THE
EFFECT
OF
ACTINOMYCIN
D ON
CANCER
IN
CHILDHOOD
Charlotte 1. C. Tan, M.D., Harold W. Dargeon, M.D., and
Joseph H. Burchenal, M.D.
Division 01: Clinical Cheniothierapy, Sloan-Kettering Institute, Departnents of Pediatrics (11(1 Iedicine,
\femorial Hospital, Memorial Center for Cancer and Allied Diseases’, New York, and
Cornell UniversIty Medical College
(Accepted April 27, 1939; stibniitted March 1:3.)
The work reported in this paper was supported in part by grants from the National Cancer Institute
(grant CY-:3215), PtIl)liC i-Ieilth Service, and institutional grants from the American Cancer Society, the Damon Runyon \Iemoriai F’und for Cancer Research, Lasker Foundation, the Black-Steve:lsoII Foundation, and the Children’s Cancer Fund of Anierica, American Legion Auxiliary, I)epartinent of
New York.
ADDRESS: (C.T.C.T.) Sloan-Kettering Institute, 444 East 68th Street, New York 21, Ness’ York. PEnIATIIIcs, October 1959
544
T
HE ACTINOMYCIN5 are a group ofanti-hiotics, the first of which was isolated
from a culture of a soil actinomyces in 1940
by Waksman and Woodruff.1 This
organ-ism was described as Actinomyces
(
Strep-tomyces) u2
THE ACTINOMYCINS
The first actiiiom’cin isolated was designated
actillonlycin A. During the intervening ears, a variety of actinomycins was isolated and studliedi, and each investigator gave thenl a iame such as “C”, “X”, and “I” b\ Brockmann et al. :-is “B”,’4-’7
“J”,15’
I “D”2 and others.21 On h’droivzing preparations of actinomvcill A and B, sarcosine, D-valine, L-threonine,L-proiine, and N-methyl-L-valine were Brockmann and Grubhofer’#{176} demon-strated that actinom’cin
C
was a mixture of very similar substances and that the actino-mycins are composed of a chromophor groupand 2 polypeptide chains. Upon hydrolysis,
D-alloisoleucine was preseiit in the hydrolvsate
in addition to the above five amino acids found
ill A and B. These complex mixtures were sepa-rated illtO three substances, C1, C2, and C3. I
Brockmann et al. determined their structures.
C1 contained D-valine in both peptides, C2 contains D-valine in one and D-ailoisoleucine
Ill the other pe1)tide, and C: d0I1tliI15
D-allo-isoleucme ill both peptides. The structure of actinomycin D was shown by Bullock et al.22
to be identical with that of actinomvcin C1.
The various preparations produced by the different species of actinomvcetes were com-posed of a mixture of actinomvcins, and the
components of the mixture varied with tile
Cill-ture method, the age of culture aii composi-tion of medium.232 Thus, the problem in nomenclature of the actinonlycins is first
ciiemi-cill’ to ch::racterize each actinonlycin and
secolldlly to determine the relative amount of
each type of actinom”cin as a pure sui)stance
ill a given filtrate. Waksman et 27 have given
each chemically distinct actinom’cin a Roman
numeral designation. At present, only actino-mvcill D, composed of actinomvcin IV27 (Fig.
1) is available in a relatively pure form, aiid
this was used 111 the present study. Actinom’cin
C (Sanamycin’( ), used widely in Europe, is
composed of C1, (actinom’ciii IV or D) C2 and
C (actinolllycili VI andl \TII).
PREVIOUS
STUDIES
OF
EFFECTS
OF ACTINOMYCINS
Waksman et al.25 ll 1941 and Robinson and Waksman2o ill 1942 reported the pharmaco-logic effect of actinomvcin A in mice, rats,
guinea pigs, and rabbits. At necropsY, the most striking phenomenon was the marked
diminu-tiOll ill the size and weight of the spleen.
Actinomycin A at 0.125 mg/kg given
intra-venously, disappeared from the blood within 15 minutes, l1ld 10 to 20 ‘as excreted! in the
urine within 6 hours.
In 1950, Stock and later Reilly et Cl.
reported tilat actiiiom’cms exerted sone
inhi-bition UO1l the growth of experimental tumors
in mice. In 1952, Hackmann2 reported that actinomcin C had some inhii)itory effects in a
number of animal tumors and! its cytostatic
FIG. 1. Structure of actinoniycin D.
Systeill. Others reported similar effects.5)9
Actinom’cin D was reported b’ Farber et
al.4_42 and other investigators to inhibit the growth of transplantable tumors in animals.13_)2
suggested that actinomvcin D inter-ferred with the synthesis of pantothenate in
lactobacillus test organisms. This mode of ac-tion \Vl5 not supported by other investiga-tors1’ 21 using Bacillus subtilis alidi
tumor-bearing animals.
