Immunostimulation before chemotherapy in cancer treatment

Pharmacological Research Communicatiohs, VoL 9, No. 8, 1977 689 I M M U N O S T I M U L A T I O N B E F O R E C H E M O T H E R A P Y IN CANCER T R E A T M E N T L.Frati, A. B a r z i , M . C . C a p r i n o , E. Menconi and E. B o n m a s s a r Institute of P h a r m a c o l o g y , S c h o o l of M e d i c i n e , U n i v e r s i t y of P e r u g i a and Ope r a t i o n s Office of the Italian C o o p e r a t i v e Oncology G r o u p , l='erugia, Italy Received 18 July 1977 S UM MARY S y n e r g i s m between c h e m o t h e r a p y and i m m u n e r e s p o n s e s h a s been e v i d e n c e d in a n i m a l s ' a n d mah.~ 'In a d d i t i o n , n o n - s p e c i f i c i m m u n o s t i m u l a t i o n s e e m s to i n c r e a s e the efficiency of a n t i c a n c e r c h e m o t h e r a p y . Up to now m o s t of the clinica~l t r i a l s have beeh c o n d u c t e d a p p l y i n g i m m u n o a d j u v a n t s afte_._r initial chemothdr,ap~utic t r e a t m e n t . S i n c e p r e s e n s i t i z e d i m m u n o c o m p e t e n t c e l l s t are more r a d i b - rand c h e m o - r e s i s t a n t than n o n - s t i m u l a t e d l y m p h o c y t e s , a tr]:al of lm,m,unos~,zmulation,P , before chemotherapy is based on rational experi/ ! m e nt t M b a s i s . S u c h pi~ogram, a c t i v a t e d in h u m a n s d u r i n g 1976, is c o n d u c t e d t a c c o r d i n ~ to the following g e n e r a l s c h e m e : 1 ;.' C}~emoth'erapy a l o n e 2.' Clahmo'thera,py followed by BCG and r e c y c l e 3., Ch+motheralSy p r e c e d e d and followed by BCG and r e c y c l e . p r o t o c o l s for b r e a s t , lung, . c o l o r e c t a l and o v a r i a n c a n c e r t r e a t m e n t a r e described. • t ' I i i ! INTRODUCTION L a r g e e x p e r i m e n t a l e v i d e n c e is p r e s e n t l y a v a i l a b l e indicating that the a n t i t u m o r a c t i v i t y of a n u m b e r of d r u g s is m o r e e f f e c t i v e when e l i c i t e d in c o r n bination with i m m u n e r e s p o n s e s of the host a g a i n s t t u m o r a l l o a n t i 9 e n s or t u m o r - a s s o c i a t e d t r a n s p l a n t a t i o n a n t i g e n s (TATA), than in a b s e n c e of h i s t o incompatibility. S y n e r g i s t i c e f f e c t s between d r u g s and t r a n s p l a n t a t i o n m u n i t y w e r e d e t e c t e d in m i c e (Glynn et a l . im- ,1963; B o n m a s s a r et a l . , 1968; The follov~ing a b b r e v i a t i o n s a r e used: ICOG, Italian C o o p e r a t i v e Oncology G r o u p - T I C C , T u m o r I m m u n o l o g y C h e m o t h e r a p y C e n t e r of ICOG - ADM, A d r i a m y c i n - B C G , B a c i l l u s C a l m e t t e Gufirin - B l e o , B l e o m y c i n - C C N U , 1--(2-chl0roethyl)-3cyclohexyl-l-nitros0-urea • Cy, Cyclophosphamide 5 : F ' U ; , 5 - f l u o r o U r a c i l - H e x a , H e x a m e t h y l m e l a m i n e - MTX, M e t h o t r e x a t e M e - C C N U , M e t h y l : C C N U - NM, N i t r o g e n M u s t a r d - L - P A M , P h e n y l a l a n i n e Mustard - VCR, Vincristine L . F . i s P r o f e s s o r of G e n e r a l P a t h o l o g y , S c h o o l of M e d i c i n e , U n i v e r s i t y of Rome, Italy. T h i s work h a s been s u p p o r t e d in p a r t by a g r a n t of the