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Chemotherapy Therapy (Larynx Cancer)
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Transcript of Chemotherapy Therapy (Larynx Cancer)
8/12/2019 Chemotherapy Therapy (Larynx Cancer)
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ABSTRACT:
Am Roenigenol 12 6 : 1082-1087, 1976
1082
A D JU V A N T C H E M O IM M U N O T H E R A P Y IN A D V A N C E D
L E S IO N S O F T H E H E A D A N D N E C K
F R E D E R I C K R . E ii.n t’ A N D D O N A L D L . M ow ro c’
G ro w th o f m aligna n t tu m o rs o f the h ea d an d ne ck ha s b ee n a ssoc ia ted w ith p ro -
g ress ive im pa irm en t o f im m u no log ic ac tiv ity . S u cc e ssfu l co n tro l o f d ise ase ha s b e en
sho w n to rev erse th is de fe ct. P re lim ina ry re su lts o f a no nra nd om iz ed tria l red uc ed
re cu rren ce o f h ea d a nd n ec k c a nc er fo r a m e d ia n tim e o f I I .5 m on ths in eigh t o f 10
p atien ts w h o rec e ive d c he m o im m u no the ra py ad ju va n t to su rg ic a l re sec tio n o r
ra d ia tio n trea tm en t. T he nu m b er o f p atie n ts in th e serie s w a s sm all an d th e fo llo w -
u p tim e to o sho rt to de te rm in e th e le ng th o f e ffec tiv en ess fo r th is tre a tm e n t. B ase d
o n th ese resu lts , a n ew p ro to co l ha s be e n in itia ted to ran do m iz e pa tie n ts w ith a d -
va nc e d T 3 a nd T 4 le sion s in to g ro up s fo r co m p a riso n o f a d ju va n t c he m oth era py
a lon e w ith a d ju va n t c he m o im m u no the ra py .
INTRODUCTION
T h e c on ce p t o f ho s t re s is ta nc e a s an im po r-
tan t fac to r in b o th th e inc ep tio n an d pro -
g ress io n o f h ea d a nd ne ck m a lig na nc y ha s
b ee n p ro po sed fo r m a ny y ea rs . I t o rig ina tes
fro m o bserv a tion s o f th e u np red ic tab le
clin ic al c ou rse fo r p atien ts w ith tum ors in
the se a na to m ic lo ca tio ns . W h ere a s som e
pa tie n ts ha ve a ra p id rec u rre nc e o f d ise ase
de sp ite a pp are n tly a de qu ate trea tm en t fo r
ea rly tu m o rs, o th e r p atien ts de m o nstra te a
re la tiv ely slow p rog ress io n o f d ise ase de -sp ite fa r-a dv an ce d m a lig na nc ies .
G ro w th o f m a lig na n t tu m o rs o f the h ea d
a nd n ec k h as be en a ssoc ia ted w ith p ro g re s-
sive im p airm e n t o f im m uno lo g ic re ac tiv ity
[I]. A n er g y h as be en ob se rve d in pa tie n ts
p rio r to the d ev elopm e n t o f c ac he x ia a nd
m a lnu tritio n , e ve n w itho u t w id esp rea d
v isc e ra l a nd bo ne m a rro w in vo lve m e n t.
T he im m u no log ic im pa irm en t no te d in
c an ce r p atie n ts w as no t a de fec t th at p re -
c ed ed th e de ve lop m e n t o f m a lign an c y
be ca u se it co u ld be re v erse d if suc ce ssfu l
co n tro l o f d ise ase w a s ac h iev ed [2 -4 ] . O pt i -
m is tic a lly , the n , it m ig h t be p oss ib le to
au gm e n t the im m u no log ic re a ctiv ity o f the
c an ce r p a tien t. H ow ev e r, a dd ition a l re-
p o rts ha v e sh ow n th at th e th era pe u tic
m od ali tie s u sed to trea t ne op lasm s o f the
he ad a n d n ec k a re th em selve s im m u no -
sup pre ss ive . T he su ppre ss ive e ffec ts o f
s u rge ry [ an d ch em o the rap y [6 ] ap pe ar to
be o f re la tive ly sho rt du rat ion ; the im -
m un osu pp ress ive effe c ts o f ra d io th era py
[7 , 8 ] m ay o r m ay n o t be m o re p ro long ed
[9 -I I ]. T h u s it w ou ld see m tha t if im m u no -
lo g ic rea c tiv i ty co u ld be m ain ta ine d d urin g
tre atm e n t, a g re ate n th era pe u tic b en efi t
m igh t be a c h ie ve d .