Schulte2l ill 1954 summarized his experience with actinomnvcin C in 1CO patients with
Hodg-kin’s disease. Twent’s-eight of 43 patients who
received actinomycin
C alone
had
an objective response and 34 of 57 patients s’ilo received a combination of actinomvcin C and x-raytherap’ were benefited. In some 55 patients with other types of cancer treated with actino-mycin C there was no regression of the tumor
noted. Schmidt2 amid 12576S other groups
re-ported
their
results with actinomvcin C inap-proximatel 140 patients. Of these, 100 had
Hodgkin’s disease. Actinomvcin C had a transient belleficial effect in an occasional
pa-tient with Hodgkin’s disease.
Farber et al. 40-42 reported that actinomycin
D in some children produced regression of Wilms’ tumor, rhabdomvosarcoma and
Hodg-kin’s disease.
0thers have reported experiences with
actillOmycill D in patients with cancer.
The present report is an evaluat:on of
actinomycin D which was initiated in
Dc-cember, 1955, in the treatment of children
with metastatic cancer and includes 111
cases.
MATERIALS
AND
METHODS
OF
PRESENT STUDY
Actinomycin D was supplied as a red
crystal-line powder which was dissolved in absolute alcohol at a concentration of 1 mg/mi for
intravenous use, and as 1 mg oral tablets. The
calculated single dose was taken from the stock
solution with a 1-mi syringe calibrated in 1/100 sui)divisions, diluted with 20 ml of normal
saline, and mixed thoroughly before injection. Special precaution was exercised to avoid
cx-travasation of the drug which might cause celluiitis.
A single course of intravenous
administra-tion of actinomycin D consisted of 15 .g/kg
of body weight per day for five doses or a
total
of
75 sg/kg. If, after 2 weeks, there were110 signs of toxicity and no therapeutic effects
were obtained, the same dosage was repeated.
Some patients have received two to five or
more separate courses over a period of several
months.
The oral dosage of actinomvcin D was 3 to
10 mg daily Ill three divided doses.
Table I summarizes the data concerning the
type of neoplastic disease, number of patients
studied, and the objective response of the
disease. Of these patients, 109 had had pre-viotis conventional therapy, i.e.
,
surgery, x-ra’therapy or aikvlating agents. During therap’,
patients were examined daih’ for signs of
toxicity and evidences of therapeutic response.
The concentration of hemoglobin and the
leukocyte count were determined daily and
platelet counts twice weekly. Concentration of
urea
nitrogen
in blood and uric acid in serumwere determined at intervals of 1 to 2 weeks
and, in some I)atients, aspirations of sternal
marrow were performed and other chemical
examinations of the blood as indicated.
Roent-genograms of chest and bones were made
serially when the pretreatment studies showed
lesions caused by the neoplastic process.
For various reasons not all the patients
started on actinomvcin
D
received an adequatetrial of therapy and these were not included
ill the evaluation of the therapeutic results.
H3C. H
H3C”
I
I
. C-CH
FH3NSARCOSINE SARCOS1NEP1-.CH3
0 L- PRLINE L-PIkLINE
D-VALINE 0-VALINE
oi4
II3CHC-CH
Hl1 l4H
NH
CH3 CH3
0 ORAL
S IV
I-z
Lu C)
a:
Lu
a.
- MOUTh GI SKIN AWPEIA WBC PITh
tic. 2. Percentage of 1)Itients shosving various toxic nianifestations after oral mud intravenous
1(1-niinistration of actinonsvcin I). Of the 108 patients Who receive(i a(lequite therapy svith actinonlycimi D, 102 received it intravenously, :32 received oral (lOS(’S (this included six who received actinonlycill
1) orally 0111%’ and 26 ‘s’ho received it by both the intravenous 111(1 oral routes l)ut with a period of at
least 4 ‘seeks separating the imitrasemious s1l(l oral
courses so that toxicity could ie attril)nted to the specific route of ac!ministration). Sixteen patients wlio received the drug 1))’ both routes within 4
weeks were not inclu(le(l here for (‘5’lllIatiOfl of
toxicity.
546 ACTINOMYCIN D
‘i’ABIE I
NI\11F:II .SNI) I)I.s;NosF” 01’ P.STIIN’I’s ‘IlOWING OnjF:’TIvF: ItF>1oNsF: TO A(TIXUS1Y(’IN I)
.IOXI .%NI) A(’TINOMY(’IN 1) i’Ll’ X-I sv i’IIF: sl
lelinoniIein I) .1/0fl(’ .te/inornycin I) /111.5.V-ray 1’/ierajiy
I)iagnosex Total . , . . . . ‘ .