Italian R e s e a r c h C o u n cil (CNR), Rome Pharmacological Research Communications, Vol. 9, No. 8, 1977 690 Mihich,, 1969) and raLs'(Sato, 196,79 with spontaneous (Martin et al, 1962)or transplanted I(Bonm,l~ssar et al, 1970,~-971; Nicolin et al, 1972; Albright et al, I " =1 f ~l . . , 1975) t u m o r s . Clj'ni~cal, daea a r e a l s o available, showing sicnilar effects in ,' 3f , : I I I: '!' : man (Mg'thg et al, 1.96'4; ~liff0rd e(:ol, t,967).. "Therefore it is r'easonable to i ~ f I ' a s s u m e that ~any 'procedure which would i n c r e a s e non-specifically the irnmu!f. t , ! t j " • ne r e s p o n s e aga,in's~ transplantation antigens, would improve also the efficaI'. l ; " I I, 't cy o~ antl--'neoplastic c h e m o t h e r a p y in the p r e s e n c e of.even minimal host[ -tumor,incompatibil'ity (~lBonmassar et al, 1970). Non-specific immunostimu-i II ; " " ' t f lation'hhs been r'epeatedlylapp'l[ed in animal model s y s t e m s , with e n c o u r a g - ing r e s u l t s (Old eL al, 1959; Wepsich eL al, 1970; Zbar et al, 1973). In clinical t r i a l s the use of non-specific immunostimulants is continuously growiro and ) i i'na n ' u m b e r o f ' c a s e s s e e m s to provide beneficial effects (Klein, 1973; I s r a el, 1973; Harsh et ;~1, 1974; C r i s p e n , 1974-; Bluming,1975; Gutterman et al, . ,t ,r '' £976). Neverth.eless, a n u m b e r at~ tr~ea~ment sche'dules Used for clinical a p plication of ,agents Capable of stimulating immune r e s p o n s e s , d o e s not seem t o have s a t i s f a c t o r y rational b a s i s . . T h e c l a s s i c a l design includes c.ytoreductive c h e m o t h e r a p y followed by immune stimulation with non-specific agents ( e . g . BCG, C. p a r v u m , etc.)(lBluming,1975). E x p e r i m e n t a l l y drug-induced i m m u n o d e p r e s s i o n in"presence of even limited antigenic stimuli, leads to spa~t' ." cific u n r e s p o n s i v e n e s s o17.t o i e r a n c e (Aisenberg)1967), wkich is not readily r e v e r s e d . b y immunosti.mulatio'n. On the othhr hand, the specific r e s p o n s i v e ness'"of,'strong!y p r e s e n s i t i z e d hosts is highly r e s i s t a n t to the d e p r e s s i o n induped .by antitumor"agents or X - r a y s (Aisenberg, 1967; IBonmassar et a1,1970). F o r exampte complete c u r e is achieved in mice bearing allogeneic t u m o r s , .~ incompatible for weak histoeompatibility loci, and treated with n i t r o s o u r e a s (IBonmassar eL al, 1971).In this case the antiLumor immune r e s p o n s e is e l i c i ted before application of the c h e m o t h e r a p y . T h e r e f o r e a m o r e rational a p proa&'h for the al3"plicati0n of i m m u n o s t i m u l a n t s would lead to a t r e a t m e n t schedule designing.immunostimulation before c h e m o t h e r a p y , whenever a p plicable to the p a t i e n t ' s conditions, r a t h e r than a f t e r drug t r e a t m e n t (Houchens et al, 1974; Barzi et al, 1977). The choice of drugs and t r e a t m e n t schedule is d e t e r m i n e d by the effectiveness of t h e a g e n t s used for each tumor ((iccording to the data a v a i l a b l e from Pharmacological Research Commun/catior}s, Vo/. 