W hile im m u no the ra py fo r tre atm e n t o f
m align an cie s in lab o ra to ry a n im als a s w e ll
as fo r m a lign a n t m e lan om a in m an ha s
be en sho w n to b e e ffe ctive its u se is
lim ite d . In la bo rato ry an im a ls it w as o f
be ne fit w he n th e tum or bu rd e n w a s in a
ra t io o f a pp rox im a te ly I07_108 cel ls [12] ;
la rge r a m o un ts o f tu m o r rare ly re spo nd ed
to im m un o lo g ic m a n ip u la tio n . T h ese sam e
prin cip le s se em to b e a pp lic ab le in m a n . A
the rap eu tic e ffec t w a s ge n era lly a ch ie ve d
in p at ien ts w ith su bc lin ica l d isea se [13 ]
w he re as fo r m ore ad va nc ed d isea se , re su ltsw ere n o t n e arly a s im p ress iv e [14] . If im -
m u no the ra py is ap p lied to the tre a tm e n t o f
pa tie n ts w ith tu m o rs o f th e he ad a nd n e ck ,
T h e se inve stig ation s w e re sup porte d by gra n ts from the U .S . P u blic H ea lth Serv ice (C A 1258 2) an d fr om S u r g ic a l S erv ic es, S epu l-
ve d a V ete ran s A d m in istr a tion H o sp ita L
1 D iv is ion o f O n co logy , D ep artm e n t o f S u rg er y , U C L A C e n ter for th e H ea lth S cie n ce s , Lo s A ngeles, C a lifo rn ia oo2 a nd S ur gic al
S e rv ices , S ep ulv eda V e terans A d m inis tra t ion H ospita l S e pulved a, C a lifo rn ia 91343 . A d d r e s s rep r in t req ue sts to the D iv isio n o f
O ncology .
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C H E M O IM M U N O T H E R A P Y IN H E A D A N D N E C K L E S IO N S 1083
it c an no t be use d a s a p rim a ry tre a tm e n t
m o da lity bu t ra the r a s a n ad juv an t to th e
e x ist ing the ra pe u tic m o da lities o f su rge ry ,
ra d ia tion , an d c h em oth e ra p y .
P re lim ina ry rep o rts from D o na ld so n
[ 15 , i6 ] h av e sh ow n tha t a g re a te r the na -
pe u tic resp on se w a s ac h ie v ed in he ad an d
n ec k p atien ts w h en B C G , a no nspe c ific im -
m u ne s tim u lan t, w a s c om bin ed w ith ch em o -
the rap y (m e th o tre xa te ) tha n w he n c he m o-
th era py a lon e w as use d .
T h is pa p er d e sc rib es a pha se I p ilo t study
d es ig ne d to de te rm in e the effe c t o f B C G
im m un o th era p y in c om bina tio n w ith
m e th o tre xa te . T h is reg im en w as e va lua te d
in p a tien ts w ith recu rren t m a lign an t d isea se
of the he ad a nd ne ck a nd in p atie n ts w ith
a dv a nc ed le s io ns w h o h ad a n 8o ch an c e
o f re c u rre nc e w ith s tan da rd m o de s o f
therapy.
S U B JE C T S A N D M E T H O D S
T he 20 pa tie n ts iR v es tiga ted w ere ev alu a ted
e ith er in th e D ep a rtm e n t o f S u rg e ry , D iv is io n
o f O n c o lo gy , U C L A S c ho o l o f M e d icin e , o r the
S epu lveda V ete rans A dm in istra tion H o sp ita l,
S e pu lv ed a, C a lifo rn ia . T he y ra ng ed in ag e fro m
29 tO 73 y e ars . A ll ha d a dva n ce d ‘F 3 or
squ am o us ce ll ne op lasm s of the he a d a nd n ec k
reg ion an d ha d no h isto ry o fp rio r m a lign a nc ies
o r e v id e nc e o f w id esp re a d tu m or b efo re a d -
m in istratio n of chem o im m u no th erapy . P a -
tie n ts w e re c lin ica lly e va lu ate d b y c om ple te
p hys ica l exam ina tion , chest x -ray , an d liv e r,
b ra in , a nd b on e sc a n p rio r to en te ring the s tu dy .
H isto log ic con firm a tion of sq uam o us C eil ca rc i-
n o m a w as o b ta ine d in e ve ry c ase .
T he ex pe rim en ta l na tu re o f the p ro ce du res
w a s ex p la in ed to ea ch pa tie n t p rio r to e n terin g
th e s tud y a nd a s ig ne d co nse n t w a s ob ta ine d .
