FROM T H E DEPARTMENTS OF DIAGNOSTIC RADIOLOGY A N D THORACIC SURGERY, MALMO A L L M A N N A S J U K H U S , S - 2 1 4 01 M A L M S , S W E D E N .
PREOPERATIVE I N F U S I O N O F MITOMYCIN-C I N THE B R O N C H I A L A R T E R Y I N S Q U A M O U S CELL C A R C I N O M A O F T H E L U N G
C . H E L L E K A N T , E. B O I J S E N a n d L . S V A N B E R G
R e c e n t reports o n t h e effect of therapy in b r o n c h o g e n i c c a r c i n o m a h a v e n o t revealed a n y significant difference in survival rate b e t w e e n patients treated
with
o p e r a t i o n a l o n e a n d t h o s e treated w i t h o p e r a t i o n in c o m b i n a t i o n w i t h c y t o s t a t i c s ( S T O T T et coll. 1 9 7 6 ) . U s u a l l y t h e c y t o s t a t i c s h a v e been g i v e n per o s o r i n t r a v e n o u s l y and severe side effects h a v e often m a d e it i m p o s s i b l e t o m a i n t a i n a n effective s e r u m level of t h e drugs. T o e n h a n c e anticancer activity of the drug a n d t o d i m i n i s h t h e side effects, it s e e m s logical t o infuse t h e drug directly i n t o t h e artery s u p p l y i n g t h e t u m o r , thereby i n creasing t h e c o n c e n t r a t i o n of t h e drug in t h e t u m o r a n d d e c r e a s i n g it in t h e rest of the b o d y . T h i s m e t h o d w a s tested in t h e sixties w i t h v a r i o u s drugs b u t since n o o b v i o u s effects were o b s e r v e d , it w a s a b a n d o n e d ( B O I J S E N et coll. 1 9 6 4 , K A H N et coll. 1965,
H A L L E R et coll.
1 9 6 6 , T A T E et coll. 1 9 6 8 , W I R T A N E N & A N S F I E L D 1 9 6 8 ) .
With
t h e d e v e l o p m e n t of m i t o m y c i n - C ( M M C ) ( W A K A K I e t coll. 1 9 5 8 ) , w h i c h h a s b e e n reported effective in several t y p e s of c a r c i n o m a s ( W A S S E R M A N e t coll. 1 9 7 5 ) , a n d w i t h the u s e of a m o d e r n a n g i o g r a p h i c t e c h n i q u e , it s e e m e d r e a s o n a b l e t o test t h e drug in selective intraarterial infusions in p u l m o n a r y c a r c i n o m a . Since D e c e m b e r 1 9 7 5 M M C has b e e n infused in t h e bronchial artery i n m o r e t h a n 4 0 patients with different t y p e s of p u l m o n a r y c a r c i n o m a . T h e present report a c c o u n t s for 9 of these patients, all with s q u a m o u s cell c a r c i n o m a . T h e y were all preSubmitted for publication 15 December 1977. Acta Radiologica
Diagnosis 19 (/97S) Fasc. 6
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1045
1046
C . H E L L E K A N T , E . BOIJSEN A N D L . SV A N B E R G
Table Results of preoperative Case
Sex and age
Chemotherapy (mg)
1
M 61
2
chemotherapy
MMC
Interval to Objective response CXR (days) CXR Bronchoscopy
—
10
28
M 65
—
10
31
3
M 70
—
10
36
4
M 63
2
10
35
20
10
21
VCR
F51
BLM
6
M 67
2
20
10
36
0
7 8
M 59 M 67
2 2
25 25
10 10
34 28
0 0
9
M 72
—
5x6 5x6
10 10
25
0
0 X X
L = lobectomy. P = pneumonectomy. E = exploration. VCR = vincristine. BLM = bleomycin. MMC = mitomycin-C. CXR = chest radiography. Tumor response: Chest films: Measurable lesions: + = - 50 % decrease of product of two largest perpendicular tumor diameters. Non-measurable but evaluable lesions: x = marked regression of tumor size or atelectases. 0 = no change. — = not evaluable. Tumor not observed even before in fusion. operatively rated as stage I t o II a c c o r d i n g t o the T N M - c l a s s i f i c a t i o n ( U 1 C C 1974). T h e rest of t h e series, i n c l u d i n g t h e stage III c a r c i n o m a s , will be reported in a later communication.
Material and Methods Eight m a l e s a n d o n e f e m a l e , m e d i a n age 6 5 , range 51 t o 7 2 years, w i t h s q u a m o u s cell c a r c i n o m a of the l u n g were e x a m i n e d with chest radiography, b r o n c h o s c o p y , a n d m e d i a s t i n o s c o p y a n d rated a c c o r d i n g to t h e T N M classification. T h e i r f u n c t i o n a l capacity w a s defined w i t h s p i r o m e t r y and
1 3 3
X e spirometry. O n l y
patients w i t h u p t o T 2 N 0 - 1 M 0 are i n c l u d e d in the present series. Selective bronchial
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF MITOMYCIN-C IN THE BRONCHIAL ARTERY
1047
Table (cont.)
Physiologic classification
Interval to op. (days)
Type of op.
Postop. TNM*
Comments
Dead 17 months postop. of pulmonary embolus Alive. No viable carcino ma in resectedspecimen Alive. No viable carcino ma in resected specimen Mixed carcinoma reveal ed at op. Dead with multiple metastases N o macroscopic tumor. A few carcinoma cells in one histologic section. Pat. dead ofanesth. com pile. Alive. Only 1/3 of tumor perfused Alive Alive. Only 1/3 of tumor perfused Alive
Prechemother.
Postchemother.
I
—
40
L
T2N2M0
1
1
48
L
T0N0M0
I
I
41
L
T0N0M0
II
III
40
L
T2N1M0
IV
III
28
P
T1N0M0
III
—
39
E
T3N2M0
I II
I II
46 33
L P
T3N0M0 T2N1M0
I
I
36
L
T3N0M0
Bronchoscopy: x = disappearance of exophytic tumor or marked regression of tumor estimated as than 50% more or marked reduction of bronchus compression. 0 = no change. — = not performed. * Before chemotherapy all were staged as T2N01M0.
a n g i o g r a p h y was performed a c c o r d i n g t o a previously reported t e c h n i q u e ( B O T E N G A 1970). T h e size of the t u m o r and its degree of vascularity w a s e s t i m a t e d f r o m the films, w h i c h were also screened for the presence of a spinal artery. F o l l o w i n g a n g i o g r a p h y in a.p. and lateral projections 10 m g of M M C diluted in 100 ml of p h y s i o l o g i c saline w a s infused i n t o the proper bronchial artery with an injection rate of 6 m l / m i n . A n g i o g r a p h y w a s then repeated. T h e first 3 patients ( N o s 1, 2, 3) received o n l y a n intraarterial infusion of M M C . Five patients ( N o s 4 - 8 ) received 2 m g of vincristine intravenously before the a n g i o g r a p h y and 4 of t h e m in a d d i t i o n 2 0 t o 25 m g of b l e o m y c i n ( B L M ) intramuscularly ( N o s 5 - 8 ) . O n e patient ( N o . 9) received 5 m g of B L M
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1048
C . H E L L E K A N T , E. BOIJSEN A N D L. S V A N B E R G
a
b
c
Fig. 1. Case 5. A 51-year-old woman with squamous cell carcinoma of left stem bronchus. Medi astinoscopy normal, a) Bronchial angiography. Richly vascularized tumor, b) Chest before and c) 3 weeks after infusion of mitomycin-C. The tumor has disappeared almost completely. At this time no tumor was observed at bronchoscopy. Pneumonectomy was performed. No tumor macroscopically but at microscopy a few tumor cells were observed in one of many sections.
