- Email: [email protected]
Long term survivors with small cell carcinoma of the lung
938
Abstracts of the Meeting of the Swiss Society for Oncology
lines, i.e. cells w i t h an a l r e a d y a l t e r e d phenotype. W h e t h e r these cells m a y be t e r m e d i n i t i a t e d and are thus the a p p r o p r i a t e targets for p r o m o t i o n is not clear. F o l l o w i n g recent o b s e r v a t i o n s p h o r b o l esters i n t e r f e r e w i t h i n t e r c e l l u l a r c o m m u n i c a tion p r o c e s s e s and thus m a y well act not only on i n i t i a t e d cells but also on their normal s u r r o u n d i n g cells, thus r e n d e r i n g the tissue p e r m i s s i v e for the e x p r e s s i o n of the t r a n s f o r m e d p h e n o t y p e and for the d e v e l o p m e n t of the i n i t i a t e d cells to v i s i b l e tumors. BLOOM'S
SYNDROME
:
A DEFICIENCY
IN THE D E T O X I F I C A T I O N
OF A C T I V E
OXYGEN
SPECIES
?
P. Cerutti, I. Emerit*, M. H i r s c h i and I. Zbinden, D e p a r t m e n t of C a r c i n o g e n e s i s , Swiss I n s t i t u t e for E x p e r i m e n t a l C a n c e r Research, Ch. des Boveresses, CH-I066 E p a l i n g e s s/Lausanne,, * I n s t i t u t B i o m e d i c a l des C o r d e l i e r s , C y t o g ~ n ~ t i q u e E x p ~ r i m e n tale, 15-21 rue de l'Ecole de M~decine, F-75006 Paris Bloom's S y n d r o m e (BS) is an a u t o s o m a l r e c e s s i v e d i s e a s e w h i c h is c h a r a c t e r i z e d clin i c a l l y by g r o w t h r e t a r d a t i o n , skin s e n s i t i v i t y to sunlight, i m m u n o d e f i c i e n c y and i n c r e a s e d s u s c e p t i b i l i t y for d e v e l o p m e n t of cancer. I n c r e a s e d f r e q u e n c i e s of spont a n e n o u s c h r o m o s o m a l a b e r r a t i o n s and sister c h r o m a t i d e x c h a n g e s have been o b s e r v e d on the c e l l u l a r level. In studies of the n e a r - u l t r a v i o l e t p h o t o b i o l o g y of skin fibrob l a s t s of BS p a t i e n t s we have i n v e s t i g a t e d the survival of the c o l o n y forming ability and the f o r m a t i o n of D N A single strand breaks f o l l o w i n g e x p o s u r e to m o n o c h r o m a t i c light at 313 nm. N e a r - u l t r a v i o l e t r e p r e s e n t s a m a j o r p o r t i o n of the solar r a d i a t i o n w h i c h reaches the surface of the earth. A b n o r m a l survival curves were o b s e r v e d in 6 of 7 BS strains, 4 strains being h y p e r s e n s i t i v e to the lethal a c t i o n of 313 nm light. In 6 of 8 strains 313 nm light induced e x c e s s i v e DNA fragmentation. T h e s e a b n o r m a l i ties in the r e s p o n s e of c u l t u r e d BS f i b r o b l a s t s to n e a r - u l t r a v i o l e t light m a y be ref l e c t i o n in v i t r o of the skin s e n s i t i v i t y of BS p a t i e n t s to sunlight. F u r t h e r insight into the p a t h o l o g y of BS was o b t a i n e d in c y t o g e n e t i c studies. A low m o l e c u l a r w e i g h t c o m p o n e n t was i d e n t i f i e d in c o n c e n t r a t e d m e d i a from 6 BS f i b r o b l a s t strains w h i c h induces c h r o m o s o m a l a b e r r a t i o n s in p h y t o h e m a g g l u t i n i n s t i m u l a t e d lymp h o c y t e s from normal donors. The a c t i v i t y of this c l a s t o g e n i c factor could be dec r e a s e d s u b s t a n t i a l l y by the a d d i t i o n of b o v i n e CU-Zn s u p e r o x i d e dismutase. The c l a s t o g e n i c factor also induced sister c h r o m a t i d e x c h a n g e s in normal lymphocytes, albeit w i t h low efficiency. In a n a l o g y to c o l l a g e n d i s e a s e s such as s y s t e m i c lupus e r y t h m a t o s u s , Crohn's d i s e a s e and p e r i a r t e r i t i s n o d o s a it is s p e c u l a t e d that BS f i b r o b l a s t s are d e f i c i e n t in the d e t o x i f i c a t i o n of active o x y g e n species (05 , OH'). On the basis of our p h o t o b i o l o g i c a l and c y t o g e n e t i c results a new h y p o t h e s i s for the p a t h o l o g y of BS will be discussed. (Supported by the F o n d s n a t i o n a l suisse de la r e c h e r c h e scientifique) PROGNOSTIC Roland W.