P a tie n ts w ere d iv id ed in to th ree c a teg o rie s :
tho se w ho h ad fa ile d o n all p rev iou s the ra py
a nd h ad e s ta b lish ed d isea se (ta b le x ) ; and tho se
w h o d id no t h av e clin ic al ly e v ide n t d ise a se b u t
w h o w ere trea te d p rop hy la ctica lly fo r sub -
c lin ic al d ise ase fo llow ing rad ia tion th era py
(table 2) or su rge ry an d rad ia tio n the rap y
table 3 .
T h e c he m o the ra pe u tic d rug m e tho tre xa te
( o m g /m 2) w as a d m in is te red o nc e a w ee k fo r
I m on th an d e ve ry o th er w e ek the rea fte r fo r
the du ration o f th e s tud y . Im m un o th e ra p y
w a s a cc om plish e d w ith B C G T ice s tra in from
C hic ag o R e se a rch , a dm in is tere d by the T in e
te ch n iq ue to the ax illa e an d bo th g ro in s ev e ry
w ee k fo r 3 m o n th s a nd the n ev ery o th er w e e k
fo r the du ration o f the s tu dy . F o llow -u p ex am i-
n ation w a s pe rfo rm e d ea c h m o n th .
A c om ple te resp on se to ch em othe rap y w as
d efine d a s th e d isap pe ara n ce o f a ll v is ib le d is-
e a se an d no ev id en ce o f ne w d isea se fo r a
p eriod o f 2 m on ths. A pa rtial re spo nse w as de -
fin ed a s o re du ction in e s tab lishe d d ise ase
and no new lesion s. W h ile su rg ical p roced ures
d iffere d fo r e ac h pa tie n t, the y ba s ic ally in -
c lud e d e n b lo c re sec tio n o f th e p rim a ry tu m or
a nd reg ion al ly m ph no de s . X -ra y trea tm en t
w a s g iv en us in g c ob alt 6o te le th era py at a
d osa ge o f oo o -6 ,o oo rads o ve r 6 w eeks.
Im m uno log ic eva lu atio ns o f de layed cu tane -
o us hy pe rsen s itiv ity w ere pe rfo rm e d w ith top i-
c al ly ap p lie d d in i troc h lo rob en z en e (D N C B )
and a ba ttery o f reca ll an tig en s. R eac tions w ere
re co rde d a fter 48 h r. S eria l D N C B sk in te s ting
w as p erfo rm ed a t m on th ly in te rva ls [J. A
hy persens itiv ity sco re w as ass igned to each
te s t, an d a sc o re o f 3 o r g re ate r w as c ons id e red
pos i t ive [17] .
R E S U L T S
T a b le I sh ow s th e re su lts o f ch em oim -
m u no the na py in s ix p at ien ts w ith es ta b -
l ishe d re c u rre n t d ise a se . A c o m p lete n e-
sp on se to c he m oim m u no th era py w a s ob -
ta m ed in o n ly on e pa tie n t , n o . i. T h is pa -
tie n t ha d ree x cis io n o f th e p rim ary tum or,
m a x illary a n tru m , a nd o rb it m on th s a fter
in itiatio n o f chem oim m un o the rap y an d has
b ee n free o f d ise a se 6 m on th s fo llow in g th is
su rge ry . M icro sco p ic re s idu al d ise ase w as
p rese n t in th e op era tiv e sp ec im en . P a tie n ts
2 an d 3 ha ve m ain ta ine d a o re duc t ion
in tum o r size fo r and 5 m o nths, re spec -
t ive ly . B o th pa tie n ts ha ve c lin ica lly e v id en t
res id ua l d ise a se bu t h av e no t de ve lop ed
ne w le s ion s. T he re m ain ing th re e p at ien tsd id no t ha ve a ny m ea su ra b le d ec rea se in
tum or s iz e , an d a ll e xp ire d .
S im u lta ne ou sly , w e be ga n a no nna n do m -
ize d p rosp ec tiv e s tud y of th e B C G -m e th o -
trex ate co m b in atio n a s a d ju va n t tre a tm e n t
to ra d ia tio n o r su rge ry . T a b le 2 sho w s the
resu lts o f trea tm en t w ith a d ju va n t c he m o-
im m u no the rap y fo r s ta ge T 3 a nd T 4
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N o ra .-N on e of th e se p atien ts w ere tr ea te d su rg ic a lly .
