e r respectively.
2.5.2. PDT treatment I r r a d i a t i o n w a s n o r m a l l y p e r f o r m e d 4 8 - 7 2 h a f t e r the injection o f HPD. A p o w e r density of 1 0 0 - 3 0 0 m W c m - e a n d a n e n e r g y density o f 1 0 0 - 3 0 0 J c m -2 w e r e u s e d in m o s t t u m o u r s . In the t r e a t m e n t o f large t u m o u r s , cylindrical fibres w e r e u s e d interstitially. In the t r e a t m e n t o f c a n c e r o f the lung, s t o m a c h , o e s o p h a g u s , b l a d d e r a n d r e c t u m , the l a s e r b e a m w a s t r a n s m i t t e d via a quartz fibre i n s e r t e d t h r o u g h the c h a n n e l o f a n e n d o s c o p e ; the flat tip of the fibre w a s p l a c e d a p p r o x i m a t e l y 0 . 5 - 1 . 0 c m f r o m the lesion. A c c o r d i n g to the n u m b e r a n d size of the lesions, multiple e x p o s u r e s w e r e o c c a s i o n a l l y n e e d e d . In the c a s e of b r o n c h o g e n i c c a r c i n o m a , a f t e r the first t r e a t m e n t , b r o n c h o s c o p i c e x a m i n a t i o n s w e r e p e r f o r m e d 1 - 3 t i m e s within the first w e e k to r e m o v e debris a n d n e c r o t i c tissues. If t h e r e w a s a n y residual visible t u m o u r , a s e c o n d or third l a s e r t r e a t m e n t w a s g i v e n w i t h o u t additional drug. Otherwise, the P D T w a s a s s e s s e d 4 - 6 w e e k s later for p o s s i b l e retreatment.
2.6. Criteria of therapeutic effectiveness The criteria e s t a b l i s h e d at the n a t i o n a l c o n f e r e n c e on P D T h e l d in 1984 w e r e as follows: c o m p l e t e r e m i s s i o n (the t u m o u r d i s a p p e a r s ; no c a n c e r cell is f o u n d o n histological e x a m i n a t i o n f o r at l e a s t 1 m o n t h ) ; partial r e m i s s i o n ( e x t e n s i v e n e c r o s i s o f t u m o u r ; the v o l u m e o f the t u m o u r d e c r e a s e s b y 50%--99% for at l e a s t 1 m o n t h ) ; mild r e m i s s i o n (the t u m o u r v o l u m e is
153
r e d u c e d b y less t h a n 5 0 % f o r at l e a s t 1 m o n t h ) ; no r e m i s s i o n (no o b v i o u s n e c r o s i s ; t u m o u r v o l u m e r e d u c e s slightly o r e v e n i n c r e a s e s ) .
3. R e s u l t s
3.1. Fluorescence o f m a l i g n a n t turnouts A p o s i t i v e o r a n g e - r e d f l u o r e s c e n c e w a s s e e n in 3 4 4 o u t of 4 0 9 c a s e s (84.1%). An e q u i v o c a l r e a c t i o n w a s o b t a i n e d in 32 c a s e s (7.8%), w h e r e t u m o u r s s h o w e d p i n k f l u o r e s c e n c e . A n e g a t i v e r e a c t i o n w a s o b s e r v e d in 33 c a s e s (8.1%).
3.2. T h e r a p e u t i c effect T h e t h e r a p e u t i c effect of P D T w a s a s s e s s e d o n the b a s i s o f t h e n e c r o s i s of m a l i g n a n t t u m o u r s . After PDT, r e d a n d swollen tissues, n e c r o s i s a n d s c a r r i n g usually o c c u r in superficial t u m o u r s , w h e r e a s o e d e m a , e x u d a t i o n , n e c r o s i s a n d s l o u g h i n g of n e c r o t i c t i s s u e s usually o c c u r in the v i s c e r a l tumours. The t h e r a p e u t i c effect w a s e v a l u a t e d in 5 4 0 c a s e s (Table 2). C o m p l e t e r e m i s s i o n w a s o b t a i n e d in 2 2 7 c a s e s (42.1%), partial r e m i s s i o n w a s o b t a i n e d in 114 c a s e s ( 2 1 . 1 % ) a n d mild r e m i s s i o n w a s o b t a i n e d in 120 c a s e s (22.2%). An effective r e s p o n s e f o r P D T w a s o b s e r v e d in 461 c a s e s (85.4%).