FACTORS Sonntag,
IN THE T R E A T M E N T Institute
OF M E T A S T A T I C
for M e d i c a l
Oncology,
GERM CELL C A N C E R University
of Bern,
Switzerland
91 p a t i e n t s w i t h m e t a s t a t i c germ cell c a n c e r were c l a s s i f i e d as having either advanced d i s e a s e (AD) or m i n i m a l d i s e a s e (MD). C r i t e r i a for staging are given. All patients were t r e a t e d s i m i l a r l y a c c o r d i n g to p r o t o c o l O1/76 of the Swiss G r o u p for C l i n i c a l C a n c e r R e s e a r c h (SAKK). C o m p l e t e r e m i s s i o n (CR) rates (95 % vs 35 %) and survival (84 % vs 33 %) were s i g n i f i c a n t l y b e t t e r ( p < 0.001) for the MD g r o u p than for the AD group. D i s e a s e sites did not i n f l u e n c e the t h e r a p y results. P a t i e n t s with MD had higher CR rates (p = 0.003 to 0.009) than AD p a t i e n t s at all sites (lung, a b d o m e n or c o m b i n e d sites). The i n c i d e n c e of MD was higher in p a t i e n t s w i t h embryonal cell c a r c i n o m a than in all other h i s t o l o g y g r o u p s (54 % vs 3 1 % , p = 0.026). This was r e f l e c t e d in a higher CR rate (77 %) for the e m b r y o n a l cell c a r c i n o m a patients than in the other h i s t o l o g i c a l g r o u p s (46 %, p = 0.003). The CR rate for patients w i t h MD was the same in all h i s t o l o g y groups (89 % to 100 %). In AD the 50 % CR rate for e m b r y o n a l cell c a r c i n o m a p a t i e n t s v e r s u s the 28 % rate for o t h e r p a t i e n t s showed a d e f i n i t e trend but did not reach s t a t i s t i c a l significance. The d o s a g e s of c h e m o t h e r a p y g i v e n had no a p p a r e n t e f f e c t upon CR rates. Relaps rates were s i g n i f i c a n t l y a f f e c t e d by d o s a g e reduction, and in AD patients, by the number of chemot h e r a p y cycles given. LONG T E R M S U R V I V O R S
WITH
S M A L L CELL
CARCINOMA
OF THE LUNG
R. Joss, P. Alberto, D i v i s i o n s of M e d i c a l Oncology, Inselspital, Berne, and HSpital Cantonal, G e n e v a for the Swiss G r o u p for C l i n i c a l Cancer R e s e a r c h (SAKK) Several authors have r e c e n t l y r e p o r t e d long term, d i s e a s e - f r e e survival in p a t i e n t s with small cell c a r c i n o m a of the lung (SCCL) after a g g r e s s i v e initial treatment. In an attempt to i d e n t i f y long term, p o t e n t i a l l y cured survivors with SCCL in S w i t z e r land a q u e s t i o n n a i r e was sent to all m e d i c a l o n c o l o g y centers t h r o u g h o u t the country. 14 p a t i e n t s with SCCL were r e p o r t e d a c h i e v i n g d i s e a s e - f r e e survival for over 24 m o n t h s after initial therapy. M e d i a n age was 61 (39 - 80), m e d i a n p e r f o r m a n c e status 0 (0 - 2), 2 were females and 12 were males. 13 p a t i e n t s were c l a s s i f i e d as limited
Abstracts o[ the Meeting o[ the Swiss Society/or Oncolo~
939