9, No. 8, 1977 691 v a r i o u s e x p e r i m e n t a l m o d e l s ) . When the e f f e c t i v e n e s s of a s e r i e s of d r u g s u n d e r i n v e s t i g a t i o n is c o m p a r a b l e , the r e g i m e n p r o v i d i n g the h i g h e s t effi- c i e n c y in c o m b i n a t i o n with a n t i - t u m o r i m m u n e r e s p o n s e s will be s e l e c t e d . F o r e x a m p l e ADM w a s found to be e q u a l l y a s a c t i v e a s MTX a g a i n s t l y m p h o ma c e l l s i n o c u l a t e d into s y n g e n e i c m i c e , w h e r e a s the a n t i b i o t i c was m o r e a c t i v e t h a n the a n t i m e t a b o l i t e a g a i n s t the s a m e t u m o r in a l l o g e n e i c h o s t s (Riccardi C., unpublished observations). On the b a s e s of a l l t h e s e c o n s i d e r a t i o n s an e x p e r i m e n t a l d e s i g n of i m m u n o - therapy~ to c o n v e n t i o n a l t h e r a p y h a s been p r o p o s e d in o u r l a b o r a t o r y for h u m a n application-. D e t a i l s of s u c h p r o g r a m a r e r e p o r t e d in the p r e s e n t paper. EXPERIMENTAL P R O C E D URE 1. G e n e r a l d e s i g n of the s t u d y T h e c a n c e r p a t i e n t s a r e s t r a t i f i e d , r a n d o m i z e d and d i v i d e d into t h r e e g r o u p s of t r e a t m e n t a s f o l l o w s : .Group 1 Chemotherapy alone ( r e g i m e n A) recy2le G r o u p _2 Chemotherapy followed by i m m u n o t h e r a p y (regimen, A + BCG) recycle (alternate -:-- ~,. i " r . I regimen As g O r e Group 3 Immunotherapy followed by c h e m o t h e r a p y ( BCG + , r e g i m e n A ) B C G and c h e m o t h e r a p y ) s | s i o n ! B alternate BCG and regimen immunostimulating agent lyophilized BCG(Lamourex B et a l , 1976) s u p p l i - ed by the P a s t e u r I n s t i t u t e , P a r i s , is u s e d . BCG (4x108 v i a b l e o r g a n i s m / d o s e ) i s a d m i n i s t e r e d by m u l t i p l e p u n c t u r e gun. W h e n e v e r p o s s i b l e an i n t e r v a l of at l e a s t 5 days f r o m B C G a d m i n i s t r a t i o n a n d d r u g t r e a t m e n t i s a d o p t e d . Breast cancer, lung c a n c e r , c o l o r e c t a l c a n c e r and o v a r i a n c a n c e r a r e i n - c l u d e d in the e x p e r i m e n t a l p l a n . 2. S t a g i n g and f o l l o w - u p S t a g i n g is s t a t e d f o r e a c h t u m o r and a s e r i e s of t e s t s a r e p e r f o r m e d b e f o r e t h e r a p y and r e p e a t e d at r e g u l a r i n t e r v a l s in o r d e r to e v a l u a t e the i m m u n e s t a t u s of the p a t i e n t s . S k i n t e s t s , B - and T - c e l l s m o n i t o r i n g p r o c e d u r e s (Ig b e a r i n g B-cell lymphocytes) counting, E-rosettes technique, r e s p o n s e to P H A a r e i n t r o d u c e d to follow the r e l a t i o n s h i p responsiveness, p e r f o r m a n c e and s u r v i v a l t i m e a s a between of immune f u n c t i o n of the t h r e e Pharmacologica/ Research Communications, Vol. 9, No. 8, 1977 692 arm protocols. Dose m o d i f i c a t i o n s w e r e i n t r o d u c e d f o l l o w i n g t o x i c i t i e s l i s t e d below: a . m y e l o s u p p r e s s i o n (all d r u g s ) b. l i v e r and k i d n e y (MTX) c. h e a r t (ADM) d. e a r l y s i g n s of lung f i b r o s i s (Bleo) e. p a r e s t h e s i a s o r c o n s t i p a t i o n (VCR) f. c y s t i t i s (Cy) Minor modifications are introduced for toxicity in o t h e r o r g a n s . 