intramuscularly per day for six d a y s and an intraarterial infusion of 10 m g of M M C the f o l l o w i n g day. In that patient the treatment w a s repeated after t w o w e e k s (Table). T h e effect of the therapy w a s recorded with clinical e x a m i n a t i o n , 1 3 3
spirometry,
X e s p i r o m e t r y and repeated chest radiography, the last chest film before o p e r a t i o n
being t a k e n from 21 to 36 d a y s after the infusion. Repeat b r o n c h o s c o p y w a s per f o r m e d in 7 patients. T h r o m b o c y t e s and white b l o o d cells were c h e c k e d in all patients o n c e a w e e k after the infusion. T h e definitions of objective response for measurable lesions o n chest films were: C o m p l e t e remission
n o e v i d e n c e of t u m o r ; partial remission
m o r e than 50 per
cent reduction of the p r o d u c t of the t w o largest perpendicular t u m o r diameters. F o r n o n - m e a s u r a b l e but e v a l u a b l e lesions an u n e q u i v o c a l marked regression of t u m o r m a s s or atelectasis w a s c o n s i d e r e d a n objective response. A t b r o n c h o s c o p y , d i s a p p e a r a n c e or m a r k e d regression of e x o p h y t i c t u m o r esti m a t e d as m o r e than 50 per cent or a marked reduction of b r o n c h u s c o m p r e s s i o n were c o n s i d e r e d an objective response.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE I N F U S I O N OF M I T O M Y C I N - C IN THE B R O N C H I A L ARTERY
1049
b
Fig. 2. Case 3. A 70-year-old man with atelec tasis of right upper lobe (a), found at broncho scopy to be caused by squamous cell carcinoma occluding the upper lobe bronchus, b) Extent of tumor outlined by bronchial angiography, c) Chest film 35 days after intraarterial infusion of MMC. Marked regression of atelectasis and at bronchoscopy no tumor was observed. Lobectomy performed and no tumor cells found at microscopy.
c
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1050
C. HELLEKANT, E. BOIJSEN AND
L. SVANBERG
Fig. 3. Case 6. A 67-year-old man with squamous cell carcinoma of the left lower lobe. Only upper part of tumor demonstrated at bronchial angiography. The tumor was only slightly smaller in its upper part 35 days later. This was the only part that received mitomycin-C at infusion.
The term no change covers all other findings at chest radiography and bronchoscopy in the absence of progressive disease. The patients were operated upon 28 to 48 days after the infusion (median 40 days). Pneumonectomy was performed in 2 patients, lobectomy in 6 and exploratory thoracotomy in one. In 5 patients a radical resection was not possible. They received postoperative irradiation and BLM according to a previously published schedule (SVANBERG 1976). Results The effect of the preoperative treatment appears in the Table. A marked regression of the tumor was found at bronchoscopy in 6 patients (Nos 2-5, 7 and 8). In one patient (No. 6) no change was observed and in 2 (Nos 1, 9) the bronchoscopy was not repeated. At chest radiography, almost complete remission of the tumor had occurred in one patient (No. 5 , Fig. I), partial remission in 2 (Nos 1, 4) and marked regrcssion in one (No. 3, Fig. 2). In 4 patients (Nos 6-9) no change was observed. It was not
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF MITOMYCIN-C I N THE BRONCHIAL ARTERY
1051
possible to evaluate one patient (No. 2), as the central tumor was not clearly seen on chest films even before the intraarterial infusion. In 2 patients (Nos 2, 3) treated with MMC only, lobectomy was performed and no viable tumor was found in the specimen. In one patient (No. 5 ) a few tumor cells could be traced in one of many histologic sections. In 5 patients (Nos 1, 4, 7, 8, 9) the tumor showed various degrees of necrosis. In one patient (No. 6) the tumor was not resectable due to mediastinal metastases and only an exploration was performed. One patient (No. 5 ) died of an anesthetic complication 10 days after the operation and another (No. 1) died 17 months postoperatively from a pulmonary embolus. In none of them was any tumor found at autopsy. One patient (No. 4) in whom the operation revealed a mixed carcinoma died two months postoperatively with multiple metastases. The other 6 patients are alive with a postoperative median time of 8 months (range 4 to 20 months). No severe complications were observed from the bronchial angiography or the intraarterial infusion. Some patients experienced a burning sensation in the chest during angiography but there was no reaction during the infusion of cytostatics. Occasionally the patients had a moderate malaise and a slight fever the day after the infusion. No toxic effect on the blood counts was recorded. In one non-responding patient (No. 6) approximately only one third of the tumor was perfused with the cytostatic drug. The physiologic classification was unchanged in 5 patients (Nos 2, 3, 7, 8,9), improved in one (No. 5) and impaired in one (No. 4). In patients Nos 1 and 6 the examination was not repeated.
Discussion As a rule one bronchial artery exists on the right side and two on the left but many variations occur (BOTENGA). Usually the right bronchial artery is easy to catheterize while it may be more difficult on the left side, especially in elderly patients. A complete demonstration of all bronchial arteries is therefore sometimes difficult to obtain, but the tumor-feeding artery is usually dilated, which facilitates the catheterization. Different opinions on the vascular supply of bronchogenic carcinoma have appeared in the literature (VIAMONTE et coll. 1965, MILNE1967). In our opinion, the tumor is mainly supplied by the bronchial arteries, and in no case was a supply from the pulmonary arteries demonstrated. In 2 of the patients only approximately one third of the tumor bulk was infused (Fig. 3). In both cases the tumor was located in the left lung and only one bronchial artery had been examined. Probably the rest of the tumor was supplied from the other bronchial artery. One of these patients (No. 6) did not respond to the therapy, otherwise no correlation between tumor vascularization and response was found. Examination in different views is recommended before the infusion therapy is carried out, in order to define the exact tumor supply and also to reveal if a spinal
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1052
C. H E L L E K A N T , E. BOUSEN A N D L. SVANBERG
artery arises f r o m t h e right bronchial artery. T h e left artery h a s n o direct c o n n e c t i o n w i t h t h e spinal arteries b u t m a y c o m m u n i c a t e v i a collaterals w i t h t h e right bronchial artery ( B O T E N G A ) . Preinfusion a n g i o g r a p h y is therefore m a n d a t o r y , e v e n if there are n o i n d i c a t i o n s of n e u r o t o x i c i t y of M M C . Transverse myelitis is a well k n o w n c o m p l i c a t i o n i n bronchial a n d intercostal angiography ( F E I G E L S O N & R A V I N 1 9 6 5 , K A R D J I E V et coll.
1 9 7 4 ,MARGOLIS
1976).