3.3. S i d e effects B l o o d routine, urine r o u t i n e a n d h e p a t i c f u n c t i o n s e x a m i n e d b e f o r e a n d a f t e r P D T w e r e n o r m a l in this series. B o d y t e m p e r a t u r e s h o w e d n o significant c h a n g e . The m a i n side effect w a s allergic dermatitis, w h i c h t o o k p l a c e in 20 c a s e s a f t e r H P D injection a n d s u b s e q u e n t e x p o s u r e to sunlight. This w a s n o t severe, a n d s u b s i d e d within s e v e r a l days. P a t i e n t s d e v e l o p e d p i g m e n t a t i o n on t h e i r b a r e skin a f t e r the injection of HPD; this usually d i s a p p e a r e d within s e v e r a l m o n t h s . One p a t i e n t of n a s o p h a r y n g e a l c a n c e r with b r a i n m e t a s t a s i s suffered f r o m v o m i t i n g a f t e r H P D injection, b u t this s y m p t o m d i s a p p e a r e d s o o n after. T h e s e r e s u l t s s u g g e s t t h a t t h e P D T p r o c e d u r e is safe, e v e n in a d v a n c e d c a n c e r patients.
4. S p e c i f i c c a s e s
4.1. Case 1 A 7 5 - y e a r - o l d m a l e c o m p l a i n e d o f d y s p h a g i a for 2 m o n t h s . A t u m o u r with a superficial u l c e r w a s f o u n d b y e n d o s c o p e in c a r d i a a n d identified as c a r d i a c a d e n o c a r c i n o m a . Since this p a t i e n t also s u f f e r e d f r o m s e v e r e c h r o n i c b r o n c h i t i s a n d w a s t o o old to risk the o p e r a t i o n , P D T w a s p e r f o r m e d . After 4 w e e k s , the s y m p t o m s h a d d i s a p p e a r e d a n d the t u m o u r size h a d significantly d e c r e a s e d . After 6 m o n t h s , a s e c o n d P D T s e s s i o n w a s p e r f o r m e d . T h e t u m o u r d i s a p p e a r e d , no c a n c e r cell w a s f o u n d pathologically, a n d a n o r m a l a p p e a r a n c e
154 w a s r e v e a l e d o n X-ray analysis 4 w e e k s a f t e r the s e c o n d PDT. F o l l o w - u p for 6 y e a r s s h o w e d s y m p t o m - f r e e , n o r m a l , n e g a t i v e tissue in e n d o s c o p i c a n d pathological examinations.
4.2. Case 2 A l o w e r lip t u m o u r w a s identified as a s e c o n d s t a g e s q u a m o u s cell c a r c i n o m a in a 6 0 - y e a r - o l d male. After PDT, the t u m o u r d i s a p p e a r e d . C o m p l e t e r e m i s s i o n o c c u r r e d . F o l l o w - u p for 7 y e a r s s h o w e d a n o r m a l a p p e a r a n c e of the t r e a t e d area. 4.3. Case 3 A 0.8 c m p a p i l l a r y c a r c i n o m a w a s o b s e r v e d at the orifice o f the left u r e t e r of a 4 2 - y e a r - o l d female; 18 d a y s a f t e r PDT, the t u m o u r b e c a m e n e c r o t i c a n d s l o u g h e d off. C o m p l e t e r e m i s s i o n o c c u r r e d . F o l l o w - u p for 20 m o n t h s showed a normal appearance. 4.4. Case 4 A c h e s t X-ray o f a 5 4 - y e a r - o l d m a l e s h o w e d a large t u m o u r l o c a t e d at the left h i l u m a n d left lung a t e l e c t a s i a . F i b r e - o p t i c b r o n c h o s c o p y s h o w e d an i r r e g u l a r t u m o u r o b s t r u c t i n g the left m a i n b r o n c h u s . The t u m o u r w a s identified as an u n d i f f e r e n t i a t e d small-cell c a r c i n o m a b y p a t h o l o g i c e x a m i n a t i o n . X-ray analysis at 12 days a f t e r P D T s h o w e d t h a t the a t e l e c t a s i a w a s partially ree x p a n d e d . At 1 m o n t h , the t u m o u r in the left m a i n b r o n c h u s h a d d i s a p p e a r e d . No c a n c e r cells w e r e o b s e r v e d in b i o p s y s p e c i m e n s . The left lung w a s entirely r e - e x p a n d e d . The s y m p t o m s w e r e significantly i m p r o v e d . H o w e v e r , this p a t i e n t h a d m e t a s t a s i s in the m e d i a s t i n u m 7 m o n t h s a f t e r P D T a n d died due to thrombocytopenia after chemotherapy.