1084 E IL B E R A N D M O R T O N
T A B L E
C H E M O IM M U N O T H E R A P Y IN P A T IE N T S W IT H E S T A B L IS H E D R E C U R R E N T D IS E A S E
Locat ion of
P atie n t A ge P rim a ry M alig nan t D ate o f X -ray D ate o f C h e m oim m u n o - R esp on se F o llo w -u p
N o. (Y r ) T u m or N ec k N o d es O p er a tion T h er ap y R ec u rr en c e th e ra p y ( ) ( M o )
I 6 Antrum - IO/’74 P reO p 4 /’7 4 M tx , B C G 10 0 6
and 8 /’73
in tra- I
cranial
2 7 3 T em p o r a l 4/1 2 I2 /’74 P o stO p I/F 75 * M tx , B C G o 4
bone 12/’74
3 54 R et r o m o l a r 10 /I 5 8 /’74 P o s t O p 10/174* M tx , B C G o9 /174
4 62 Larynx 4 /10 8 /’74 P o stO p 12/’74 M tx , B C G o 39/174
5 6 i T o nsil + . . 8 /’73 I2 /’73 M tx , B C G o 3
6 5 T o n g u e + . . . 8 /’73 Io /’73 M tx , B C G o 2
base
I Dur i ng x-ra y th er ap y.
squ am ou s c e ll ca rc ino m a of the he a d an d pa tie n ts ha d po stop era tiv e ra d ia tio n the n -
n e ck in w h ich rad ia tion th era py w a s th e ap y to the tum o r b ed a nd the re g io na l
p rim ary m od ality . O f the fou r pa tien ts lym pha tic s excep t fo r pa tien ts 4 an d w ho
tre ate d th us far, th re e a re free o f re cu rren t w ere op era te d on afte r ra d ia tio n th era py
d isea se a fter a m ed ia n o f 6 m o n th s . O n e fa ilu re .
p atien t h ad ra p id re cu rren ce de sp ite ra d i-
a tio n a nd ch e m o im m un o the rap y a nd cx - Toxici ty
p ired w ith in 4 m on ths o f on se t o f trea t- F o r s ix o f th e 14 pat ien ts (40 ) t rea ted
m en t. A ltho ugh the fo llow -u p tim e is w ith ad ju van t ch em oim m un o the rap y , it
re la tive ly sh o rt fo r the se p atien ts , th e ir w a s n ec e ssa ry to d ec rea se the sc he du le d
c lin ica l resp on se ha s be e n d ram a tic . d osa ge o f m e tho tre xa te . T he m a jo r tox ic
A serie s o f io p atien ts w a s tre ated w ith e ffec t w a s he m ato po etic , m a n ife s ted b y
ad juv an t c h em oim m un o th era py fo llow in g w hite ce ll co un ts low e r tha n 2 ,000 . T h e de -
su rg ica l ex cis ion of all g ross tu m or p lus lay in treatm en t w as n ev er m ore than i
rad ia t ion the rap y (ta b le 3 . E igh t o f th e 10 w e ek . N o inc id en ce o fre na l tox ic ity , se ps is ,
( 8o ) are a live and free o f recu rren t d is- o r pe rm anen t bon e m arrow tox ic ity w as
ea se after a m e d ian o f i i . m o nth s . A ll o bse rv e d . O ra l u lc era tio n w as ob se rv ed in
T A B L E 2
C H E M O IM M U N O T H E R A P Y A S A D JU V A N T T R E A T M E N T T O R A D IA T IO N T H E R A P Y
Locat on of
P a tien t A ge Pr imary M align an t X -R ay T h er ap y C h em oim m u n o- F o llow -u p
N o . (Y r ) T u m o r N ec k N od e s (R ad ) th e rap y S ta tu s (M o)
I 6 8 R e trom o lar + s ,o oo M tx , B C G N .E .D . 4
2 48 T ong ue base + 5 , 000 M tx , B C G N .E .D . 8
3 47 T on gue ba se - 5 ,o oo M tx , B C G N .E .D . 6
4 6 L a r y n x 5 , 000 M t x , B C G E xp ired 4
(r u r re nc e )
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1086 E IL B E R A N D M O R T O N
o ur o p in ion , th e B C G -m etho trex ate c om -
b ina tion app ears to h ave lim ited v alu e fo r
th is type of pa tien t. O n ly one of six pa -
tien ts ach ieved a co m ple te re spo nse , and
th a t ha d to be fo llo w e d by fu rthe r su rg ic a l
in te rve n tio n . T h us i t a pp ea rs u n like ly tha t
c om plete tu m o r de s truc tio n w a s e ve r
a c h ie ve d .