disease, 1 p a t i e n t s had e x t e n s i v e d i s e a s e with b o n e ~ metastases. 2 of the 13 patients w i t h limited d i s e a s e had a small p e r i p h e r a l n o d u l e d e t e c t e d on routine chest films. Only 2 p a t i e n t s had w e i g h t loss in the 6 m o n t h s p r i o r to the diagnosis. 5 p a t i e n t s were treated w i t h local t h e r a p y alone (surgery 3, r a d i o t h e r a p y i, surgery plus radiotherapy i), 9 p a t i e n t s r e c e i v e d s y s t e m i c t r e a t m e n t (chemotherapy 5, c h e m o t h e r a p y plus r a d i o t h e r a p y 4). M e d i a n d u r a t i o n of c y t o s t a t i c t r e a t m e n t was 17 m o n t h s (3 - 39) w i t h 3 of 9 p a t i e n t s r e c e i v i n g c h e m o t h e r a p y for less than 6 months. Chest r a d i o t h e r a p y doses v a r i e d from 2000 rads over 1 week to 7000 rads over 7 weeks. Only 1 p a t i e n t r e c e i v e d p r o p h y l a c t i c cranial irradiation. 3 p a t i e n t s r e l a p s e d after initial treatm e n t (surgery I, r a d i o t h e r a p y i, r a d i o t h e r a p y plus c h e m o t h e r a p y i) after 27, 34 and 54 months. M e d i a n survival is 56+ m o n t h s (27+ - 81+). P a t i e n t s have been off treatment for a m e d i a n of 41+ m o n t h s (2+ - 75+). We c o n c l u d e that long term, d i s e a s e - f r e e survival can be a c h i e v e d in p a t i e n t s w i t h limited d i s e a s e SCCL even w i t h r e l a t i v e l y short inital treatment. PHASE I C L I N I C A L T R I A L AND P H A R M A C O K I N E T I C STUDY OF 5 ' - D E O X Y - 5 - F L U O R O U R I D I N E R. Abele, JP. Cano,
P. Alberto, R.J. Seematter, R. Heintz, G. Germano, W. Weber, JP. Obrecht, D i v i s i o n of Oncology, H~pital C a n t o n a l U n i v e r s i t a i r e , CH-1211 Gen~ve
5 ' - d e o x y - 5 - f l u o r o u r i d i n e (DFUR) is a new f l u o r o u r i d i n e analog lacking a 5'-hydroxyl g r o u p in the c h e m i c a l s t r u c t u r e of its p e n t o s e ring. Under the action of uridine p h o s p h o r y l a s e , 5 - f l u o r o u r a c i l (FU) is released. D F U R is thus acting p r o b a b l y as a prodrug. D F U R is active against several e x p e r i m e n t a l animal tumors. Further, it has a higher t h e r a p e u t i c index c o m p a r e d to FU in animals. DFUR has been a d m i n i s t e r e d as a rapid i n t r a v e n o u s bolus i n j e c t i o n d a i l y x 5 and r e p e a t e d every 3 weeks. 21 patients were t r e a t e d at various dose levels. The m a j o r i t y of p a t i e n t s were non pretreated and had g a s t r o - i n t e s t i n a l a d e n o c a r c i n o m a or non small cell lung cancer. 2 courses of DFUR or m o r e w e r e a d m i n i s t e r e d to 15 patients. A m i n i m u m of 4 p a t i e n t s were entered at each dose level. Doses were e s c a l a t e d from 3 O O - 3 0 0 0 m g / m 2 / d a y . Intrap a t i e n t dose e s c a l a t i o n was not done. No s i g n i f i c a n t l e u c o p e n i a was detected, but o c c a s i o n a l t h r o m b o p e n i a was seen at each dose level. There was no e v i d e n c e of cumulative m y e l o t o x i c i t y on s u b s e q u e n t courses of DFUR. A n o r e x i a and nausea was seen in 4 patients, w i t h o u t drug induced vomiting. 