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Treatment of inoperable non-small-cell bronchogenic carcinoma with etoposide and cis-platinum
Cancer TreatmentRe~.iew~( 1982 ) 9 (SupplementA ), ! 39- 142
Treatment of inoperable non-small-cell bronchogenic c a r c i n o m a w i t h e t o p o s i d e ~ n d ¢is-platlnm P. S. M i t r o u , * M . F i s c h e r , * I. W e i s s e n f e l s , t V. D i e h l , t (3. G r o p p , ~ A. L i e s e n f e l d , ~ M . S c h m i d t , § W . E. B e r d e l , II U. Finktl a n d M . G r a u b n e r ¶
* Division of Hematology/Oncology, Department of Internal Medicine, University of Frankfurt, t Division of Hematology~Ontology, Department of Internal Medicine, Hannot~er Medical School, Department of HematologylOncology, University of Marburg, § Department of Internal Medicine, Protestant Denominational Hospital, Bremen, [[ Department of Hematology/Oncology, Medical Ctinic, Technical University of Munich, and ¶ University Medical Clinic, Giessen, F.R.G.
T h e effectiveness o f t h e c o m b i n a t i o n o f e t o p o s i d e a n d cis-platinum in i n o p e r a b l e s q u a m o u s cell c a r c i n o m a , a d e n o c a r c i n o m a a n d large-cell b r o n c h o g e n i c c a r c i n o m a w a s s t u d i e d in a m u l t i - c e n t e r P h a s e II s t u d y . E t o p o s i d e w a s a d m i n i s t e r e d in a single d o s e o f 100 m g ] m 2 o n d a y s l, 3 a n d 5. T h e D D P d o s e w a s 90 m g ] m 2 o n the first d a y o f t r e a t m e n t . S u p p l e m e n t a r y fluids w e r e a d m i n i s t e r e d to a v o i d n e p h r o t o x i c side effect~ ( T a b l e 1). So far 32 p a t i e n t s h a v e b e e n e n t e r e d into the s t u d y , a n d in 26 tile results c a n b e e v a l u a t e d ( T a b l e 2). T w o cases c a n n o t b e e v a l u a t e d b e c a u s e t r e a t m e n t w a s d i s c o n t i n u e d after t h e first c o u r s e . I n 2 o t h e r cases, the p e r i o d o f o b s e r v a t i o n is t o o s h o r t for a n e v a l u a t i o n . O n e p a t i e n t d i e d i m m e d i a t e l y after the first c o u r s e o f t r e a t m e n t , a n d 1 p a t i e n t h a d small-cell b r o n c h i a l c a r c i n o m a ( T a b l e
3). T w e n t y - t w o o f the 26 p a t i e n t s w e r e m a l e , a n d the m e a n a g e w a s 6 0 years. T h e g e n e r a l s t a t e o f t h e p a t i e n t s r a t e d 7 0 % ( 6 0 - 9 0 % ) o n the K a r n o f s k y scale. F o r 7 0 % o f t h e p a t i e n t s , t h e Karnofsky i n d e x w a s 60--70~/o w i t h c l e a r s u b j e c t i v e s y m p t o m s . I n t h e m a j o r i t y o f t h e
chemothez'spy Table I. C,ombls~tion wlth e4~oposide and ¢.~splatinum C/J-p~atinum Etoposide Hydration
90 mg/m a day ] 100 mg/m 2 days 1, 3, 5 3 lira 2 day 1 2 l/m 2 day 2
Reprint requests: Dr P, S. Mitrou, Center for Internal Medicine of the University, Department of Hematology and Oncolog),, Theodor Stern Kal 7, I)-6000 Frankfurt]M 70, F.R.O. 0305---7372/82/9A0139 + 04 S03.0010
1982 Academic Press Inc. (Lo~-.4.on) Limited
139
t40
P.S. Table
2.
Patients
NtiTROU entered
ET
AL.
into the study No. ufpatJents
Bremen Gi~s.*,en Frankfurt Hanover Marburg Munich Total
Table
3.