5. D i s c u s s i o n
5.1. A p p l i c a t i o n s o f P D T The effective p e n e t r a t i o n d e p t h of r e d light with a w a v e l e n g t h o f 6 3 0 n m w h i c h is u s e d in PDT is to within 1 c m only [3, 4]. T h u s P D T c a n act as a superficial a n d local m e t h o d o f t r e a t m e n t . It is m a i n l y u s e d for m a l i g n a n t t u m o u r s w h i c h are i n o p e r a b l e due to v a r i o u s r e a s o n s . F o r m a l i g n a n t t u m o u r s of the face, hand, f o o t a n d genital organs, o p e r a t i o n m a y b r i n g loss o f f u n c t i o n or c a u s e a e s t h e t i c d a m a g e . This t e c h n i q u e m a y be a n alternative m e t h o d f o r the t h e r a p y o f m a l i g n a n t t u m o u r s a n d m a y b e m o r e readily a c c e p t e d b y s o m e patients. A d v a n c e d c a s e s a n d c a n c e r s o f the t r a c h e a , larynx a n d high level o e s o p h a g u s usually p r e s e n t difficulties f o r o p e r a t i o n . Selective action s e e m s to o c c u r with PDT; it kills t u m o u r cells b u t l e a v e s n o r m a l tissue u n d a m a g e d [5]. B l a d d e r c a n c e r c a n also b e t r e a t e d well with PDT; r e s u l t s for superficial b l a d d e r t u m o u r s are g e n e r a l l y g o o d a n d the p r o c e d u r e is m u c h e a s i e r t h a n r e g u l a r r e s e c t i o n [6]. This m e t h o d c a n b e u s e in i n o p e r a b l e early s t a g e c e n t r a l - t y p e lung c a n c e r in w h i c h the t u m o u r
155 invades the m u c o s a of a r e a s t h a t c a n be r e a c h e d by the laser b e a m . PDT c a n also be u s e d to r e d u c e the e x t e n t o f r e s e c t i o n in o r d e r to p r e s e r v e the f u n c t i o n of the o r g a n or i m p r o v e the g e n e r a l c o n d i t i o n s o f the p a t i e n t ' s airway or o e s o p h a g e a l tract. 5.2. F l u o r e s c e n c e d i a g n o s i s o f m a l i g n a n t turnouts A large p r o p o r t i o n of patients (84.1%) r e v e a l e d positive fluorescence. This result was i m p r o v e d b y u s i n g a k r y p t o n ion laser instead of the a r g o n ion laser, an i m a g e intensifier a n d a m u l t i c h a n n e l analyser for the d e t e c t i o n of the HPD f l u o r e s c e n c e a n d c o r r e c t i o n for a u t o f l u o r e s c e n c e . If a n e w p h o t o s e n s i t i z e r c o u l d be f o u n d with less side effects ( e . g . one that d o e s n o t c a u s e skin sensitivity on e x p o s u r e to sunlight after injection), p h o t o d y n a m i c t r e a t m e n t s h o u l d be widely a c c e p t e d as an early diagnosis p r o c e d u r e . 5.3. F a c t o r s i n f l u e n c i n g t h e t h e r a p e u t i c e f f e c t s The t h e r a p e u t i c effects v a r y widely a c c o r d i n g to the size or stage of the t u m o u r s , the e x t e n t involved, the l o c a t i o n and the m e t h o d s a d o p t e d . Superficial t u m o u r s yield b e t t e r results since t h e y are b e t t e r e x p o s e d to the laser; the m u c o u s e x u d a t e a n d o b s t r u c t i o n o f the l u m e n of visceral t u m o u r s m a y interfere with e x p o s u r e to light. All of the various p a t h o l o g i c a l t y p e s of t u m o u r s in this s t u d y r e s p o n d to PDT. Different t y p e s of fibre o p t i c s suit different l o c a t i o n s or s h a p e s of t u m o u r s . Cylindrical fibres are a p p r o p r i a t e for t r e a t m e n t of lesions l o c a t e d o n the b r o n c h i a l or o e s o p h a g e a l wall a n d for interstitial irradiation of large t u m o u r s . The lens-type fibres are suitable for t r e a t m e n t o f large t u m o u r s during external irradiation. The bulb-type fibre is a p p r o p r i a t e for t r e a t m e n t o f b l a d d e r c a n c e r b e c a u s e lesions usually s p r e a d on its spherical wall. The flat tip fibre is v e r y c h e a p a n d is suitable for small lesions w h i c h can be p o s i t i o n e d in front o f the tip.