A spinal artery m a y arise f r o m t h e f o u r t h o r fifth right o r left intercostal arteries ( F A U R E e t coll. 1 9 6 7 , B O T E N G A ) a n d special care s h o u l d b e t a k e n if these vessels are catheterized while searching f o r t h e b r o n c h i a l artery a n d t h e catheter i m m e d i a t e l y w i t h d r a w n . W i t h that t e c h n i q u e a n d m o d e r n contrast m e d i a t h e risks s h o u l d be small ( D J I N D J I A N & F A U R E 1 9 6 7 ) .
A o r t i c rupture h a s been reported after infusion of nitrogen mustard i n t o t h e b r o n c h i a l artery ( S T E C K E L et coll. 1 9 6 7 ) , a n d a t this h o s p i t a l severe local necrosis h a s o c c u r r e d w h e n M M C h a s e x t r a v a s a t e d a t i n t r a v e n o u s injection. N o i n d i c a t i o n s of injury t o t h e arterial wall h a v e a p p e a r e d in t h e present series, p r o b a b l y d u e t o t h e d i l u t i o n of t h e drug a n d t o t h e s l o w infusion rate. T h e r e c o m m e n d e d daily d o s e of M M C intravenously is 0 . 0 5 m g / k g b o d y weight for t e n d a y s t o b e repeated until t o x i c effects are o b s e r v e d . H o w e v e r , recent reports indicate that intermittent large-dose a d m i n i s t r a t i o n is m o r e effective ( C R O O K E BRADNER
&
1976).
T h e literature o n intraarterial treatment with M M C is scarce b u t usually it h a s b e e n u s e d i n c o m b i n a t i o n with o t h e r cytostatics, e.g. 5 F U ( M I U R A et coll. 1 9 7 1 ) . I n this preliminary series it w a s t h o u g h t w o r t h w h i l e t o try a different
schedule;
vincristine a n d B L M were used t o s y n c h r o n i z e a n d stabilize t h e cell cycle at t h e G
2
stage w h e r e t h e t u m o r cells are believed t o be m o s t susceptible t o M M C ( T E R A S I M A 1 9 7 5 , M I Y A M O T O et coll. 1 9 7 7 ) . T h e c o m b i n a t i o n of B L M a n d M M C also has t h e a d v a n t a g e of a different toxicity. B L M has b e e n used previously against p u l m o n a r y car c i n o m a w i t h s o m e results, a l o n e o r i n c o m b i n a t i o n with irradiation, but the d o s e s h a v e b e e n m u c h higher ( O K A & K O M O 1 9 7 4 , S V A N B E R G 1 9 7 6 ) . R e c e n t reports f r o m J a p a n s h o w that a similar s c h e d u l e w i t h small d o s e s of B L M a n d large intermittent d o s e s of M M C h a s b e e n effective in treating c a r c i n o m a of t h e uterine cervix ( M I Y A M O T O et coll.). In a d d i t i o n , vincristine s e e m s t o p o t e n t i a t e M M C ( P O U I L L A R T et coll. 1 9 7 4 ) . T h e p r o b l e m in e s t i m a t i n g t h e effect of a n anticancer drug is mainly t h e difficulty in o b t a i n i n g objectively m e a s u r a b l e d i a m e t e r s of t h e t u m o r . U s u a l l y t h e p r o d u c t of t h e t w o largest d i a m e t e r s is u s e d a n d t h e result given a s m o r e o r less than a 5 0 p e r cent r e d u c t i o n . I n centrally l o c a t e d l u n g t u m o r s these m e a s u r e m e n t s m a y n o t be possible t o carry o u t a n d o n e h a s t o rely o n e v a l u a b l e b u t n o n - m e a s u r a b l e signs of regression s u c h a s decreasing m a s s effect a n d better aeration of t h e l u n g p a r e n c h y m a distal t o t h e t u m o r . T h e reliability of such e v a l u a t i o n s has been confirmed by D A W S O N et coll. ( 1 9 6 6 ) .
Often t h e chest films s h o w very little regression, while b r o n c h o s c o p y m a y reveal a m a r k e d regression, a s w a s t h e case in 3 of t h e present patients ( N o s 2 , 7 , 8 ) with
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION O F MITOMYCTN-C IN THE B R O N C H I A L ARTERY
1053
central t u m o r s . H o w e v e r , these p r o b l e m s s e e m m o r e i m p o r t a n t in i n o p e r a b l e patients than in a series like the present o n e where all patients were o p e r a t e d u p o n a n d the effect of the treatment c o u l d be e v a l u a t e d at the o p e r a t i o n or in the resected speci men. In 4 patients the preoperative T N M - c l a s s i f i c a t i o n turned o u t t o be t o o o p t i m i s t i c . It is well k n o w n that direct spread t o mediastinal structures is very difficult to detect preoperatively and that m e d i a s t i n o s c o p y is reliable only c o n c e r n i n g l y m p h
nodes
in the upper parts of the m e d i a s t i n u m ( L A R S S O N 1976). In o n e patient a metastasis in the l o w e r part of the hilum c o u l d be d e m o n s t r a t e d (Fig. 4) and in a n o t h e r t u m o r vessels were d e m o n s t r a t e d in the m e d i a s t i n u m . T h i s indicates that a n g i o g r a p h y m a y be of h e l p in the preoperative staging. Concluding
remarks.
T h e present material is small and the p o s t o p e r a t i v e
time
short but s o m e c o n c l u s i o n s m a y be d r a w n . M M C is well tolerated, given as a s l o w infusion into the bronchial arteries. In patients where the preoperative T N M - c l a s sification of T 2 N 0 1 MO held true, a remarkable effect occurred after a single infusion of 10 m g of M M C , w i t h c o m p l e t e r e m i s s i o n of the t u m o r in 2 patients, a l m o s t c o m plete remission in o n e , partial remission in o n e , a n d a m a r k e d but u n m e a s u r a b l e regression in another.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1054
C. H E L L E K A N T , E. E O U S E N A N D L. S V A N B E R G
In patients where t h e o p e r a t i o n revealed a m o r e a d v a n c e d stage the response w a s less e v i d e n t , b u t partial r e m i s s i o n w a s a c h i e v e d in o n e a n d a m a r k e d regression in a n o t h e r of these patients. O n t h e basis of t h e s e preliminary results a r a n d o m i z e d investigation has been started w i t h r e p e a t e d intraarterial i n f u s i o n s of M M C i n t o the bronchial arteries of patients w i t h s q u a m o u s cell c a r c i n o m a of the lung.
SUMMARY Bronchial angiography was performed in 9 patients with squamous cell carcinoma of the lung. The tumor-feeding vessel was identified and infused with 10 mg of mitomycin-C ( M M C ) diluted in saline. At operation after 28 to 48 days complete remission of the tumor had occurred in 2 patients, almost complete in one, partial remission in 2 and a marked regression in 2. In 2 patients no change was noted. N o side effects except moderate malaise and slight fever occurred.