2 p a t i e n t s had d i s c r e t e and 1 patient severe d i f f u s e stomatitis. P r e c o r d i a l pain w i t h r e v e r s i b l e e l e c t r o c a r d i o g r a p h i c changes or t r a n s i e n t cardiac e n z y m a t i c e l e v a t i o n s was o b s e r v e d in 2 patients. The m a x i m a l t o l e r a t e d dose has not yet been reached. P h a r m a c o k i n e t i c data are a v a i l a b l e for 5 p a t i e n t s after a d m i n i s t r a t i o n of i000 to 2100 mg of DFUR. The u n c h a n g e d drug e l i m i n a t i o n has a m e a n t~2 e of 5.6 min. (range 3 - 8.3 min.) and a m e a n t~2 8 of 20.5 min. (range 14.5 to 30.8 min.). D i s t r i b u t i o n volume 8 is between 27 and 50 liters. Total p l a s m a t i c c l e a r a n c e lies between 0.8 and 1.8 liter/min. We c o n c l u d e that D F U R can be given at higher doses than FU and that its clinical t o l e r a n c e is good, at the dose levels tested. PHASE I T R I A L OF ~ 1 , 3 , 5 - T R I G L Y C I D Y L - S - T R I A Z E N E T R I O N E
(TGT, NSC-296934)
F. Cavalli, S. Kaplan, M. V a r i n i and R. Joss, D i v i s i o n of Oncology, O s p e d a l e San Giovanni, Bellinzona, S w i t z e r l a n d and Institute for M e d i c a l Oncology, Inselspital Berne, S w i t z e r l a n d TGT is a new a n t i c a n c e r agent that was i d e n t i f i e d by r a n d o m screening. It is a triepoxide d e r i v a t i v e w i t h a l k y l a t i n g properties. The drug is active against a wide v a r i e t y of e x p e r i m e n t a l m u r i n e tumors i n c l u d i n g P388 leukemia r e s i s t a n t to cyclophosphamide, i n t r a c e r e b r a l l y i m p l a n t e d LI210 leukemia and e p e n d y m o b l a s t o m a . This ongoing phase I trial was d e s i g n e d to d e t e r m i n e the m a x i m u m t o l e r a t e d dose (MTD) in adult patient with solid tumors using d a i l y t r e a t m e n t s for 5 c o n s e c u t i v e days. The therapy course is r e p e a t e d every 3 weeks. The drug is given iv. bolus. A total of 33 p a t i e n t s have been e n t e r e d in the trial w i t h a m e d i a n age of 59 (38 - 73) and a m e d i a n p e r f o r m a n c e status of 70 (40-90). All have r e c e i v e d prior c h e m o t h e r a p y and had r e c o v e r e d from prior d r u g - i n d u c e d side-effects. P a t i e n t s had following tumors : 8 colo-rectal, 8 lung, 6 breast, 4 melanoma, 2 upper-GI, 2 headneck, 2 u n k n o w n origin, 1 sarcoma. The trial was i n i t i a t e d at a starting dose of 12 m g / m 2 / d c o r r e s p o n ding to i/i0 LDI0 in the mouse. To date, doses have been e s c a l a t e d up to 600 m g / m 2 / d (= level 13). Dose levels have been o c c a s i o n a l l y i n c r e a s e d w i t h i n the same p a t i e n t s when no t o x i c i t y was e n c o u n t e r e d in p r e v i o u s courses. So far not c l e a r l y d o s e - r e l a ted toxic effects have been observed. Toxic m a n i f e s t a t i o n s include n a u s e a - v o m i t i n g (6 patients), p h l e b i t i s (7 patients) and e r r a t i c m y e l o - s u p p r e s s i o n (5 patients). So far a n t i t u m o r a c t i v i t y has not been detected. Since the MTD has not yet been c l e a r l y reached, the trial as well as p h a r m a c o k i n e t i c studies are ongoing.