3. S c h e d u l e s I. Breast cancer a . Adjuvant c h e m o t h e r a p y in h i g h - r i s k p a t i e n t s ( S t a g e T 1 - T3a) f o l l o w i n g radical surgery In the c l i n i c a l t r i a l , i n i t i a t e d in u s e d ( F i s h e r et a l . , donna et a l . , and 1976, 1975) . L a t e r , Bonadonnats 1976) w a s a d o p t e d a n d t'OMFWW r e g i m e n 3-arm protocol (Bona- T I C C 24, TIOO Mastectomy I I TICC TICC 24 21 --34 ( day 0 ) 25 TICC 26 B C G 5, 10, 15 Cy 21-'34 M T X 21, 28 5 - F U 21, 28 B C G 37, 41, 45 5 - F U 21, 28 Cy 21 ~ 34 M T X 21, 28 5 - F U 21, 28 B C G 37, 41, 45 2 weeks interval r e c y c l e x 12 c y c l e s r e c y c l e on day 49 T I C C 25 x 12 c y c l e s MTX 25 T I C C 26 w a s a c t i v a t e d . Radical Cy L-PAM adjuvant chemotherapy was 21, 28 C y , 100 m g / m 2 po b. Adjuvant MTX, 40 m s / m 2 iv - 5-FU, 600 m s / m 2 c h e m o t h e r a p y f o r S t a g e T3b - T 4 The s e q u e n c e of t r e a t m e n t s w a s a s f o l l o w s : a . Induction p h a s e (ADM + VCR w i t h / w i t h o u t BCG) b. R e g i o n a l R a d i o t h e r a p y ( 6 , 0 0 0 r a d s within 60 days) c. Maintenance P h a s e ( C M F regimen ) iv Pharmacological Research Communications, Vol. 9, No. 8, 1977 TICC 4 693 TICC 5 .Induction ADM 0, 21, 42, 63 VCR 0 , 7 , 2 1 , 2 9 , 4 2 , 49, 63, 70 15 d interval from last VCR Radiothera~py 85 -~i45 I Maintenance (day 170-0) I Cy 0"13; MTX 0,7; 5-1=13 0 , 7 2 weeks interval x8 c y c l e s TICC 6 Induction A D M 0, 21, 42, 63 V C R 0, 7, 21,'29, 42, 49, 63; 70 B O G 25,32,37,46, 53,5~, 74,80 Induction BOG 0, 5, i0 A D M 15,36,57,78 VCR 15, 22,36,43, 57,64, 78,85 B O O 61,68,73,89,95 Radiotherapy 85 d,145 \ BOG 150,157, 164 Radiotherapy i00-'~160 / / BCG 165, 172, 179 Maintenance (d 170 TICC 5 185 TICC 6-=0) I Cy0--13; MTX 0, 7; 5-1=11 0, 7; BCG 17, 22 Recycle on day 27 x 8 c y c l e s ADM 75 m g / m 2 iv (60 m g / m 2) - Cy 100 m g / m 2 pc - 5-FLI 600 m g / m 2 iv (400 m g / m 2) - MTX 40 m g / m 2 iv (30 m s / m 2) - VCR 1.4 m g / m 2 iv In p a r e n t h e s i s r e d u c e d d o s e s for patients older than 60 y e a r s c. Advanced C a r c i n o m a ADM, VCR, Cy, MTX, 5 - F U and BOG a r e used at the s a m e doses s e l e c t e d for TICC 4. In patients older than 65 y e a r s o r with multiple bone m e t a s t a s i s , MTX is reduced to 30 m g / m 2 and 5 - F U to 400 m g / m 2. TICC 7 TICC 8 Cycle I ADM O, 21 VCR 0, 7,121, 28 TICC 9 Cycle I ADM 0, 21 VCR 0, 7, 21, 28 BCG 12, 17",33, 38 , I Cycle II (day 42 = = day 0). Cycle I BCG0, 5 ADM 10, 31 VCR 10,17, 31, 38 - BCG 43, 48 Cycle II (day 42 for TICQ 8 9 = day0) Oy 0"¢13; 27-,,'40 MTX 0, 7, 27, 34 5-FLI 0, 7, 27, 34 / nd day 52 for TICC Cy 0 -" 13, 27 "-'40 MTX 0, 7, 27, 34 5-FU 0, 7, 27, 34 BCG 16, 20, 24, 43, 47, 51 Recycle baIck f r o m Cycle I on day 54 (of Cycle II) Recycle back from Cycle I on day 54 of Cycle If, and adopt TICC 8 for both schedules I_I. Lun.q cancer a. Epidermoid carcinoma, Stage I and If. Immunostimulation alone was designed for such patients after radical surgery (TICC I0: no further therapy - TICC Ii: B C G weekly × 4, q 2 months × 2 years). Pharmacological Research Communications, Vo/. 