ZUSAMMENFASSUNG Eine bronchiale Angiographie wurde bei 9 Patienten mit Schuppenzell-Karzinom der Lunge vorgenommen. D i e Tumor-versorgenden Gefasse wurden identifiziert und mit 10 mg Mitomycin-C, verdiinnt in Kochsalzlosung, infundiert. Bei Operation nach 28 bis 48 Tagen war eine komplette Remission des Tumors bei zwei Patienten erfolgt, eine beinahe komplette bei einem, eine partielle Remission bei zwei und eine kraftige Riickbildung bei zwei Patienten. Bei 2 Patienten war keine Veranderung festzustellen. Keine Neben-Effekte, mit Ausnahme einer leichten Obelkeit und leichten Fiebers, waren festzustellen.
RESUME U n e angiographie bronchique a ete faite chez 9 malades atteints de carcinome epidermoi'de du p o u m o n . Le vaisseau nourricier de la tumeur a ete identifie et perfuse avec 10 mg de Mitomycine-C ( M M C ) diluee dans du serum sale. A l'operation apres 28 a 48 jours une remission complete de la tumeur s'etait produite chez 2 malades, remission presque complete chez un malade, partielle chez 2 malades et regression marquee chez 2 malades. Chez 2 malades il n'y avait pas eu de modification. Les auteurs n'ont pas observe d'effet secondaire excepte un malaise modere et une legere fievre.
REFERENCES BOIJSEN E., D A H L B A C K O., KUGELBERG J., SCHULLER H . und ZSIGMOND M.: D i e
Behandlung
des inoperablen Bronchuskarzinoms mit Zytostaticainfusion via Aa. bronciales. Thoraxchirurgie 12 (1964), 198. BOTENGA A. S. J.: Selective bronchial and intercostal arteriography. H . E. Stenfert Kroese, Leiden 1970. CROOKE S. T. and BRADNER W . T.: Mitomycin C. A review. Cancer Treat. Rev. 3 (1976), 121. D A W S O N J. M.,
H A L L T. C ,
SCHNEIDERMAN M. A., SCHNIDER B. I., O W E N S A. H . , A N D R E W S
J. R., BAXTER D . H . , BRENNER S., H U N T E R C ,
LEVENE M. B., SHEEHAN F. R. and
WHITE
G.: Objective evaluation of change in tumor size in lung cancer patients with nonmeasurable disease. Cancer 19 (1966), 415.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF M1TOMYCIN-C IN THE BRONCHIAL ARTERY
1055
DJINDJIAN R. et FAURE C : Accidents medullaires de l'aortographie. J. beige Radiol. 50 (1967), 207. FAURE C , LEFEBVRE J., D E B R U N G. et DJINDJIAN R.: La vascularisation arterielle normale
et pathologique du renflement lombaire de la moelle epiniere chez 1'enfant. L'artere d'Adamkiewicz. Ann. Radiol. 10 (1967), 129. FEIGELSON H. H. and RAVIN H . A . Transverse myelitis following selective bronchial arterio graphy. Radiology 85 (1965), 663. HALLER J. D . , BRON K. M., WHOLEY M. H . , POLLER S. and ENERSON D . M.: Selective
bronchial artery catheterization for diagnostic and physiologic studies and chemo therapy for bronchogenic carcinoma. J. thorac. cardiovasc. Surg. 51 (1966), 143. K A H N P. C , P A U L R. E. and RHEINLANDER H . F . : Selective bronchial arteriography and
intra-arterial chemotherapy in carcinoma of the lung. J. thorac. cardiovasc. Surg. 50 (1965), 640. KARDJIEV V . , SYMENOV A. and CHANKOV I.: Etiology, pathogenesis and prevention of spinal cord lesions in selective angiography of the bronchial and intercostal arteries. Radiology 112 (1974), 81. LARSSON S.: Mediastinoscopy in bronchogenic carcinoma. Scand. J. thorac. cardiovasc. Surg. (1976) Suppl. N o . 19. MARGOLIS G.: Spinal cord complications of angiography. In: Complications in diagnostic radiology, p. 134. Edited by G. Ansell. Blackwell Scientific Publications, Oxford 1976. MILNE E. N . C : Circulation of primary and metastatic pulmonary neoplasms. A post mortem microarteriographic study. Amer. J. Roentgenol. 100 (1967), 603. MIURA T., ISHIDA M. and HATANO S.: Combination cancer chemotherapy by regional intra-arteriai or intra-aortic infusion of 5-Fluorouracil and Mitomycin-C with or with out irradiation. Jap. J. Surg. 1 (1971), 133. MIYAMOTO T., TABAKE Y., WATANABE M. and TERASIMA T.: Drastic remission effect of a
sequential combination of Bleomycin and Mitomycin-C ( B - M ) on advanced cervical cancer. Cancer Chemother. 4 (1977), 273. O K A S. and KOMO K..: Treatment of lung cancer with bleomycin. Abstr. X I Int. Cancer Congr. 1974, p. 589. POUILLART P., H O A N G T H Y H U O N G T., BRUGERIE E. and LHERITIER J.: Sequential adminis
tration of two oncostatic drugs. Study of modalities for pharmacodynamic potentiation. Biomedicine 21 (1974), 471. STECKEL R. J., D O P P M A N J. L . , ROLLEY R. T. and MARTOS E. J.: Rupture of the aorta after
mechlorethamine HC1 infusion of a bronchial artery. J. Amer. med. Ass. 199 (1967), 186. STOTT H . , STEPHENS R. J., F o x W . and R O Y D . C : 5-year follow-up of cytotoxic chemo therapy as an adjuvant t o surgery in carcinoma of the bronchus. Brit. J. Cancer 34 (1976), 167. SVANBERG L . : Regional functional decrease in bronchial carcinoma. A n n . thorac. Surg. 13 (1972), 170. — Bleomycin and lung cancer. Gann 19 (1976), 193. TATE JR C. F., VIAMONTE JR M. and A G N E W J. R.: Bronchial arterial perfusion with cyto toxic agents for bronchogenic carcinoma. Amer. Rev. resp. D i s . 97 (1968), 685. TERASIMA T.: Proposals of tumor therapy based o n cell cycle dependent sensitivity change. (In Japanese.) Gann t o Kagakuryoho 1 (1975), 533. U I C C , International U n i o n Against Cancer. T N M . Classification of malignant tumors. Second edition. Geneva 1974. VIAMONTE JR M., PARKS R. E. and SMOAK W. M.: Guided catheterization of the bronchial
arteries. Part II. Pulmonary and mediastinal neoplasms. Radiology 85 (1965), 214.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1056
C . H E L L E K A N T , E. B O I J S E N A N D L . S V A N B E R G
W A K A K I S., M A R U M O H . , TOMIOKA K . , SHIMIZU G . ,
KATO E., KAMADA H . ,
K U D O S.