References 1 J. H. Li et al., Application of hematoporphyrin derivative and laser-induced photodynamical reaction in the treatment of lung cancer, Laser Surg. Med., 4 (1984) 31. 2 J. H. Li et al., Hematoporphyrin derivative and laser photodynamic reaction in the diagnosis and treatment of malignant tumors, Natl. Med. J. China, 66 (1986) 388. 3 T.J. Dougherty et al., Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light, J. Natl. Cancer Inst., 55 (1975) 115. 4 J. F. Kelly and M. E. Snell, Hematoporphyrin derivative: a possible aid in the diagnosis and therapy of carcinoma of the bladder, J. Urol., 115 (1976) 150. 5 Y. Hayata et al., Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer, Chest, 81 (1982) 269. 6 J.H.Kinseyetal.•Detecti•n•fhemat•p•rphyrin•u•rescenceduring•ber•pticbr•nch•sc•py to localize early bronchogenic carcinoma, Mayo Clin. Proc., 53 (1978) 594.
149
PHOTODYNAMIC THERAPY IN THE TREATMENT OF MALIGNANT TUMOURS: AN ANALYSIS OF 540 CASES* JUN-HENG LI and ZHONG-HE GUO
Great Wall Hospital of China, Beijing (China) MAO-LIN JIN
Beijing Cancer Institute, Belling (China) FU-YUN ZHAO
Beijing Medical University, Stomatological Hospital, Beijing (China) WEI-MING CAI
Cancer Hospital, Chinese Academy of Medical Sciences, Beijing (China) MEN-LIN GAO
PUMC Hospital, Beijing (China) MING-YAN SHU
Beijing Obstetrics and Gynaecology Hospital, Beijing (China) JIN ZOU
Tong Ren Hospital, Beijing (China) (Received October 5, 1989; accepted December 18, 1989)
Keywords. Haematoporphyrin derivative, photodynamic therapy, cancer, malignant tumours, laser.
Summary Malignant tumours (540 cases), including tumours of the lung, oesophagus, cardia, stomach, rectum, bladder, other urinary genital organs, face and mouth, eyes, ear, nose and throat (ENT), head and neck, breast and skin, were treated using photodynamic therapy (PDT) between 1982 and 1985 in Beijing. All of the cases were identified pathologically and the patients received haematoporphyrin derivative (HPD) (5 mg k g - 1) intravenously 4 8 - 7 2 h prior to PDT. An argon-pumped dye laser emitting at 630 nm was used for the treatment. The results were as follows: complete response (CR) was obtained in 227 cases (42.1%), partial response (PR) was obtained in 114 cases (21.1%), mild response (MR) was obtained in 120 cases (22.2%) and 79 cases (14.6%) showed no response (NR). The effectiveness of PDT in the different organs was compared. HPD fluorescence was examined in 409 *Paper presented at the Congress on Photodynamic Therapy of Tumours, Sofia, Bulgaria, October, 1989.
Elsevier Sequoia/Printed in The Netherlands
150 cases of malignant tumours: 344 lesions (84.1%) revealed red fluorescence (positive reaction), 32 gave an equivocal response and 33 gave a negative reaction. Positive fluorescence was seen in all types of malignant t um our in our study. Indications and limitations of PDT for the different organs are discussed and compared.
1. I n t r o d u c t i o n The clinical treatment of malignant tumours using photodynamic therapy (PDT) has been applied in Beijing since 1980; however, research on the clinical application of PDT in China was started after the establishment of a special PDT study group (the Beijing cooperative hospital experimental laser group) in 1982 [1, 2]. In this paper, we r e por t on 540 cases of malignant tumours which received PDT and 409 cases of malignant tumours which were examined for haematoporphyrin derivative (HPD) fluorescence in the period 1 9 8 2 - 1 9 8 5 . 2. M a t e r i a l s a n d m e t h o d s
2.1. Patients 409 cases were examined for HPD fluorescence and 540 cases (393 male, 147 female) received PDT. All cases were identified by histological examination before the HPD laser fluorescence test and treatment. In the PDT group, 124 patients (23.0%) were aged between 41 and 50 years and 364 patients (67.4%) were over 51 years. The various types of t um our examined and treated are summarized in Tables 1 and 2. The pathologic types of t um our included squamous cell carcinoma, undifferentiated carcinoma, adenocarcinoma, basal cell carcinoma, colloid carcinoma, papillary carcinoma, osteoblastic sarcoma, m y o s a r c o m a and rhabdomyosarcoma. Most of the patients were inoperable. 2.2. H a e m a t o p o r p h y r i n d e r i v a t i v e (HPD) HPD was supplied by the Beijing Institute of Medicine Industry. Skin tests were p er f or m e d before administration of HPD to ensure that no anaphylactic reaction occurred. If no evidence of hypersensitivity was observed, HPD (5 mg kg-1 body weight) was diluted with 250 ml normal saline and injected by intravenous drip 4 8 - 7 2 h prior to laser treatment. The patients were p r o tected from exposure to sunlight for 1 month after injection of HPD to avoid sunburn. 2.3. Light source An argon ion laser (emission at 4 8 8 - 5 1 4 . 5 nm) was used for the fluorescence tests in most cases. A black lamp (365 nm) and an H e - C d laser (441.6 nm) were also used.