9, No. 8, 1977 694 b. I n o p e r a b l e c a r c i n o m a SLage II (except s m a l l c e l l c a r c i n o m a ) "l Lung r a d i o t h e r a p y f r o m 6OCo s o u r c e , w e e k s (3 t i m e s / w e e k , 4,500 Rads, ±s d e l i v e r e d within 5 a p p r o x i m a t e l y 900 R a d s / w e e k ) . R a d i o t h e r a p y is a s s o c i a t e d with Cy + VCR with o r without BCG g i v e n b e f o r e o r a f t e r r a d i o t h e r a p y , f o l l o w e d by m o d i f i e d LivingstonWs BACON (1974) using a r e g i m e n of A D M , V C R a n d C C N U . NM and B l e o a p e h e r e o m i t t e d s i n c e e x c e e d i n g h i g h t o k i c i t y ; i s e x p e c t e d , due to the py ( S k a r i n et a l . , preceeding radiothera- 1 9 7 5 ) . Upon r e l a p s e or p r o g r e s s i o n , In the c a s e of b r a i n m e t a s t a s i s , to w h o l e b r a i n in 2-3 w e e k s . by MTX is a d m i n i s t e r e d . 3,000 Rads through f-irradiation a r e given Upon f u r t h e r r e l a p s e a l l p a t i e n t s a r e t r e a t e d with H e x a . T I C C 12 Induction R a d i o t h e r a p y 0--~ 35 C y 0, 28 VCR 0, 7, 28, 35 18 d a y s i n t e r v a l I C o n s o l i d a t i o n ( day 53 = day 0) ADM q . 4 wks V C R q . 2 wks (day 1 a f t e r ADM) C C N U q . 8 wks Induction R a d i o t h e r a p y 0 -~35 Cy O, 28 VCR097928~35 BCG 39, 4 3 ~ 4 8 Induction BCG 0, 5, 10 R a d i o t h e r a p y 15 - - 5 0 Cy 15, 43 VCR~15, 22, 43, 50 18 d a y s i n t e r v a l Progressi~on or relapse MTX q . 3 weeks I T I C C 14 C o n s q l i d a t i o n (day 53 f o r T I C C 13 a n d day P68 f o r T I C C 14 = day 0) ADM q . 4 w k s - V C R q . 4 w k s ( d a y 1 a f t e r A D M ) - C C N U q . 8 wks BCG w e e k l y x 2 b e g i n n i n g on d a y 7 a f t e r /kDM, q . 4 wks p r o g r e s s! i o n o r . r e l a p s e Progression T I C C 13 M T X q . 3 wks - BCG day 7, 14 a f t e r M T X , q . 3 wks 1 or relapse Progression Hexa d a i l y or relapse Hexa d a i l y - BCG w e e k l y x 4 , q . 6 wks Cy 1 . 2 g / m 2 iv - VCR 1.5 m g / m 2 d u r i n g lung r a d i o t h e r a p y and 1 . 4 m g / m 2 a f t e r lung r a d i o t h e r a p y - ADM 4 0 r a g / m 2 - C C N U 65 m g / m 2 - M T X 40 m g / m 2 iv - Hexa 150 m g / m 2 c . A d v a n c e d c a r c i n o m a ( S t a g e Ill), e x c e p t s m a l l cell When the t u m o r is e x t e n d e d to c o n t r o l a t e r a l s u p r a c l a v i c u l a r the o p p o s i t e lung a n d / o r adopted. Such regimen with m e t a s t a s e s , is region, or a r e d u c e d BACON p r o t o c o l well t o l e r a t e d by p a t i e n t s . to is Pharmacological Research Communications," VoL 9, No. 8, 1977 TICC 15 TICC 17 TICC 16 CCNU, ADM, NM, VCR, B l e o a s in CCNU q . 8 wks ADM q . 4 wks NM q . 4 wks VCR and Bleo day 1 and 8 a f t e r ADM Remission / Recycle 695 B C G 0, 4, 8 C C N U , ADM, NM, VCR TIcc. Bleo a s in TICC 15, b e g i n n i n g on day 12, then BCG w e e k l y , b e g i n n i n g on day 18 a f t e r the f i r s t ADM i n j e c t i o n B C G day 6, i0,14 , 18 and l a t e r once a week Romiss on/ / Progression \ MTX q,.3 wks Progression R e c y c l e a s in TICO 16 M T X q . 