and
FUJIMOTO Y.: Isolation of new fractions of antitumor Mitomycins. Antibiot. and Chemo ther. 8 (1958), 228. WASSERMAN T. H . , COMIS R. L.,
GOLDSMITH C ,
HANDELSMAN H . , PENTA J. S., SLAVIK
M.,
SOPER W . T. and CARTER S . K.: Tabular analyses of the clinical chemotherapy of solid tumors. Cancer chemother. Rep. 3 (1975), 399. WIRTANEN G . W . and ANSFIELD F . J . : Bronchial artery infusion in bronchogenic carcinoma. Cancer chemother. Rep. 52 (1968), 263.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE I N F U S I O N O F MITOMYCIN-C I N THE B R O N C H I A L A R T E R Y I N S Q U A M O U S CELL C A R C I N O M A O F T H E L U N G
C . H E L L E K A N T , E. B O I J S E N a n d L . S V A N B E R G
R e c e n t reports o n t h e effect of therapy in b r o n c h o g e n i c c a r c i n o m a h a v e n o t revealed a n y significant difference in survival rate b e t w e e n patients treated
with
o p e r a t i o n a l o n e a n d t h o s e treated w i t h o p e r a t i o n in c o m b i n a t i o n w i t h c y t o s t a t i c s ( S T O T T et coll. 1 9 7 6 ) . U s u a l l y t h e c y t o s t a t i c s h a v e been g i v e n per o s o r i n t r a v e n o u s l y and severe side effects h a v e often m a d e it i m p o s s i b l e t o m a i n t a i n a n effective s e r u m level of t h e drugs. T o e n h a n c e anticancer activity of the drug a n d t o d i m i n i s h t h e side effects, it s e e m s logical t o infuse t h e drug directly i n t o t h e artery s u p p l y i n g t h e t u m o r , thereby i n creasing t h e c o n c e n t r a t i o n of t h e drug in t h e t u m o r a n d d e c r e a s i n g it in t h e rest of the b o d y . T h i s m e t h o d w a s tested in t h e sixties w i t h v a r i o u s drugs b u t since n o o b v i o u s effects were o b s e r v e d , it w a s a b a n d o n e d ( B O I J S E N et coll. 1 9 6 4 , K A H N et coll. 1965,
H A L L E R et coll.
1 9 6 6 , T A T E et coll. 1 9 6 8 , W I R T A N E N & A N S F I E L D 1 9 6 8 ) .
With
t h e d e v e l o p m e n t of m i t o m y c i n - C ( M M C ) ( W A K A K I e t coll. 1 9 5 8 ) , w h i c h h a s b e e n reported effective in several t y p e s of c a r c i n o m a s ( W A S S E R M A N e t coll. 1 9 7 5 ) , a n d w i t h the u s e of a m o d e r n a n g i o g r a p h i c t e c h n i q u e , it s e e m e d r e a s o n a b l e t o test t h e drug in selective intraarterial infusions in p u l m o n a r y c a r c i n o m a . Since D e c e m b e r 1 9 7 5 M M C has b e e n infused in t h e bronchial artery i n m o r e t h a n 4 0 patients with different t y p e s of p u l m o n a r y c a r c i n o m a . T h e present report a c c o u n t s for 9 of these patients, all with s q u a m o u s cell c a r c i n o m a . T h e y were all preSubmitted for publication 15 December 1977. Acta Radiologica
Diagnosis 19 (/97S) Fasc. 6
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1045
1046
C . H E L L E K A N T , E . BOIJSEN A N D L . SV A N B E R G
Table Results of preoperative Case
Sex and age
Chemotherapy (mg)
1
M 61
2
chemotherapy
MMC
Interval to Objective response CXR (days) CXR Bronchoscopy
—
10
28
M 65
—
10
31
3
M 70
—
10
36
4
M 63
2
10
35
20
10
21
VCR
F51
BLM
6
M 67
2
20
10
36
0
7 8
M 59 M 67
2 2
25 25
10 10
34 28
0 0
9
M 72
—
5x6 5x6
10 10
25
0
0 X X
L = lobectomy. P = pneumonectomy. E = exploration. VCR = vincristine. BLM = bleomycin. MMC = mitomycin-C. CXR = chest radiography. Tumor response: Chest films: Measurable lesions: + = - 50 % decrease of product of two largest perpendicular tumor diameters. Non-measurable but evaluable lesions: x = marked regression of tumor size or atelectases. 0 = no change. — = not evaluable. Tumor not observed even before in fusion. operatively rated as stage I t o II a c c o r d i n g t o the T N M - c l a s s i f i c a t i o n ( U 1 C C 1974). T h e rest of t h e series, i n c l u d i n g t h e stage III c a r c i n o m a s , will be reported in a later communication.
Material and Methods Eight m a l e s a n d o n e f e m a l e , m e d i a n age 6 5 , range 51 t o 7 2 years, w i t h s q u a m o u s cell c a r c i n o m a of the l u n g were e x a m i n e d with chest radiography, b r o n c h o s c o p y , a n d m e d i a s t i n o s c o p y a n d rated a c c o r d i n g to t h e T N M classification. T h e i r f u n c t i o n a l capacity w a s defined w i t h s p i r o m e t r y and
1 3 3
X e spirometry. O n l y
patients w i t h u p t o T 2 N 0 - 1 M 0 are i n c l u d e d in the present series. Selective bronchial
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF MITOMYCIN-C IN THE BRONCHIAL ARTERY
1047
Table (cont.)
Physiologic classification
Interval to op. (days)
Type of op.
Postop. TNM*
Comments
Dead 17 months postop. of pulmonary embolus Alive. No viable carcino ma in resectedspecimen Alive. No viable carcino ma in resected specimen Mixed carcinoma reveal ed at op. Dead with multiple metastases N o macroscopic tumor. A few carcinoma cells in one histologic section. Pat. dead ofanesth. com pile. Alive. Only 1/3 of tumor perfused Alive Alive. Only 1/3 of tumor perfused Alive
Prechemother.
Postchemother.
I
—
40
L
T2N2M0
1
1
48
L
T0N0M0
I
I
41
L
T0N0M0
II
III
40
L
T2N1M0
IV
III
28
P
T1N0M0
III
—
39
E
T3N2M0
I II
I II
46 33
L P
T3N0M0 T2N1M0
I
I
36
L
T3N0M0
Bronchoscopy: x = disappearance of exophytic tumor or marked regression of tumor estimated as than 50% more or marked reduction of bronchus compression. 0 = no change. — = not performed. * Before chemotherapy all were staged as T2N01M0.
a n g i o g r a p h y was performed a c c o r d i n g t o a previously reported t e c h n i q u e ( B O T E N G A 1970). T h e size of the t u m o r and its degree of vascularity w a s e s t i m a t e d f r o m the films, w h i c h were also screened for the presence of a spinal artery. F o l l o w i n g a n g i o g r a p h y in a.p. and lateral projections 10 m g of M M C diluted in 100 ml of p h y s i o l o g i c saline w a s infused i n t o the proper bronchial artery with an injection rate of 6 m l / m i n . A n g i o g r a p h y w a s then repeated. T h e first 3 patients ( N o s 1, 2, 3) received o n l y a n intraarterial infusion of M M C . Five patients ( N o s 4 - 8 ) received 2 m g of vincristine intravenously before the a n g i o g r a p h y and 4 of t h e m in a d d i t i o n 2 0 t o 25 m g of b l e o m y c i n ( B L M ) intramuscularly ( N o s 5 - 8 ) . O n e patient ( N o . 9) received 5 m g of B L M
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1048
C . H E L L E K A N T , E. BOIJSEN A N D L. S V A N B E R G
a
b
c
Fig. 1. Case 5. A 51-year-old woman with squamous cell carcinoma of left stem bronchus. Medi astinoscopy normal, a) Bronchial angiography. Richly vascularized tumor, b) Chest before and c) 3 weeks after infusion of mitomycin-C. The tumor has disappeared almost completely. At this time no tumor was observed at bronchoscopy. Pneumonectomy was performed. No tumor macroscopically but at microscopy a few tumor cells were observed in one of many sections.