Abstracts of the Meeting of the Swiss Society for Oncology
lines, i.e. cells w i t h an a l r e a d y a l t e r e d phenotype. W h e t h e r these cells m a y be t e r m e d i n i t i a t e d and are thus the a p p r o p r i a t e targets for p r o m o t i o n is not clear. F o l l o w i n g recent o b s e r v a t i o n s p h o r b o l esters i n t e r f e r e w i t h i n t e r c e l l u l a r c o m m u n i c a tion p r o c e s s e s and thus m a y well act not only on i n i t i a t e d cells but also on their normal s u r r o u n d i n g cells, thus r e n d e r i n g the tissue p e r m i s s i v e for the e x p r e s s i o n of the t r a n s f o r m e d p h e n o t y p e and for the d e v e l o p m e n t of the i n i t i a t e d cells to v i s i b l e tumors. BLOOM'S
SYNDROME
:
A DEFICIENCY
IN THE D E T O X I F I C A T I O N
OF A C T I V E
OXYGEN
SPECIES
?
P. Cerutti, I. Emerit*, M. H i r s c h i and I. Zbinden, D e p a r t m e n t of C a r c i n o g e n e s i s , Swiss I n s t i t u t e for E x p e r i m e n t a l C a n c e r Research, Ch. des Boveresses, CH-I066 E p a l i n g e s s/Lausanne,, * I n s t i t u t B i o m e d i c a l des C o r d e l i e r s , C y t o g ~ n ~ t i q u e E x p ~ r i m e n tale, 15-21 rue de l'Ecole de M~decine, F-75006 Paris Bloom's S y n d r o m e (BS) is an a u t o s o m a l r e c e s s i v e d i s e a s e w h i c h is c h a r a c t e r i z e d clin i c a l l y by g r o w t h r e t a r d a t i o n , skin s e n s i t i v i t y to sunlight, i m m u n o d e f i c i e n c y and i n c r e a s e d s u s c e p t i b i l i t y for d e v e l o p m e n t of cancer. I n c r e a s e d f r e q u e n c i e s of spont a n e n o u s c h r o m o s o m a l a b e r r a t i o n s and sister c h r o m a t i d e x c h a n g e s have been o b s e r v e d on the c e l l u l a r level. In studies of the n e a r - u l t r a v i o l e t p h o t o b i o l o g y of skin fibrob l a s t s of BS p a t i e n t s we have i n v e s t i g a t e d the survival of the c o l o n y forming ability and the f o r m a t i o n of D N A single strand breaks f o l l o w i n g e x p o s u r e to m o n o c h r o m a t i c light at 313 nm. N e a r - u l t r a v i o l e t r e p r e s e n t s a m a j o r p o r t i o n of the solar r a d i a t i o n w h i c h reaches the surface of the earth. A b n o r m a l survival curves were o b s e r v e d in 6 of 7 BS strains, 4 strains being h y p e r s e n s i t i v e to the lethal a c t i o n of 313 nm light. In 6 of 8 strains 313 nm light induced e x c e s s i v e DNA fragmentation. T h e s e a b n o r m a l i ties in the r e s p o n s e of c u l t u r e d BS f i b r o b l a s t s to n e a r - u l t r a v i o l e t light m a y be ref l e c t i o n in v i t r o of the skin s e n s i t i v i t y of BS p a t i e n t s to sunlight. F u r t h e r insight into the p a t h o l o g y of BS was o b t a i n e d in c y t o g e n e t i c studies. A low m o l e c u l a r w e i g h t c o m p o n e n t was i d e n t i f i e d in c o n c e n t r a t e d m e d i a from 6 BS f i b r o b l a s t strains w h i c h induces c h r o m o s o m a l a b e r r a t i o n s in p h y t o h e m a g g l u t i n i n s t i m u l a t e d lymp h o c y t e s from normal donors. The a c t i v i t y of this c l a s t o g e n i c factor could be dec r e a s e d s u b s t a n t i a l l y by the a d d i t i o n of b o v i n e CU-Zn s u p e r o x i d e dismutase. The c l a s t o g e n i c factor also induced sister c h r o m a t i d e x c h a n g e s in normal lymphocytes, albeit w i t h low efficiency. In a n a l o g y to c o l l a g e n d i s e a s e s such as s y s t e m i c lupus e r y t h m a t o s u s , Crohn's d i s e a s e and p e r i a r t e r i t i s n o d o s a it is s p e c u l a t e d that BS f i b r o b l a s t s are d e f i c i e n t in the d e t o x i f i c a t i o n of active o x y g e n species (05 , OH'). On the basis of our p h o t o b i o l o g i c a l and c y t o g e n e t i c results a new h y p o t h e s i s for the p a t h o l o g y of BS will be discussed. (Supported by the F o n d s n a t i o n a l suisse de la r e c h e r c h e scientifique) PROGNOSTIC Roland W.