Patients
Tot'dl
Asse*.sable
N o t as.sea,sable
3 1 16 7 3 2 32
1 1 13 6 3 ~ 2t5
2 0 3 I 0 0 6
for whom
no assessment
could
be made
N o t a s s e s s a b l e b e c a u s e of:
No. of patients
T r e a t m e n t d i s c o n t i n u e d a f t e r t h e first c y c l e Too early for evaluation Early death tA'rong diagnosis
2 l t
Table
4.
Characteristics
of the 26 asauesamble patients
Age (years), median Male Female P e r f o r m a n c e s t a t u s ( K a r n o E s k y ) ~/o, m e d i a n Limited disease Extensive disease Histology Squamous-cell carcinoma Adenocarcinoma Large-cell, undifferentiated carcinoma
Table
5.
Side effects of the combination c/s-platlnum
Hemoglobin decline > 2 g% L o w e s t w h i t e cell c o u n t ( × 1 0 S / m m 3 ) , m e d i a n W h i t e c e l l c o u n t <: 2 0 0 0 White cell count < 1000 Bacterial infections Lowest platelet count ( x 103/am3), median Platelets < 100,000 P l a t e l e t a < 50,0(K} C r e a t i n i n e > 1.5 m g / d l Irreversible renal function impairment D e a t h rr.latecl t o t r e a t m e n t
6 0 (42- 6 7 ) 22 4 70 (60~ 90) 7 19 15 5 6
etoposide
and
13/! 6 4.0 3/16 0116
0[16 "226 4/16 2/16
1/26 1/26 1[ 2 6
CHEMOTHERAPY OF INOPERABLE BRONCHOGENIC CARCINOMA
141
T a b l e 6. R e s u l t s o f t r e a t m e n t
Partied rerni~ion No change Progression
No, of patients
(%)
5/26 8[26 13•26
19 3l 30
cases, a d v a n c e d b r o n c h o g e n i c c a r c i n o m a (extensive disease) was present (Table 4). I n 15 cases, squamous-cell c a r c i n o m a was diagnosed histologically, a n d 11 of the 26 patients had an a d e n o c a r c i n o m a or a large-cell, undifferentiated c a r c i n o m a (Table 4). T h e side effects of t h e r a p y were mild (Table 5). Bone m a r r o w toxicity was most in evidence in a decrease in the hemoglobin level. T h i r t e e n of the 16 patients w h o could be fully evaluated for hematological toxicity showed a 2 g % or more decrease in the hemoglobin level. Blood transfusions were necessary in only 1 p~.tient. T h e m e d i a n value of the lowest white cell c o u n t was 4000/#1; a decrease in the white cell count to below 2000/#1 was observed in only 3 of the 16 fully assessable cases (Table 5). T h e effect on thrombocytopoesis was slight. In 2 5 % of the cases the platelet c o u n t fell to below 100,000/#1. In i patient, irreversible kidney failure occurred after the first course o f t r e a t m e n t and the patient died as a consequence. O t h e r side eflkcts were also generally m o d e r a t e , lncomF~ete to complete loss of hair, nausea, vomiting a n d transitory reduction in general well-being were recorded a m o n g all 26 patients. No neurological symptoms were observed. In the 26 patients w h o could be evaluated, 5 partial r, xnissions ( I 9 % ) were achieved, while 13 patients progressed on therapy (Table 6). Thre,: of the 15 cases o f s q u a m o u s - c e l l c a r c i n o m a and 2 of the 6 cases o f large-cell c a r c i n o m a :'esponded to therapy. Remissions lasted 6-11 months, a n d 2 of 5 patients are still in re.,aission 9 and 10 m o n t h s after the beginning of therapy, respectively. Calculation o f the d u r a t i o n of remission from the beginning of t h e r a p y seems justified, since the patients responded as early as the first 2 cycles of treatment. T u m o r s w h i c h were u n c h a n g e d or progressive in the first 2 cycles o f t r e a t m e n t were not r e d u c e d in subsequent cycles. D a t a on survival times for the individual groups are not yet possible because of the relatively short observation time. A l t h o u g h the n u m b e r of patients is small, a s u b g r o u p with unfavorable prognosis has emerged. These w e r e patients for w h o m the leading s y m p t o m was " m a j o r atelectasis" ("/'able 7). M a j o r atelectasis is defined as collapse o f o n e superior or inferior lobe o f t h e l u n g or the entire lung. Eleven of the 26 patients showed this sign a n d as a rule progressed o n therapy (Table 7). T h e r e m a i n i n g patients w i t h o u t collapse showed 5 partial remissions (remission rate 3 3 % ) . It is not possible, however, to speak of possible statistical differences given the small n u m b e r of patients. O n the other h a n d , the identification of factors with
of" t r e a t m e n t o f II l~t~enta with t h e d o n ~ m m t sign o f lung c o l l a p s e
T a b l e 7. R e s u l t
1/26 (42~)