intramuscularly per day for six d a y s and an intraarterial infusion of 10 m g of M M C the f o l l o w i n g day. In that patient the treatment w a s repeated after t w o w e e k s (Table). T h e effect of the therapy w a s recorded with clinical e x a m i n a t i o n , 1 3 3
spirometry,
X e s p i r o m e t r y and repeated chest radiography, the last chest film before o p e r a t i o n
being t a k e n from 21 to 36 d a y s after the infusion. Repeat b r o n c h o s c o p y w a s per f o r m e d in 7 patients. T h r o m b o c y t e s and white b l o o d cells were c h e c k e d in all patients o n c e a w e e k after the infusion. T h e definitions of objective response for measurable lesions o n chest films were: C o m p l e t e remission
n o e v i d e n c e of t u m o r ; partial remission
m o r e than 50 per
cent reduction of the p r o d u c t of the t w o largest perpendicular t u m o r diameters. F o r n o n - m e a s u r a b l e but e v a l u a b l e lesions an u n e q u i v o c a l marked regression of t u m o r m a s s or atelectasis w a s c o n s i d e r e d a n objective response. A t b r o n c h o s c o p y , d i s a p p e a r a n c e or m a r k e d regression of e x o p h y t i c t u m o r esti m a t e d as m o r e than 50 per cent or a marked reduction of b r o n c h u s c o m p r e s s i o n were c o n s i d e r e d an objective response.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE I N F U S I O N OF M I T O M Y C I N - C IN THE B R O N C H I A L ARTERY
1049
b
Fig. 2. Case 3. A 70-year-old man with atelec tasis of right upper lobe (a), found at broncho scopy to be caused by squamous cell carcinoma occluding the upper lobe bronchus, b) Extent of tumor outlined by bronchial angiography, c) Chest film 35 days after intraarterial infusion of MMC. Marked regression of atelectasis and at bronchoscopy no tumor was observed. Lobectomy performed and no tumor cells found at microscopy.
c
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1050
C. HELLEKANT, E. BOIJSEN AND
L. SVANBERG
Fig. 3. Case 6. A 67-year-old man with squamous cell carcinoma of the left lower lobe. Only upper part of tumor demonstrated at bronchial angiography. The tumor was only slightly smaller in its upper part 35 days later. This was the only part that received mitomycin-C at infusion.
The term no change covers all other findings at chest radiography and bronchoscopy in the absence of progressive disease. The patients were operated upon 28 to 48 days after the infusion (median 40 days). Pneumonectomy was performed in 2 patients, lobectomy in 6 and exploratory thoracotomy in one. In 5 patients a radical resection was not possible. They received postoperative irradiation and BLM according to a previously published schedule (SVANBERG 1976). Results The effect of the preoperative treatment appears in the Table. A marked regression of the tumor was found at bronchoscopy in 6 patients (Nos 2-5, 7 and 8). In one patient (No. 6) no change was observed and in 2 (Nos 1, 9) the bronchoscopy was not repeated. At chest radiography, almost complete remission of the tumor had occurred in one patient (No. 5 , Fig. I), partial remission in 2 (Nos 1, 4) and marked regrcssion in one (No. 3, Fig. 2). In 4 patients (Nos 6-9) no change was observed. It was not
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF MITOMYCIN-C I N THE BRONCHIAL ARTERY
1051
possible to evaluate one patient (No. 2), as the central tumor was not clearly seen on chest films even before the intraarterial infusion. In 2 patients (Nos 2, 3) treated with MMC only, lobectomy was performed and no viable tumor was found in the specimen. In one patient (No. 5 ) a few tumor cells could be traced in one of many histologic sections. In 5 patients (Nos 1, 4, 7, 8, 9) the tumor showed various degrees of necrosis. In one patient (No. 6) the tumor was not resectable due to mediastinal metastases and only an exploration was performed. One patient (No. 5 ) died of an anesthetic complication 10 days after the operation and another (No. 1) died 17 months postoperatively from a pulmonary embolus. In none of them was any tumor found at autopsy. One patient (No. 4) in whom the operation revealed a mixed carcinoma died two months postoperatively with multiple metastases. The other 6 patients are alive with a postoperative median time of 8 months (range 4 to 20 months). No severe complications were observed from the bronchial angiography or the intraarterial infusion. Some patients experienced a burning sensation in the chest during angiography but there was no reaction during the infusion of cytostatics. Occasionally the patients had a moderate malaise and a slight fever the day after the infusion. No toxic effect on the blood counts was recorded. In one non-responding patient (No. 6) approximately only one third of the tumor was perfused with the cytostatic drug. The physiologic classification was unchanged in 5 patients (Nos 2, 3, 7, 8,9), improved in one (No. 5) and impaired in one (No. 4). In patients Nos 1 and 6 the examination was not repeated.
Discussion As a rule one bronchial artery exists on the right side and two on the left but many variations occur (BOTENGA). Usually the right bronchial artery is easy to catheterize while it may be more difficult on the left side, especially in elderly patients. A complete demonstration of all bronchial arteries is therefore sometimes difficult to obtain, but the tumor-feeding artery is usually dilated, which facilitates the catheterization. Different opinions on the vascular supply of bronchogenic carcinoma have appeared in the literature (VIAMONTE et coll. 1965, MILNE1967). In our opinion, the tumor is mainly supplied by the bronchial arteries, and in no case was a supply from the pulmonary arteries demonstrated. In 2 of the patients only approximately one third of the tumor bulk was infused (Fig. 3). In both cases the tumor was located in the left lung and only one bronchial artery had been examined. Probably the rest of the tumor was supplied from the other bronchial artery. One of these patients (No. 6) did not respond to the therapy, otherwise no correlation between tumor vascularization and response was found. Examination in different views is recommended before the infusion therapy is carried out, in order to define the exact tumor supply and also to reveal if a spinal
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1052
C. H E L L E K A N T , E. BOUSEN A N D L. SVANBERG
artery arises f r o m t h e right bronchial artery. T h e left artery h a s n o direct c o n n e c t i o n w i t h t h e spinal arteries b u t m a y c o m m u n i c a t e v i a collaterals w i t h t h e right bronchial artery ( B O T E N G A ) . Preinfusion a n g i o g r a p h y is therefore m a n d a t o r y , e v e n if there are n o i n d i c a t i o n s of n e u r o t o x i c i t y of M M C . Transverse myelitis is a well k n o w n c o m p l i c a t i o n i n bronchial a n d intercostal angiography ( F E I G E L S O N & R A V I N 1 9 6 5 , K A R D J I E V et coll.
1 9 7 4 ,MARGOLIS
1976).