T h e re su lts o f c he m o im m u no the ra py a s
ad ju van t to su rge ry o r irrad ia tion w ere
m u ch m o re im pre ss iv e . S in ce , s ta tis tic a lly ,
8 o o f the se p atien ts w ou ld deve lop re -
c u rre n t d ise ase , re sidu al sub cl in ic a l d ise a se
w a s ve ry like ly p re sen t a t th e c om pletion
o f su rg ery an d /o r rad ia t ion th era p y . T he
fa vo rab le re su lts re po rted he re m ust be
te m pe red by the fac t tha t th is w a s n o t a
ra n dom iz ed tria l n o r d id it inc lu de c on -
se c u tiv e pa tie n ts ; a lso , the du ration o f the
s tu dy w a s re la tiv ely sho rt. H o w ev er, the
re su lts a re encourag ing since th e c lin ical
c ou rse o f pa tie n ts w ith a dva n ce d tu m o rs o f
th e he a d an d n ec k is re la tiv ely c on s ta n t.
T he m e d ia n tim e to rec u rre nc e in sev era l
se rie s is ap p ro x im ately 8 m o n th s . A m uc h
lon ge r fo llo w -up tim e is o bv iou s ly re qu ired
b efo re th e a c tua l ou tco m e fo r the se pa -
tien ts c an b e d e term in ed . H o w e ve r, it d oe s
a pp ea r th at the p roc e du re o f c he m o -
im m un o th era py is w ell to lera te d w ith a c-
c ep ta b le tox ic ity a nd th at it d e cre ase s th e
re cu rren c e ra te , a t le as t b ase d on the sho rt-
te rm fo llow -u p of the se pa tie n ts . W he th er
th e d ise ase w ill e ve n tu al ly re c u r rem a ins
to b e see n .
In ad d ition , the qu es tio n rem ains o f
w h ethe r B C G im m un o th era py c on tribu te d
to the ch em othe rap eu tic re g im e n . O n th e
b asis o f th ese lim ited da ta , the answ er is
u nc erta in . A lth ou gh the n on spe cific re-
a ctiv ity to D N C B w as m ain ta ine d in fou r
p atien ts and even rev e rsed fro m n eg ativ eto p os it ive in 12 patients , it is no t c le ar
w h eth er B C G w a s respo ns ib le . C o nse -
q ue n tly w e ha ve b eg un a p ro spe ctive tria l
th at w ill ran do m ize pa tie n ts w ith a d -
v an ce d T 3 a nd T 4 les io ns in to a d ju va n t
c he m o the ra py a lon e v ersu s ch em oim m un o-
the ra py .
H op efu lly a c om bin at ion o f p rese n tly
a va ila b le tre a tm e n t m od a litie s -su rge ry ,
rad ia tion the rapy , chem oth e rapy , and im -
m u no th erapy-w ill re su lt in a m ore su c -
c e ssfu l m e an s fo r d isea se c on tro l in a
g rea te r p ercen tag e of th ese pa tien ts .
R E F E R E N C E S
I . E ilber FR , M o rton D L , K e tcham A S : C orre la -
tion o f im m uno lo g ic reac tiv ity and c lin ica l
co urse in pa tien ts w ith so lid neop la sm s o f th e
h ead and n eck in N eop la sia o fthe H ead an d N eck,
Proceed ings 17th A nnu a l C lin ica l C onfe rence
o n C ancer , M . D . A nd erson H o sp ita l and T u m o r
Institu te, C h icag o , Y ea r B ook M edica l P ub -
lishers ‘974 pp. 2 1 1 -21 9
2 . Y ou ng R C , C o rde r M P , H ay ne s H A , e t. a /.:
D elay ed hyp ersensitiv ity in H odgk in ’s d isease -
a s tud y o f 10 3 un trea ted pa tie n ts . A m 7 M ed
52:63-72 1972
3. E ilber F R , N izze JA , M o rton D L: S eq ue n tia l
ev alu atio n of gene ral im m une com pe ten ce in
cance r p a tien ts: co rrela tion w ith c lin ica l cou rse .
C ancer 35 :6 60 -66 5, 1975
4. E ilb e r FR , M orto n D L , K e tch am A S : Im m u no-
lo g ic abno rm a litie s in head and n eck cance r.
. .lm 7 S u r g 12 8 :534 -538 , 1974
5. R oth JA , E ilbe r F R , M orton D L : E ffec t o f
su rge ry on in v itro lym pho cy te fun ctio n . S u r g
Forum 25:102-104 1974
6 . H ersh E M : M o difica tion o f ho st de fense m ech a-
n ism s, in C ancer M ed icine , ed ited by H olland
JF , F re i E , P h ilade lph ia, L ea & F eb ige r, 1973 ,
p p 6 8 1-699
7. C o sim i A B , B run ste tter F H , K em m ere r W T ,
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