FACTORS Sonntag,
IN THE T R E A T M E N T Institute
OF M E T A S T A T I C
for M e d i c a l
Oncology,
GERM CELL C A N C E R University
of Bern,
Switzerland
91 p a t i e n t s w i t h m e t a s t a t i c germ cell c a n c e r were c l a s s i f i e d as having either advanced d i s e a s e (AD) or m i n i m a l d i s e a s e (MD). C r i t e r i a for staging are given. All patients were t r e a t e d s i m i l a r l y a c c o r d i n g to p r o t o c o l O1/76 of the Swiss G r o u p for C l i n i c a l C a n c e r R e s e a r c h (SAKK). C o m p l e t e r e m i s s i o n (CR) rates (95 % vs 35 %) and survival (84 % vs 33 %) were s i g n i f i c a n t l y b e t t e r ( p < 0.001) for the MD g r o u p than for the AD group. D i s e a s e sites did not i n f l u e n c e the t h e r a p y results. P a t i e n t s with MD had higher CR rates (p = 0.003 to 0.009) than AD p a t i e n t s at all sites (lung, a b d o m e n or c o m b i n e d sites). The i n c i d e n c e of MD was higher in p a t i e n t s w i t h embryonal cell c a r c i n o m a than in all other h i s t o l o g y g r o u p s (54 % vs 3 1 % , p = 0.026). This was r e f l e c t e d in a higher CR rate (77 %) for the e m b r y o n a l cell c a r c i n o m a patients than in the other h i s t o l o g i c a l g r o u p s (46 %, p = 0.003). The CR rate for patients w i t h MD was the same in all h i s t o l o g y groups (89 % to 100 %). In AD the 50 % CR rate for e m b r y o n a l cell c a r c i n o m a p a t i e n t s v e r s u s the 28 % rate for o t h e r p a t i e n t s showed a d e f i n i t e trend but did not reach s t a t i s t i c a l significance. The d o s a g e s of c h e m o t h e r a p y g i v e n had no a p p a r e n t e f f e c t upon CR rates. Relaps rates were s i g n i f i c a n t l y a f f e c t e d by d o s a g e reduction, and in AD patients, by the number of chemot h e r a p y cycles given. LONG T E R M S U R V I V O R S
WITH
S M A L L CELL
CARCINOMA
OF THE LUNG
R. Joss, P. Alberto, D i v i s i o n s of M e d i c a l Oncology, Inselspital, Berne, and HSpital Cantonal, G e n e v a for the Swiss G r o u p for C l i n i c a l Cancer R e s e a r c h (SAKK) Several authors have r e c e n t l y r e p o r t e d long term, d i s e a s e - f r e e survival in p a t i e n t s with small cell c a r c i n o m a of the lung (SCCL) after a g g r e s s i v e initial treatment. In an attempt to i d e n t i f y long term, p o t e n t i a l l y cured survivors with SCCL in S w i t z e r land a q u e s t i o n n a i r e was sent to all m e d i c a l o n c o l o g y centers t h r o u g h o u t the country. 14 p a t i e n t s with SCCL were r e p o r t e d a c h i e v i n g d i s e a s e - f r e e survival for over 24 m o n t h s after initial therapy. M e d i a n age was 61 (39 - 80), m e d i a n p e r f o r m a n c e status 0 (0 - 2), 2 were females and 12 were males. 13 p a t i e n t s were c l a s s i f i e d as limited
Abstracts o[ the Meeting o[ the Swiss Society/or Oncolo~
939