A spinal artery m a y arise f r o m t h e f o u r t h o r fifth right o r left intercostal arteries ( F A U R E e t coll. 1 9 6 7 , B O T E N G A ) a n d special care s h o u l d b e t a k e n if these vessels are catheterized while searching f o r t h e b r o n c h i a l artery a n d t h e catheter i m m e d i a t e l y w i t h d r a w n . W i t h that t e c h n i q u e a n d m o d e r n contrast m e d i a t h e risks s h o u l d be small ( D J I N D J I A N & F A U R E 1 9 6 7 ) .
A o r t i c rupture h a s been reported after infusion of nitrogen mustard i n t o t h e b r o n c h i a l artery ( S T E C K E L et coll. 1 9 6 7 ) , a n d a t this h o s p i t a l severe local necrosis h a s o c c u r r e d w h e n M M C h a s e x t r a v a s a t e d a t i n t r a v e n o u s injection. N o i n d i c a t i o n s of injury t o t h e arterial wall h a v e a p p e a r e d in t h e present series, p r o b a b l y d u e t o t h e d i l u t i o n of t h e drug a n d t o t h e s l o w infusion rate. T h e r e c o m m e n d e d daily d o s e of M M C intravenously is 0 . 0 5 m g / k g b o d y weight for t e n d a y s t o b e repeated until t o x i c effects are o b s e r v e d . H o w e v e r , recent reports indicate that intermittent large-dose a d m i n i s t r a t i o n is m o r e effective ( C R O O K E BRADNER
&
1976).
T h e literature o n intraarterial treatment with M M C is scarce b u t usually it h a s b e e n u s e d i n c o m b i n a t i o n with o t h e r cytostatics, e.g. 5 F U ( M I U R A et coll. 1 9 7 1 ) . I n this preliminary series it w a s t h o u g h t w o r t h w h i l e t o try a different
schedule;
vincristine a n d B L M were used t o s y n c h r o n i z e a n d stabilize t h e cell cycle at t h e G
2
stage w h e r e t h e t u m o r cells are believed t o be m o s t susceptible t o M M C ( T E R A S I M A 1 9 7 5 , M I Y A M O T O et coll. 1 9 7 7 ) . T h e c o m b i n a t i o n of B L M a n d M M C also has t h e a d v a n t a g e of a different toxicity. B L M has b e e n used previously against p u l m o n a r y car c i n o m a w i t h s o m e results, a l o n e o r i n c o m b i n a t i o n with irradiation, but the d o s e s h a v e b e e n m u c h higher ( O K A & K O M O 1 9 7 4 , S V A N B E R G 1 9 7 6 ) . R e c e n t reports f r o m J a p a n s h o w that a similar s c h e d u l e w i t h small d o s e s of B L M a n d large intermittent d o s e s of M M C h a s b e e n effective in treating c a r c i n o m a of t h e uterine cervix ( M I Y A M O T O et coll.). In a d d i t i o n , vincristine s e e m s t o p o t e n t i a t e M M C ( P O U I L L A R T et coll. 1 9 7 4 ) . T h e p r o b l e m in e s t i m a t i n g t h e effect of a n anticancer drug is mainly t h e difficulty in o b t a i n i n g objectively m e a s u r a b l e d i a m e t e r s of t h e t u m o r . U s u a l l y t h e p r o d u c t of t h e t w o largest d i a m e t e r s is u s e d a n d t h e result given a s m o r e o r less than a 5 0 p e r cent r e d u c t i o n . I n centrally l o c a t e d l u n g t u m o r s these m e a s u r e m e n t s m a y n o t be possible t o carry o u t a n d o n e h a s t o rely o n e v a l u a b l e b u t n o n - m e a s u r a b l e signs of regression s u c h a s decreasing m a s s effect a n d better aeration of t h e l u n g p a r e n c h y m a distal t o t h e t u m o r . T h e reliability of such e v a l u a t i o n s has been confirmed by D A W S O N et coll. ( 1 9 6 6 ) .
Often t h e chest films s h o w very little regression, while b r o n c h o s c o p y m a y reveal a m a r k e d regression, a s w a s t h e case in 3 of t h e present patients ( N o s 2 , 7 , 8 ) with
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION O F MITOMYCTN-C IN THE B R O N C H I A L ARTERY
1053
central t u m o r s . H o w e v e r , these p r o b l e m s s e e m m o r e i m p o r t a n t in i n o p e r a b l e patients than in a series like the present o n e where all patients were o p e r a t e d u p o n a n d the effect of the treatment c o u l d be e v a l u a t e d at the o p e r a t i o n or in the resected speci men. In 4 patients the preoperative T N M - c l a s s i f i c a t i o n turned o u t t o be t o o o p t i m i s t i c . It is well k n o w n that direct spread t o mediastinal structures is very difficult to detect preoperatively and that m e d i a s t i n o s c o p y is reliable only c o n c e r n i n g l y m p h
nodes
in the upper parts of the m e d i a s t i n u m ( L A R S S O N 1976). In o n e patient a metastasis in the l o w e r part of the hilum c o u l d be d e m o n s t r a t e d (Fig. 4) and in a n o t h e r t u m o r vessels were d e m o n s t r a t e d in the m e d i a s t i n u m . T h i s indicates that a n g i o g r a p h y m a y be of h e l p in the preoperative staging. Concluding
remarks.
T h e present material is small and the p o s t o p e r a t i v e
time
short but s o m e c o n c l u s i o n s m a y be d r a w n . M M C is well tolerated, given as a s l o w infusion into the bronchial arteries. In patients where the preoperative T N M - c l a s sification of T 2 N 0 1 MO held true, a remarkable effect occurred after a single infusion of 10 m g of M M C , w i t h c o m p l e t e r e m i s s i o n of the t u m o r in 2 patients, a l m o s t c o m plete remission in o n e , partial remission in o n e , a n d a m a r k e d but u n m e a s u r a b l e regression in another.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1054
C. H E L L E K A N T , E. E O U S E N A N D L. S V A N B E R G
In patients where t h e o p e r a t i o n revealed a m o r e a d v a n c e d stage the response w a s less e v i d e n t , b u t partial r e m i s s i o n w a s a c h i e v e d in o n e a n d a m a r k e d regression in a n o t h e r of these patients. O n t h e basis of t h e s e preliminary results a r a n d o m i z e d investigation has been started w i t h r e p e a t e d intraarterial i n f u s i o n s of M M C i n t o the bronchial arteries of patients w i t h s q u a m o u s cell c a r c i n o m a of the lung.
SUMMARY Bronchial angiography was performed in 9 patients with squamous cell carcinoma of the lung. The tumor-feeding vessel was identified and infused with 10 mg of mitomycin-C ( M M C ) diluted in saline. At operation after 28 to 48 days complete remission of the tumor had occurred in 2 patients, almost complete in one, partial remission in 2 and a marked regression in 2. In 2 patients no change was noted. N o side effects except moderate malaise and slight fever occurred.
ZUSAMMENFASSUNG Eine bronchiale Angiographie wurde bei 9 Patienten mit Schuppenzell-Karzinom der Lunge vorgenommen. D i e Tumor-versorgenden Gefasse wurden identifiziert und mit 10 mg Mitomycin-C, verdiinnt in Kochsalzlosung, infundiert. Bei Operation nach 28 bis 48 Tagen war eine komplette Remission des Tumors bei zwei Patienten erfolgt, eine beinahe komplette bei einem, eine partielle Remission bei zwei und eine kraftige Riickbildung bei zwei Patienten. Bei 2 Patienten war keine Veranderung festzustellen. Keine Neben-Effekte, mit Ausnahme einer leichten Obelkeit und leichten Fiebers, waren festzustellen.