151 TABLE 1 The results of fluorescence tests on various types of malignant tumours
Location of turnout
Positive
Lung Oesophagus Cardia Stomach Rectum Urinary bladder Other urinary and genital organs Face and oral cavity Eye ENT Head and neck Breast Skin Bone and muscle Brain Total cases (%)
Equivocal
Negative
33 24 41 21 9 3 16
4 6 3 6 1 2 1
3 5
93 12 9 2 9 35 25 12
2 1 1 1 2 2 4
16
344 84.1
32 7.8
Total 40 35 44 28 10 5 18
1
1
1
111 13 10 3 12 38 29 13
33 8.1
409 100
1 1
All types of turnouts gave a positive reaction.
TABLE 2 Therapeutic results of PDT on different types of malignant tumours
Location of turnout
Lung Oesophagus Cardia Stomach Rectum Urinary bladder Other urinary and genital organs Face and oral cavity Eye ENT Head and neck Breast Skin Total cases (%)
Complete remission 9
Partial remission
Mild remission
19 6 21 6 9 4
20 23 15 5
76 10 14 4 7 48
15 11 3 3 3 14
17 2 2 6 3 15
227 42.1
114 21.1
120 22.2
3 2 40 14
4 8
No remission
Total
6 14 9 3 4 2 3
54 43 48 16 13 50 25
11 10 5 1 11
119 33 19 18 14 88
79 14.6
540 100
152 An a r g o n - p u m p e d dye l a s e r delivering a 630 n m b e a m w a s u s e d for t h e r a p y in m o s t cases. T h e l a s e r a p p a r a t u s w a s built b y the Nanjing E l e c t r o n T u b e F a c t o r y , the Beijing Institute o f O p t o - E l e c t r o n i c T e c h n o l o g y a n d the R e s e a r c h Institute of E l e c t r o n i c T e c h n o l o g y o f the C h i n e s e A c a d e m y o f Science. S o m e c a s e s w e r e e x a m i n e d for f l u o r e s c e n c e or t r e a t e d u s i n g a S p e c t r a P h y s i c s 171-09 a r g o n ion l a s e r a n d a S p e c t r a P h y s i c s 3 7 5 B dye laser r e s p e c t i v e l y .
2.4. Fibre optics Quartz optical fibres ( 3 0 0 - 4 0 0 ~ m ) including flat tip type, lens t y p e a n d bulb type, w e r e m a n u f a c t u r e d b y the Chinese Institute of Building Materials a n d the Beijing Institute of Glass T e c h n o l o g y or O n c o l o g y R e s e a r c h a n d D e v e l o p m e n t , Inc., NY, U.S.A.
2.5. Methods 2.5.1. E x a m i n a t i o n of fluorescence Red f l u o r e s c e n c e of H P D in c a n c e r tissue, e x c i t e d b y the a r g o n ion l a s e r or the H e - C d laser, w a s o b s e r v e d t h r o u g h a b r o w n filter. L e s i o n s in canalized o r g a n s w e r e o b s e r v e d t h r o u g h an e n d o s c o p e ; a quartz fibre c o u p l e d to the a r g o n ion l a s e r w a s i n s e r t e d t h r o u g h the e n d o s c o p e c h a n n e l until its tip p r o t r u d e d a b o u t 1 - 1 . 5 c m f r o m the tip of the e n d o s c o p e . The p o w e r densities w e r e 50 m W c m -2 a n d 2 0 - 4 0 m W c m - z for the a r g o n ion l a s e r a n d the H e - C d l a s e r respectively.