"Major atelectasis" Partial remission No change Progression
0/11 3/1 ! 8/11
14P
P. S. M 1 T R O U E T AL.
unfaw~rable pmgn¢~sis is important for the planning oflater studies, and perhaps to help us answer the question of why the results of therapy are so variable for non-small-cell bronchogeniq- carcinoma.
Summary Etoposide and cis-platinum were used to treat iooperable non-small-cell bronchogenic carcinoma in 32 patients; 15 of tile 26 patients who could be evaluated had squamous-cell carcinoma, 5 had adenocarcinomas and 6 had large-cell, undilti?rentiated carcinomas. Five (197;~) of the patients had a partial remission, which lasted 6-11 months. Remissions were observed in cases of squamous- and large-cell carcinoma. Of 11 patients with collapsed lobes, 8 progressed on treatment and 3 had unchanged tumor parameters. Patients without collapse had a remission rate of 33'}~ (5/15). Thus pulmonary collapse must be regarded as a prognostically unfavorable parameter. The side effects of therapy are moderate, and most, especially bone marrow toxicity, art. mild.
Treatment of inoperable non-small-cell bronchogenic c a r c i n o m a w i t h e t o p o s i d e ~ n d ¢is-platlnm P. S. M i t r o u , * M . F i s c h e r , * I. W e i s s e n f e l s , t V. D i e h l , t (3. G r o p p , ~ A. L i e s e n f e l d , ~ M . S c h m i d t , § W . E. B e r d e l , II U. Finktl a n d M . G r a u b n e r ¶
* Division of Hematology/Oncology, Department of Internal Medicine, University of Frankfurt, t Division of Hematology~Ontology, Department of Internal Medicine, Hannot~er Medical School, Department of HematologylOncology, University of Marburg, § Department of Internal Medicine, Protestant Denominational Hospital, Bremen, [[ Department of Hematology/Oncology, Medical Ctinic, Technical University of Munich, and ¶ University Medical Clinic, Giessen, F.R.G.