3 wks a f l e r MTX Progression or relapse BCG 7 , 1 4 Progression or relapse / Hex~ d a i l y Hexa d a i l y J BCG w e e k l y CCNU 50 m g / m 2 po - ADM 30 r a g / m 2 iv - NM 6.5 m g / m 2 iv - VCR l m g / r n 2 iv - Bleo 20 m g / m 2 iv - MTX 40 m g / m 2 iv - Hexa 150 m g / m 2 / d a y po d. S m a l l c e l l c a r c i n o m a All small cell c a r c i n o m a s w e r e c o n s i d e r e d a generalflzed disease and t r e a t e d with CCNU, C y , f o l l o w e d by ADM, VCR. B l e o w a s found not to be a c t i v e in s m a l l cell c a r c i n o m a and h e n c e not i n c l u d e d . TICC 27 TICC 28 TICC 29 CCNU0 Cy 0, 21 A D M 42, 63 V C R 42, 63 CCNU 0- Cy0,21 A D M 42, 63 V C R 42, 63 B C G 28,32,36,49, 50, 70.~77 Recycle on day 84 Recycle on d a y 8 4 I Progression B C G 0, 3, 6 - C C N U . J 0 Cy I0, 3 1 - A D M 52, 73 V C R 52, 73 B C G 59, 66, 80, 87 / / \ or relapse Progression or relapse MTX MTIX q.3 wks Hexa d a i l y q.3 wks - B C G 7, 14 .I [ Progression or relapse R e c y c l e on day 84 f r o m CCNU Progresslon or relapse Hexa d a i l y - BCG w e e k l y x 4, q . 4 wks CCNU 70 m g / m 2 po - C y 700 m g / m 2 iv - ADM 60 m g / m 2 iv - VCR 1 . 2 r a g / / m 2 i v - M T X 4 0 m g / m 2 i v - Hexa 1 5 0 m g / m 2 p o , III. C o l o r e c t a l ,,. , . . . = cancer Lesions of type B and C following Dukes classification (Carter, 1976) were subjected to radical surgery. Because type B and C lesions have a rather poor prognosis for 5-years sur- vival (Thomas, 1969), attempts for prophylactic chemotherapy or immuno- Pharmacological Research Communications, Vol. 9, No. 8, 1977 696 c h e m o t h e r a p y s e e m to be justified. S i n c e u n t r e a t e d c o n t r o l s a r e u t i l i z e d , no d i f f e r e n t i a l i m m u n o c h e m o t h e r a p y p r o t o c o l s a r e adopted. I m m u n o c h e m o t h e r a p y is p e r f o r m e d on the b a s i s of b e f o r e - a f t e r - c h e m o t h e r a p y i m m u n o s t i m u lation. M o d e r a t e d o s e s of Me-CCNU a r e a s s o c i a t e d with 5 - F U ( C a r t e r , 1976; M o e r t e l et a l . , 1975). ] R a d i c' ' !a l - TICC 18 (day surgery TICC 20 TICC 19 no f u r t h e r treatment M e - C C N U q . 6 wks 5 - F U daily x 5 q.6 wks (begin on day 25 after surgery) MeCCNU 120 m g / m 2 p o 0 ) BCG 10, 15, 20 - M e - C C N U q. 6 wks f r o m day 25 5-FU daily x 5 q.6 wks f r o m day 25 - BCG weekly x 4 q . 6 wks f r o m day 35 - 5 - F U 9 m g / K g iv b. R e s i d u a l d i s e a s e a f t e r s u r g e r y o r advanced c a r c i n o m a (Dukes D) S i n c e c h e m o t h e r a p e u t i c t r e a t m e n t is m a n d a t o r y , the protocol p r e v i o u s l y r e p o r t e d (TICC 19) is adopted, but at h i g h e r d o s e s (Moertel et a l . , 1975). In addition differential s c h e d u l e s TICC 21 TICC 22 M e C C N U q.6 wks 5 - F U daily x 5 q. 6 wks MeCCNU, of BCG a d m i n i s t r a t i o n a r e u s e d . TICC 23 MeCCNU q . 6 wks 5 - F U daily x 5 q . 6 wks BCG day 9, 14, 19 a f t e r MeCCNU, then weekly f r o m day 24 B O G 0, 4, 8 M e C C N U q. 6 wks from day l2 5 - F U daily x 5 q.6 wks from day 12 - B O G weekly from day 24 after M e C C N U treatment 175 m g / m 2 pc - 5-1:'U, 10 m g / K g iv IV. O v a r i a n cancer In stages I and II adjuvant therapy with a single alkylating agent (L-PAM) is widely used; 25 ~ dose reduction is employed if the patient received pelvic radiotherapy in the previous 6 months. of Hexa, Oy, A D M In Stages Ill and IV a combination and 5 - F U is adopted. A D M , a very active drug in ova- Plan cancer treatment (Slum and Carter, 1974; F'vei et al., 1974; Greenspan 1975}, was introduced in the