2.5.2. PDT treatment I r r a d i a t i o n w a s n o r m a l l y p e r f o r m e d 4 8 - 7 2 h a f t e r the injection o f HPD. A p o w e r density of 1 0 0 - 3 0 0 m W c m - e a n d a n e n e r g y density o f 1 0 0 - 3 0 0 J c m -2 w e r e u s e d in m o s t t u m o u r s . In the t r e a t m e n t o f large t u m o u r s , cylindrical fibres w e r e u s e d interstitially. In the t r e a t m e n t o f c a n c e r o f the lung, s t o m a c h , o e s o p h a g u s , b l a d d e r a n d r e c t u m , the l a s e r b e a m w a s t r a n s m i t t e d via a quartz fibre i n s e r t e d t h r o u g h the c h a n n e l o f a n e n d o s c o p e ; the flat tip of the fibre w a s p l a c e d a p p r o x i m a t e l y 0 . 5 - 1 . 0 c m f r o m the lesion. A c c o r d i n g to the n u m b e r a n d size of the lesions, multiple e x p o s u r e s w e r e o c c a s i o n a l l y n e e d e d . In the c a s e of b r o n c h o g e n i c c a r c i n o m a , a f t e r the first t r e a t m e n t , b r o n c h o s c o p i c e x a m i n a t i o n s w e r e p e r f o r m e d 1 - 3 t i m e s within the first w e e k to r e m o v e debris a n d n e c r o t i c tissues. If t h e r e w a s a n y residual visible t u m o u r , a s e c o n d or third l a s e r t r e a t m e n t w a s g i v e n w i t h o u t additional drug. Otherwise, the P D T w a s a s s e s s e d 4 - 6 w e e k s later for p o s s i b l e retreatment.
2.6. Criteria of therapeutic effectiveness The criteria e s t a b l i s h e d at the n a t i o n a l c o n f e r e n c e on P D T h e l d in 1984 w e r e as follows: c o m p l e t e r e m i s s i o n (the t u m o u r d i s a p p e a r s ; no c a n c e r cell is f o u n d o n histological e x a m i n a t i o n f o r at l e a s t 1 m o n t h ) ; partial r e m i s s i o n ( e x t e n s i v e n e c r o s i s o f t u m o u r ; the v o l u m e o f the t u m o u r d e c r e a s e s b y 50%--99% for at l e a s t 1 m o n t h ) ; mild r e m i s s i o n (the t u m o u r v o l u m e is
153
r e d u c e d b y less t h a n 5 0 % f o r at l e a s t 1 m o n t h ) ; no r e m i s s i o n (no o b v i o u s n e c r o s i s ; t u m o u r v o l u m e r e d u c e s slightly o r e v e n i n c r e a s e s ) .
3. R e s u l t s
3.1. Fluorescence o f m a l i g n a n t turnouts A p o s i t i v e o r a n g e - r e d f l u o r e s c e n c e w a s s e e n in 3 4 4 o u t of 4 0 9 c a s e s (84.1%). An e q u i v o c a l r e a c t i o n w a s o b t a i n e d in 32 c a s e s (7.8%), w h e r e t u m o u r s s h o w e d p i n k f l u o r e s c e n c e . A n e g a t i v e r e a c t i o n w a s o b s e r v e d in 33 c a s e s (8.1%).
3.2. T h e r a p e u t i c effect T h e t h e r a p e u t i c effect of P D T w a s a s s e s s e d o n the b a s i s o f t h e n e c r o s i s of m a l i g n a n t t u m o u r s . After PDT, r e d a n d swollen tissues, n e c r o s i s a n d s c a r r i n g usually o c c u r in superficial t u m o u r s , w h e r e a s o e d e m a , e x u d a t i o n , n e c r o s i s a n d s l o u g h i n g of n e c r o t i c t i s s u e s usually o c c u r in the v i s c e r a l tumours. The t h e r a p e u t i c effect w a s e v a l u a t e d in 5 4 0 c a s e s (Table 2). C o m p l e t e r e m i s s i o n w a s o b t a i n e d in 2 2 7 c a s e s (42.1%), partial r e m i s s i o n w a s o b t a i n e d in 114 c a s e s ( 2 1 . 1 % ) a n d mild r e m i s s i o n w a s o b t a i n e d in 120 c a s e s (22.2%). An effective r e s p o n s e f o r P D T w a s o b s e r v e d in 461 c a s e s (85.4%).
3.3. S i d e effects B l o o d routine, urine r o u t i n e a n d h e p a t i c f u n c t i o n s e x a m i n e d b e f o r e a n d a f t e r P D T w e r e n o r m a l in this series. B o d y t e m p e r a t u r e s h o w e d n o significant c h a n g e . The m a i n side effect w a s allergic dermatitis, w h i c h t o o k p l a c e in 20 c a s e s a f t e r H P D injection a n d s u b s e q u e n t e x p o s u r e to sunlight. This w a s n o t severe, a n d s u b s i d e d within s e v e r a l days. P a t i e n t s d e v e l o p e d p i g m e n t a t i o n on t h e i r b a r e skin a f t e r the injection of HPD; this usually d i s a p p e a r e d within s e v e r a l m o n t h s . One p a t i e n t of n a s o p h a r y n g e a l c a n c e r with b r a i n m e t a s t a s i s suffered f r o m v o m i t i n g a f t e r H P D injection, b u t this s y m p t o m d i s a p p e a r e d s o o n after. T h e s e r e s u l t s s u g g e s t t h a t t h e P D T p r o c e d u r e is safe, e v e n in a d v a n c e d c a n c e r patients.