T h e effectiveness o f t h e c o m b i n a t i o n o f e t o p o s i d e a n d cis-platinum in i n o p e r a b l e s q u a m o u s cell c a r c i n o m a , a d e n o c a r c i n o m a a n d large-cell b r o n c h o g e n i c c a r c i n o m a w a s s t u d i e d in a m u l t i - c e n t e r P h a s e II s t u d y . E t o p o s i d e w a s a d m i n i s t e r e d in a single d o s e o f 100 m g ] m 2 o n d a y s l, 3 a n d 5. T h e D D P d o s e w a s 90 m g ] m 2 o n the first d a y o f t r e a t m e n t . S u p p l e m e n t a r y fluids w e r e a d m i n i s t e r e d to a v o i d n e p h r o t o x i c side effect~ ( T a b l e 1). So far 32 p a t i e n t s h a v e b e e n e n t e r e d into the s t u d y , a n d in 26 tile results c a n b e e v a l u a t e d ( T a b l e 2). T w o cases c a n n o t b e e v a l u a t e d b e c a u s e t r e a t m e n t w a s d i s c o n t i n u e d after t h e first c o u r s e . I n 2 o t h e r cases, the p e r i o d o f o b s e r v a t i o n is t o o s h o r t for a n e v a l u a t i o n . O n e p a t i e n t d i e d i m m e d i a t e l y after the first c o u r s e o f t r e a t m e n t , a n d 1 p a t i e n t h a d small-cell b r o n c h i a l c a r c i n o m a ( T a b l e
3). T w e n t y - t w o o f the 26 p a t i e n t s w e r e m a l e , a n d the m e a n a g e w a s 6 0 years. T h e g e n e r a l s t a t e o f t h e p a t i e n t s r a t e d 7 0 % ( 6 0 - 9 0 % ) o n the K a r n o f s k y scale. F o r 7 0 % o f t h e p a t i e n t s , t h e Karnofsky i n d e x w a s 60--70~/o w i t h c l e a r s u b j e c t i v e s y m p t o m s . I n t h e m a j o r i t y o f t h e
chemothez'spy Table I. C,ombls~tion wlth e4~oposide and ¢.~splatinum C/J-p~atinum Etoposide Hydration
90 mg/m a day ] 100 mg/m 2 days 1, 3, 5 3 lira 2 day 1 2 l/m 2 day 2
Reprint requests: Dr P, S. Mitrou, Center for Internal Medicine of the University, Department of Hematology and Oncolog),, Theodor Stern Kal 7, I)-6000 Frankfurt]M 70, F.R.O. 0305---7372/82/9A0139 + 04 S03.0010
1982 Academic Press Inc. (Lo~-.4.on) Limited
139
t40
P.S. Table
2.
Patients
NtiTROU entered
ET
AL.
into the study No. ufpatJents
Bremen Gi~s.*,en Frankfurt Hanover Marburg Munich Total
Table
3.
Patients
Tot'dl
Asse*.sable
N o t as.sea,sable
3 1 16 7 3 2 32
1 1 13 6 3 ~ 2t5
2 0 3 I 0 0 6
for whom
no assessment
could
be made
N o t a s s e s s a b l e b e c a u s e of:
No. of patients
T r e a t m e n t d i s c o n t i n u e d a f t e r t h e first c y c l e Too early for evaluation Early death tA'rong diagnosis
2 l t
Table
4.
Characteristics
of the 26 asauesamble patients
Age (years), median Male Female P e r f o r m a n c e s t a t u s ( K a r n o E s k y ) ~/o, m e d i a n Limited disease Extensive disease Histology Squamous-cell carcinoma Adenocarcinoma Large-cell, undifferentiated carcinoma
Table
5.
Side effects of the combination c/s-platlnum
Hemoglobin decline > 2 g% L o w e s t w h i t e cell c o u n t ( × 1 0 S / m m 3 ) , m e d i a n W h i t e c e l l c o u n t <: 2 0 0 0 White cell count < 1000 Bacterial infections Lowest platelet count ( x 103/am3), median Platelets < 100,000 P l a t e l e t a < 50,0(K} C r e a t i n i n e > 1.5 m g / d l Irreversible renal function impairment D e a t h rr.latecl t o t r e a t m e n t
6 0 (42- 6 7 ) 22 4 70 (60~ 90) 7 19 15 5 6
etoposide
and
13/! 6 4.0 3/16 0116
0[16 "226 4/16 2/16
1/26 1/26 1[ 2 6
CHEMOTHERAPY OF INOPERABLE BRONCHOGENIC CARCINOMA
141
T a b l e 6. R e s u l t s o f t r e a t m e n t
Partied rerni~ion No change Progression
No, of patients
(%)
5/26 8[26 13•26
19 3l 30