disease, 1 p a t i e n t s had e x t e n s i v e d i s e a s e with b o n e ~ metastases. 2 of the 13 patients w i t h limited d i s e a s e had a small p e r i p h e r a l n o d u l e d e t e c t e d on routine chest films. Only 2 p a t i e n t s had w e i g h t loss in the 6 m o n t h s p r i o r to the diagnosis. 5 p a t i e n t s were treated w i t h local t h e r a p y alone (surgery 3, r a d i o t h e r a p y i, surgery plus radiotherapy i), 9 p a t i e n t s r e c e i v e d s y s t e m i c t r e a t m e n t (chemotherapy 5, c h e m o t h e r a p y plus r a d i o t h e r a p y 4). M e d i a n d u r a t i o n of c y t o s t a t i c t r e a t m e n t was 17 m o n t h s (3 - 39) w i t h 3 of 9 p a t i e n t s r e c e i v i n g c h e m o t h e r a p y for less than 6 months. Chest r a d i o t h e r a p y doses v a r i e d from 2000 rads over 1 week to 7000 rads over 7 weeks. Only 1 p a t i e n t r e c e i v e d p r o p h y l a c t i c cranial irradiation. 3 p a t i e n t s r e l a p s e d after initial treatm e n t (surgery I, r a d i o t h e r a p y i, r a d i o t h e r a p y plus c h e m o t h e r a p y i) after 27, 34 and 54 months. M e d i a n survival is 56+ m o n t h s (27+ - 81+). P a t i e n t s have been off treatment for a m e d i a n of 41+ m o n t h s (2+ - 75+). We c o n c l u d e that long term, d i s e a s e - f r e e survival can be a c h i e v e d in p a t i e n t s w i t h limited d i s e a s e SCCL even w i t h r e l a t i v e l y short inital treatment. PHASE I C L I N I C A L T R I A L AND P H A R M A C O K I N E T I C STUDY OF 5 ' - D E O X Y - 5 - F L U O R O U R I D I N E R. Abele, JP. Cano,
P. Alberto, R.J. Seematter, R. Heintz, G. Germano, W. Weber, JP. Obrecht, D i v i s i o n of Oncology, H~pital C a n t o n a l U n i v e r s i t a i r e , CH-1211 Gen~ve
5 ' - d e o x y - 5 - f l u o r o u r i d i n e (DFUR) is a new f l u o r o u r i d i n e analog lacking a 5'-hydroxyl g r o u p in the c h e m i c a l s t r u c t u r e of its p e n t o s e ring. Under the action of uridine p h o s p h o r y l a s e , 5 - f l u o r o u r a c i l (FU) is released. D F U R is thus acting p r o b a b l y as a prodrug. D F U R is active against several e x p e r i m e n t a l animal tumors. Further, it has a higher t h e r a p e u t i c index c o m p a r e d to FU in animals. DFUR has been a d m i n i s t e r e d as a rapid i n t r a v e n o u s bolus i n j e c t i o n d a i l y x 5 and r e p e a t e d every 3 weeks. 21 patients were t r e a t e d at various dose levels. The m a j o r i t y of p a t i e n t s were non pretreated and had g a s t r o - i n t e s t i n a l a d e n o c a r c i n o m a or non small cell lung cancer. 2 courses of DFUR or m o r e w e r e a d m i n i s t e r e d to 15 patients. A m i n i m u m of 4 p a t i e n t s were entered at each dose level. Doses were e s c a l a t e d from 3 O O - 3 0 0 0 m g / m 2 / d a y . Intrap a t i e n t dose e s c a l a t i o n was not done. No s i g n i f i c a n t l e u c o p e n i a was detected, but o c c a s i o n a l t h r o m b o p e n i a was seen at each dose level. There was no e v i d e n c e of cumulative m y e l o t o x i c i t y on s u b s e q u e n t courses of DFUR. A n o r e x i a and nausea was seen in 4 patients, w i t h o u t drug induced vomiting. 