4. S p e c i f i c c a s e s
4.1. Case 1 A 7 5 - y e a r - o l d m a l e c o m p l a i n e d o f d y s p h a g i a for 2 m o n t h s . A t u m o u r with a superficial u l c e r w a s f o u n d b y e n d o s c o p e in c a r d i a a n d identified as c a r d i a c a d e n o c a r c i n o m a . Since this p a t i e n t also s u f f e r e d f r o m s e v e r e c h r o n i c b r o n c h i t i s a n d w a s t o o old to risk the o p e r a t i o n , P D T w a s p e r f o r m e d . After 4 w e e k s , the s y m p t o m s h a d d i s a p p e a r e d a n d the t u m o u r size h a d significantly d e c r e a s e d . After 6 m o n t h s , a s e c o n d P D T s e s s i o n w a s p e r f o r m e d . T h e t u m o u r d i s a p p e a r e d , no c a n c e r cell w a s f o u n d pathologically, a n d a n o r m a l a p p e a r a n c e
154 w a s r e v e a l e d o n X-ray analysis 4 w e e k s a f t e r the s e c o n d PDT. F o l l o w - u p for 6 y e a r s s h o w e d s y m p t o m - f r e e , n o r m a l , n e g a t i v e tissue in e n d o s c o p i c a n d pathological examinations.
4.2. Case 2 A l o w e r lip t u m o u r w a s identified as a s e c o n d s t a g e s q u a m o u s cell c a r c i n o m a in a 6 0 - y e a r - o l d male. After PDT, the t u m o u r d i s a p p e a r e d . C o m p l e t e r e m i s s i o n o c c u r r e d . F o l l o w - u p for 7 y e a r s s h o w e d a n o r m a l a p p e a r a n c e of the t r e a t e d area. 4.3. Case 3 A 0.8 c m p a p i l l a r y c a r c i n o m a w a s o b s e r v e d at the orifice o f the left u r e t e r of a 4 2 - y e a r - o l d female; 18 d a y s a f t e r PDT, the t u m o u r b e c a m e n e c r o t i c a n d s l o u g h e d off. C o m p l e t e r e m i s s i o n o c c u r r e d . F o l l o w - u p for 20 m o n t h s showed a normal appearance. 4.4. Case 4 A c h e s t X-ray o f a 5 4 - y e a r - o l d m a l e s h o w e d a large t u m o u r l o c a t e d at the left h i l u m a n d left lung a t e l e c t a s i a . F i b r e - o p t i c b r o n c h o s c o p y s h o w e d an i r r e g u l a r t u m o u r o b s t r u c t i n g the left m a i n b r o n c h u s . The t u m o u r w a s identified as an u n d i f f e r e n t i a t e d small-cell c a r c i n o m a b y p a t h o l o g i c e x a m i n a t i o n . X-ray analysis at 12 days a f t e r P D T s h o w e d t h a t the a t e l e c t a s i a w a s partially ree x p a n d e d . At 1 m o n t h , the t u m o u r in the left m a i n b r o n c h u s h a d d i s a p p e a r e d . No c a n c e r cells w e r e o b s e r v e d in b i o p s y s p e c i m e n s . The left lung w a s entirely r e - e x p a n d e d . The s y m p t o m s w e r e significantly i m p r o v e d . H o w e v e r , this p a t i e n t h a d m e t a s t a s i s in the m e d i a s t i n u m 7 m o n t h s a f t e r P D T a n d died due to thrombocytopenia after chemotherapy.