cases, a d v a n c e d b r o n c h o g e n i c c a r c i n o m a (extensive disease) was present (Table 4). I n 15 cases, squamous-cell c a r c i n o m a was diagnosed histologically, a n d 11 of the 26 patients had an a d e n o c a r c i n o m a or a large-cell, undifferentiated c a r c i n o m a (Table 4). T h e side effects of t h e r a p y were mild (Table 5). Bone m a r r o w toxicity was most in evidence in a decrease in the hemoglobin level. T h i r t e e n of the 16 patients w h o could be fully evaluated for hematological toxicity showed a 2 g % or more decrease in the hemoglobin level. Blood transfusions were necessary in only 1 p~.tient. T h e m e d i a n value of the lowest white cell c o u n t was 4000/#1; a decrease in the white cell count to below 2000/#1 was observed in only 3 of the 16 fully assessable cases (Table 5). T h e effect on thrombocytopoesis was slight. In 2 5 % of the cases the platelet c o u n t fell to below 100,000/#1. In i patient, irreversible kidney failure occurred after the first course o f t r e a t m e n t and the patient died as a consequence. O t h e r side eflkcts were also generally m o d e r a t e , lncomF~ete to complete loss of hair, nausea, vomiting a n d transitory reduction in general well-being were recorded a m o n g all 26 patients. No neurological symptoms were observed. In the 26 patients w h o could be evaluated, 5 partial r, xnissions ( I 9 % ) were achieved, while 13 patients progressed on therapy (Table 6). Thre,: of the 15 cases o f s q u a m o u s - c e l l c a r c i n o m a and 2 of the 6 cases o f large-cell c a r c i n o m a :'esponded to therapy. Remissions lasted 6-11 months, a n d 2 of 5 patients are still in re.,aission 9 and 10 m o n t h s after the beginning of therapy, respectively. Calculation o f the d u r a t i o n of remission from the beginning of t h e r a p y seems justified, since the patients responded as early as the first 2 cycles of treatment. T u m o r s w h i c h were u n c h a n g e d or progressive in the first 2 cycles o f t r e a t m e n t were not r e d u c e d in subsequent cycles. D a t a on survival times for the individual groups are not yet possible because of the relatively short observation time. A l t h o u g h the n u m b e r of patients is small, a s u b g r o u p with unfavorable prognosis has emerged. These w e r e patients for w h o m the leading s y m p t o m was " m a j o r atelectasis" ("/'able 7). M a j o r atelectasis is defined as collapse o f o n e superior or inferior lobe o f t h e l u n g or the entire lung. Eleven of the 26 patients showed this sign a n d as a rule progressed o n therapy (Table 7). T h e r e m a i n i n g patients w i t h o u t collapse showed 5 partial remissions (remission rate 3 3 % ) . It is not possible, however, to speak of possible statistical differences given the small n u m b e r of patients. O n the other h a n d , the identification of factors with
of" t r e a t m e n t o f II l~t~enta with t h e d o n ~ m m t sign o f lung c o l l a p s e
T a b l e 7. R e s u l t
1/26 (42~)
"Major atelectasis" Partial remission No change Progression
0/11 3/1 ! 8/11
14P
P. S. M 1 T R O U E T AL.
unfaw~rable pmgn¢~sis is important for the planning oflater studies, and perhaps to help us answer the question of why the results of therapy are so variable for non-small-cell bronchogeniq- carcinoma.
Summary Etoposide and cis-platinum were used to treat iooperable non-small-cell bronchogenic carcinoma in 32 patients; 15 of tile 26 patients who could be evaluated had squamous-cell carcinoma, 5 had adenocarcinomas and 6 had large-cell, undilti?rentiated carcinomas. Five (197;~) of the patients had a partial remission, which lasted 6-11 months. Remissions were observed in cases of squamous- and large-cell carcinoma. Of 11 patients with collapsed lobes, 8 progressed on treatment and 3 had unchanged tumor parameters. Patients without collapse had a remission rate of 33'}~ (5/15). Thus pulmonary collapse must be regarded as a prognostically unfavorable parameter. The side effects of therapy are moderate, and most, especially bone marrow toxicity, art. mild.