2 p a t i e n t s had d i s c r e t e and 1 patient severe d i f f u s e stomatitis. P r e c o r d i a l pain w i t h r e v e r s i b l e e l e c t r o c a r d i o g r a p h i c changes or t r a n s i e n t cardiac e n z y m a t i c e l e v a t i o n s was o b s e r v e d in 2 patients. The m a x i m a l t o l e r a t e d dose has not yet been reached. P h a r m a c o k i n e t i c data are a v a i l a b l e for 5 p a t i e n t s after a d m i n i s t r a t i o n of i000 to 2100 mg of DFUR. The u n c h a n g e d drug e l i m i n a t i o n has a m e a n t~2 e of 5.6 min. (range 3 - 8.3 min.) and a m e a n t~2 8 of 20.5 min. (range 14.5 to 30.8 min.). D i s t r i b u t i o n volume 8 is between 27 and 50 liters. Total p l a s m a t i c c l e a r a n c e lies between 0.8 and 1.8 liter/min. We c o n c l u d e that D F U R can be given at higher doses than FU and that its clinical t o l e r a n c e is good, at the dose levels tested. PHASE I T R I A L OF ~ 1 , 3 , 5 - T R I G L Y C I D Y L - S - T R I A Z E N E T R I O N E
(TGT, NSC-296934)
F. Cavalli, S. Kaplan, M. V a r i n i and R. Joss, D i v i s i o n of Oncology, O s p e d a l e San Giovanni, Bellinzona, S w i t z e r l a n d and Institute for M e d i c a l Oncology, Inselspital Berne, S w i t z e r l a n d TGT is a new a n t i c a n c e r agent that was i d e n t i f i e d by r a n d o m screening. It is a triepoxide d e r i v a t i v e w i t h a l k y l a t i n g properties. The drug is active against a wide v a r i e t y of e x p e r i m e n t a l m u r i n e tumors i n c l u d i n g P388 leukemia r e s i s t a n t to cyclophosphamide, i n t r a c e r e b r a l l y i m p l a n t e d LI210 leukemia and e p e n d y m o b l a s t o m a . This ongoing phase I trial was d e s i g n e d to d e t e r m i n e the m a x i m u m t o l e r a t e d dose (MTD) in adult patient with solid tumors using d a i l y t r e a t m e n t s for 5 c o n s e c u t i v e days. The therapy course is r e p e a t e d every 3 weeks. The drug is given iv. bolus. A total of 33 p a t i e n t s have been e n t e r e d in the trial w i t h a m e d i a n age of 59 (38 - 73) and a m e d i a n p e r f o r m a n c e status of 70 (40-90). All have r e c e i v e d prior c h e m o t h e r a p y and had r e c o v e r e d from prior d r u g - i n d u c e d side-effects. P a t i e n t s had following tumors : 8 colo-rectal, 8 lung, 6 breast, 4 melanoma, 2 upper-GI, 2 headneck, 2 u n k n o w n origin, 1 sarcoma. The trial was i n i t i a t e d at a starting dose of 12 m g / m 2 / d c o r r e s p o n ding to i/i0 LDI0 in the mouse. To date, doses have been e s c a l a t e d up to 600 m g / m 2 / d (= level 13). Dose levels have been o c c a s i o n a l l y i n c r e a s e d w i t h i n the same p a t i e n t s when no t o x i c i t y was e n c o u n t e r e d in p r e v i o u s courses. So far not c l e a r l y d o s e - r e l a ted toxic effects have been observed. Toxic m a n i f e s t a t i o n s include n a u s e a - v o m i t i n g (6 patients), p h l e b i t i s (7 patients) and e r r a t i c m y e l o - s u p p r e s s i o n (5 patients). So far a n t i t u m o r a c t i v i t y has not been detected. Since the MTD has not yet been c l e a r l y reached, the trial as well as p h a r m a c o k i n e t i c studies are ongoing.