5. D i s c u s s i o n
5.1. A p p l i c a t i o n s o f P D T The effective p e n e t r a t i o n d e p t h of r e d light with a w a v e l e n g t h o f 6 3 0 n m w h i c h is u s e d in PDT is to within 1 c m only [3, 4]. T h u s P D T c a n act as a superficial a n d local m e t h o d o f t r e a t m e n t . It is m a i n l y u s e d for m a l i g n a n t t u m o u r s w h i c h are i n o p e r a b l e due to v a r i o u s r e a s o n s . F o r m a l i g n a n t t u m o u r s of the face, hand, f o o t a n d genital organs, o p e r a t i o n m a y b r i n g loss o f f u n c t i o n or c a u s e a e s t h e t i c d a m a g e . This t e c h n i q u e m a y be a n alternative m e t h o d f o r the t h e r a p y o f m a l i g n a n t t u m o u r s a n d m a y b e m o r e readily a c c e p t e d b y s o m e patients. A d v a n c e d c a s e s a n d c a n c e r s o f the t r a c h e a , larynx a n d high level o e s o p h a g u s usually p r e s e n t difficulties f o r o p e r a t i o n . Selective action s e e m s to o c c u r with PDT; it kills t u m o u r cells b u t l e a v e s n o r m a l tissue u n d a m a g e d [5]. B l a d d e r c a n c e r c a n also b e t r e a t e d well with PDT; r e s u l t s for superficial b l a d d e r t u m o u r s are g e n e r a l l y g o o d a n d the p r o c e d u r e is m u c h e a s i e r t h a n r e g u l a r r e s e c t i o n [6]. This m e t h o d c a n b e u s e in i n o p e r a b l e early s t a g e c e n t r a l - t y p e lung c a n c e r in w h i c h the t u m o u r
155 invades the m u c o s a of a r e a s t h a t c a n be r e a c h e d by the laser b e a m . PDT c a n also be u s e d to r e d u c e the e x t e n t o f r e s e c t i o n in o r d e r to p r e s e r v e the f u n c t i o n of the o r g a n or i m p r o v e the g e n e r a l c o n d i t i o n s o f the p a t i e n t ' s airway or o e s o p h a g e a l tract. 5.2. F l u o r e s c e n c e d i a g n o s i s o f m a l i g n a n t turnouts A large p r o p o r t i o n of patients (84.1%) r e v e a l e d positive fluorescence. This result was i m p r o v e d b y u s i n g a k r y p t o n ion laser instead of the a r g o n ion laser, an i m a g e intensifier a n d a m u l t i c h a n n e l analyser for the d e t e c t i o n of the HPD f l u o r e s c e n c e a n d c o r r e c t i o n for a u t o f l u o r e s c e n c e . If a n e w p h o t o s e n s i t i z e r c o u l d be f o u n d with less side effects ( e . g . one that d o e s n o t c a u s e skin sensitivity on e x p o s u r e to sunlight after injection), p h o t o d y n a m i c t r e a t m e n t s h o u l d be widely a c c e p t e d as an early diagnosis p r o c e d u r e . 5.3. F a c t o r s i n f l u e n c i n g t h e t h e r a p e u t i c e f f e c t s The t h e r a p e u t i c effects v a r y widely a c c o r d i n g to the size or stage of the t u m o u r s , the e x t e n t involved, the l o c a t i o n and the m e t h o d s a d o p t e d . Superficial t u m o u r s yield b e t t e r results since t h e y are b e t t e r e x p o s e d to the laser; the m u c o u s e x u d a t e a n d o b s t r u c t i o n o f the l u m e n of visceral t u m o u r s m a y interfere with e x p o s u r e to light. All of the various p a t h o l o g i c a l t y p e s of t u m o u r s in this s t u d y r e s p o n d to PDT. Different t y p e s of fibre o p t i c s suit different l o c a t i o n s or s h a p e s of t u m o u r s . Cylindrical fibres are a p p r o p r i a t e for t r e a t m e n t of lesions l o c a t e d o n the b r o n c h i a l or o e s o p h a g e a l wall a n d for interstitial irradiation of large t u m o u r s . The lens-type fibres are suitable for t r e a t m e n t o f large t u m o u r s during external irradiation. The bulb-type fibre is a p p r o p r i a t e for t r e a t m e n t o f b l a d d e r c a n c e r b e c a u s e lesions usually s p r e a d on its spherical wall. The flat tip fibre is v e r y c h e a p a n d is suitable for small lesions w h i c h can be p o s i t i o n e d in front o f the tip.
References 1 J. H. Li et al., Application of hematoporphyrin derivative and laser-induced photodynamical reaction in the treatment of lung cancer, Laser Surg. Med., 4 (1984) 31. 2 J. H. Li et al., Hematoporphyrin derivative and laser photodynamic reaction in the diagnosis and treatment of malignant tumors, Natl. Med. J. China, 66 (1986) 388. 3 T.J. Dougherty et al., Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light, J. Natl. Cancer Inst., 55 (1975) 115. 4 J. F. Kelly and M. E. Snell, Hematoporphyrin derivative: a possible aid in the diagnosis and therapy of carcinoma of the bladder, J. Urol., 115 (1976) 150. 5 Y. Hayata et al., Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer, Chest, 81 (1982) 269. 6 J.H.Kinseyetal.•Detecti•n•fhemat•p•rphyrin•u•rescenceduring•ber•pticbr•nch•sc•py to localize early bronchogenic carcinoma, Mayo Clin. Proc., 53 (1978) 594.