protocol together with Cy and 5-FU instead of MTX. The H e x a - C y - M T X - 5 F U schedule assessed by Young and DeVita (1976) is u s e d for c r o s s o v e r in c a s e of f a i l u r e o r p r o g r e s s i o n . The MTX - Pharmacological Research Communications, VoL 9, No. 8, 1977 697 - ADM exchange is justified by lower i m m u n o s u p p r e s s i v e action of the :~,~j~.t:er drug in r e s p e c t to MTX (see introduction). a. Adjuvant c h e m o t h e r a p y in h i g h - r i s k patients (Stage I and II) following surgery Moderate d o s e s of L - P A M and i m m u n o t h e r a p h y with BCG a r e given following the usual t h r e e - a r m design. ,,, S u . . . . TICC 41 L - P A M 0 - 4 , 28-32 r e c y c l e on day 84 x 8 cycles r e g i. r y \ I I TICC 42 L-PAM 0-4 BCG 11, 14, 17, 20, 23 2nd cycle TICC 43 BCG0, 3, 6 L - P A M 10-14 B c c 20, 23 I L-PAM 28-32 ; BOG 38, 45, 52 L - P A M O. 2 m g / K g rest 4 wks; recycle twice the 2nd cycle of TICC 42/43 on day 84 x 8 c y c l e s b. Chemotherapy in patients on Stage Ill-IV (with/w~houtPrevious surgery) An e x p e r i m e n t a l design with H e x a - C y - A D M - 5 F U with/without BCG and c r o s s over to H o x a - C y - M T X - 5 F U ( i n case of progression or when a total dose of 540 m g / m 2 of A D M TICC 44 is reached) is adopted. TICC 45 Hexa 0-~13; Cy 0,7 ; ADM 0, 7; 5-FU 0, 7 day 30=day 0 TICC 46 Hexa 0-.13; Cy 0,7; ADM 0, 7; 5-FU 0,7; BCG 18, 22, 26 BCG 0, 4, 8 Hexa 12-~25; Cy 12, 19; ADM 12, 19; 5-FU 12, 19; BCG 30, 34, 38 \ day 30 -- day 0 --. da~ 42 = day 0 (cross to TICC 45) recycle x 6 cycles recycles x 6 cycles H e x a 150 rag/m2 pc - C y 400 m g / m 2 iv - A D M 30 m g / m 2 iv (to reach a total dose of 540 rag/m2) - 5 - F U 400 rag/m2 iv I I TICC 47 Hexa 0~,13; Cy 0 --~13 MTX 0, 7; 5 - F U 0,7 TICC 48 Hexa 0-.13; C y 0--I 3 NITX 0,7; 5 - F U 0, 7; BCG 1 8 , 2 2 , 26 / I T I C C 49 B C O 0, 4, 8 Hexa 12.25; C y 12-*25 MTX 12,19; 5 - F U 12, 19; BCG 3 0 , 3 4 , 38 day 30 (day 42 for TICC 49) = day 0 day 30=day 0 ! recycle recycle TICC I 48 Hexa 150 m g l m 2 pc - C y 150 rag/m2 p c - M T X 5 - F U 600 m g l m 2 iv II m II i i i 40 rng/m 2 iv - Pharmacological Research Communications, Vo/. 9, No. 8, 1977 698 PRELIMINARY CONSIDERATIONS The efficacy of the t h e r a p y was evaluated in t e r m s of com pl e t e r e m i s s i o n , p a r t i a l r e m i s s i o n 9 no p r o g r e s s i o n , p r o g r e s s i o n and r e l a p s e . P e r f o r m a n c e s and s u r v i v a l t i m e w e r e a l s o c o n s i d e r e d . B e c a u s e the t r i a l was a c t i v a t e d during 1976, c o n c l u s i o n s cannot be made at this m o m e n t . R e s u l t s c o m p a r a b l e to those of l i t e r a t u r e a r e obtained with the p r o p o s e d p r o t o c o l s , but no s i g n i f i c a t i v e i n f o r m a t i o n s were pro- vided for evaluating the BCG t r e a t m e n t before a n d / o r a f t e r c h e m o t h e r a p y r e s p e c t to the c h e m o t h e r a p y alone. The data available f r o m clinical t e s t s in b r e a s t c a n c e r s e e m to s u g g e s t that BCG a d m i n i s t e r e d before c h e m o t h e r a p y i m p r o v e s T - l y m p h o c y t e s r e s p o n s e s to phytohemagglutinin in vitro ( B a r z i et a l . , 1977). 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