RESUME U n e angiographie bronchique a ete faite chez 9 malades atteints de carcinome epidermoi'de du p o u m o n . Le vaisseau nourricier de la tumeur a ete identifie et perfuse avec 10 mg de Mitomycine-C ( M M C ) diluee dans du serum sale. A l'operation apres 28 a 48 jours une remission complete de la tumeur s'etait produite chez 2 malades, remission presque complete chez un malade, partielle chez 2 malades et regression marquee chez 2 malades. Chez 2 malades il n'y avait pas eu de modification. Les auteurs n'ont pas observe d'effet secondaire excepte un malaise modere et une legere fievre.
REFERENCES BOIJSEN E., D A H L B A C K O., KUGELBERG J., SCHULLER H . und ZSIGMOND M.: D i e
Behandlung
des inoperablen Bronchuskarzinoms mit Zytostaticainfusion via Aa. bronciales. Thoraxchirurgie 12 (1964), 198. BOTENGA A. S. J.: Selective bronchial and intercostal arteriography. H . E. Stenfert Kroese, Leiden 1970. CROOKE S. T. and BRADNER W . T.: Mitomycin C. A review. Cancer Treat. Rev. 3 (1976), 121. D A W S O N J. M.,
H A L L T. C ,
SCHNEIDERMAN M. A., SCHNIDER B. I., O W E N S A. H . , A N D R E W S
J. R., BAXTER D . H . , BRENNER S., H U N T E R C ,
LEVENE M. B., SHEEHAN F. R. and
WHITE
G.: Objective evaluation of change in tumor size in lung cancer patients with nonmeasurable disease. Cancer 19 (1966), 415.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
PREOPERATIVE INFUSION OF M1TOMYCIN-C IN THE BRONCHIAL ARTERY
1055
DJINDJIAN R. et FAURE C : Accidents medullaires de l'aortographie. J. beige Radiol. 50 (1967), 207. FAURE C , LEFEBVRE J., D E B R U N G. et DJINDJIAN R.: La vascularisation arterielle normale
et pathologique du renflement lombaire de la moelle epiniere chez 1'enfant. L'artere d'Adamkiewicz. Ann. Radiol. 10 (1967), 129. FEIGELSON H. H. and RAVIN H . A . Transverse myelitis following selective bronchial arterio graphy. Radiology 85 (1965), 663. HALLER J. D . , BRON K. M., WHOLEY M. H . , POLLER S. and ENERSON D . M.: Selective
bronchial artery catheterization for diagnostic and physiologic studies and chemo therapy for bronchogenic carcinoma. J. thorac. cardiovasc. Surg. 51 (1966), 143. K A H N P. C , P A U L R. E. and RHEINLANDER H . F . : Selective bronchial arteriography and
intra-arterial chemotherapy in carcinoma of the lung. J. thorac. cardiovasc. Surg. 50 (1965), 640. KARDJIEV V . , SYMENOV A. and CHANKOV I.: Etiology, pathogenesis and prevention of spinal cord lesions in selective angiography of the bronchial and intercostal arteries. Radiology 112 (1974), 81. LARSSON S.: Mediastinoscopy in bronchogenic carcinoma. Scand. J. thorac. cardiovasc. Surg. (1976) Suppl. N o . 19. MARGOLIS G.: Spinal cord complications of angiography. In: Complications in diagnostic radiology, p. 134. Edited by G. Ansell. Blackwell Scientific Publications, Oxford 1976. MILNE E. N . C : Circulation of primary and metastatic pulmonary neoplasms. A post mortem microarteriographic study. Amer. J. Roentgenol. 100 (1967), 603. MIURA T., ISHIDA M. and HATANO S.: Combination cancer chemotherapy by regional intra-arteriai or intra-aortic infusion of 5-Fluorouracil and Mitomycin-C with or with out irradiation. Jap. J. Surg. 1 (1971), 133. MIYAMOTO T., TABAKE Y., WATANABE M. and TERASIMA T.: Drastic remission effect of a
sequential combination of Bleomycin and Mitomycin-C ( B - M ) on advanced cervical cancer. Cancer Chemother. 4 (1977), 273. O K A S. and KOMO K..: Treatment of lung cancer with bleomycin. Abstr. X I Int. Cancer Congr. 1974, p. 589. POUILLART P., H O A N G T H Y H U O N G T., BRUGERIE E. and LHERITIER J.: Sequential adminis
tration of two oncostatic drugs. Study of modalities for pharmacodynamic potentiation. Biomedicine 21 (1974), 471. STECKEL R. J., D O P P M A N J. L . , ROLLEY R. T. and MARTOS E. J.: Rupture of the aorta after
mechlorethamine HC1 infusion of a bronchial artery. J. Amer. med. Ass. 199 (1967), 186. STOTT H . , STEPHENS R. J., F o x W . and R O Y D . C : 5-year follow-up of cytotoxic chemo therapy as an adjuvant t o surgery in carcinoma of the bronchus. Brit. J. Cancer 34 (1976), 167. SVANBERG L . : Regional functional decrease in bronchial carcinoma. A n n . thorac. Surg. 13 (1972), 170. — Bleomycin and lung cancer. Gann 19 (1976), 193. TATE JR C. F., VIAMONTE JR M. and A G N E W J. R.: Bronchial arterial perfusion with cyto toxic agents for bronchogenic carcinoma. Amer. Rev. resp. D i s . 97 (1968), 685. TERASIMA T.: Proposals of tumor therapy based o n cell cycle dependent sensitivity change. (In Japanese.) Gann t o Kagakuryoho 1 (1975), 533. U I C C , International U n i o n Against Cancer. T N M . Classification of malignant tumors. Second edition. Geneva 1974. VIAMONTE JR M., PARKS R. E. and SMOAK W. M.: Guided catheterization of the bronchial
arteries. Part II. Pulmonary and mediastinal neoplasms. Radiology 85 (1965), 214.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
1056
C . H E L L E K A N T , E. B O I J S E N A N D L . S V A N B E R G
W A K A K I S., M A R U M O H . , TOMIOKA K . , SHIMIZU G . ,
KATO E., KAMADA H . ,
K U D O S.
and
FUJIMOTO Y.: Isolation of new fractions of antitumor Mitomycins. Antibiot. and Chemo ther. 8 (1958), 228. WASSERMAN T. H . , COMIS R. L.,
GOLDSMITH C ,
HANDELSMAN H . , PENTA J. S., SLAVIK
M.,
SOPER W . T. and CARTER S . K.: Tabular analyses of the clinical chemotherapy of solid tumors. Cancer chemother. Rep. 3 (1975), 399. WIRTANEN G . W . and ANSFIELD F . J . : Bronchial artery infusion in bronchogenic carcinoma. Cancer chemother. Rep. 52 (1968), 263.
Downloaded from acr.sagepub.com at MCMASTER UNIV LIBRARY on June 29, 2015