.\0. “uiIablc for Objeehre .\ o. ‘ table/or ()bjeelre
Eralnation Response km/nation lies/ooze
%iIII15 t uiimor 38 1 (; 6 1 7 1 l
Neurol)lastolna () 7 3 11 3
ithahdonmvosar(oI1Ia 1’, .5 1 7 5
HoII sar(oIIla 1.? 3 (1 9
ar(oI11mL hotryoi(Ies 4 1 0 3 3
En11)rvollal (areilloIlla 4 1 1 1 0
‘oft tissue sarcona ‘2 1 (1
ie(IL1IlII})IastoI1ma 2 1 0
ilepatonia 1 1 (I
Carcinonma of kidney 1 1 0
llodgkins (lisease S .1 1 1
lteti(uhiln eiI sarconia 4 i I
Lylnpllosar(omlla 3 1 1
A(llte 1(’tlkeIIlia I 2 (1
( i11OIIi( leukemia I 1 0
lotal 1 1 1 49 0; So
RESULTS
Toxic Effects of Actinomycin D
Tile toxic effects of actinomycin D (Fig.
2) were: 1) Redness and ulceration of the
tongue and! th(. huccal mucosa, usually
de-‘eloping within 1 to 3 clays after the
comnple-tion of tue course of intravenous therapy
and lasting for 3 to 5 clays. 2)
Gastrointes-tinal dlisturi)ances: vomiting 4 to 5 hours
after each injection and nausea, anorexia,
aild occasionally abdominal I)clifl or diarrhea
(luring tile course of tilerapY. 3) Skin
re-iction over previtisly irradiate(I areas,
con-sisting of ervthema and, occasionally,
vesi-culation illdl exfoiittion (Fig. 3).
Twenty-seven of 57 patients had skin reaction after
intravenous administration of actinomycin
D at 1, 2, 3, tild! 4 months in one patient as
long as 17 months after radiation therapy.
Sixty-seven per cent of the patients
receiv-ing actinomycin D had this reaction at 1
montil, and 50 silowed this reaction at 2
months after radiation therapy. When
FII:. :3. Photograph of l)dck of SB., a 9-year-old boy vith Ewing’s sarcoua of the left hip with
involve-imiemit of tile left knee 111(1spine; tiicse httter ares svere given lOOt) r and 1750 r tumor (lose, respectively, alx)11t 1 sve’ek’ l)efore admuinistration of actinoni”,’ciii I). The extent of skin reaction ssts ninch nore
tildIl 550111(1 l1d’(’ l)((Il antici1)atc(l froul these (105(5 of x-ray therapy alone.
x-ray tiierapv, the skimi reaction ‘as greater
than that eX1)ected fronl x-ray therapy alone.
4) Tue ilair amid! sollletimes tile eyebrows
began to fall out in ‘arying severity at 7 to
10 (lays after the intravenous course. Loss
of ilair continued for 2 to 4 weeks and then regrowth occurred. 5) Depression of the
leukocvte count ustialiy was ten)porary an (I
consisted of decrease from nornial to 2000/
111111 imid occasionally to less than 1000/
111111, particularly if the I)ltie1lts ‘ere
re-ceiving irradiation simultaneously. 6) Dc-crease of platelet count fronl normal to less
than 100,()00/II1l \y55 cOllSid!ered! signifi-(tflt ctll(! occurred in 30 of the patients.
A total of 108 I)ttiellts received! adequate
therapy with actinomycin D. Sortie fornl of
toxicity was observed at different tinles
diur-rug or after til(’ course of therapy. The
I)er-centage of 1)ttie11ts showing each type of toxicity when given the drug orally or
intra-venously is shown in Figure 2. The local gastrointestinal toxicity was greater Witil tile
oral route, \Vilile
tue
intravenous routepro-duced greater systemic toxicity.
Tile toxicity after intravenous adllllillistra-tion of actinomycin D usually developed!
within the first 2 weeks audi di5a)peared1
xvithin tile next 2 weeks; vitii oral
adlIllillis-tration, patients developed toxicity in ap-f)rOxinlately 10 weeks and it dlisappeared
when tile drug was stopped. AI)Out 5% of
the dose of actinomvcin
D
given orally wasai)sOrbed as evidenced! by the 1)ro!uction of
systemic toxicity.
Aspirations of bone marrow were
cx-anlifled 111 42 pttients before and after
actinonlycin
D
therapy. Of the 30 suitable for evaluation, 15 silo\Ved no cilange;11, a
decrease in tile nuniher of nlegakaryocytes
amid 1)iatelets; four, evidence of myeloid arrest; and eigllt, slight to moderate
megalo-blastosis. Patients with marked alteration in
tile l)one marrow of tile tyl)eS Iloted above
invariai)ly showed a decrease in the
formed
elements of the peri)ileral blood.
After adnlinistration of actinomycin
D,
concentrations of uric acid in the serum rose
in 24 of 9:3 patients and excretion of uric acid
tls() increased! for :3 to 5 days in 8 of 10
pa-tieiits studied. This increase of urinary
cx-cretion of uric acid was associated witil re-gression of tumor in t\V() patients Witil
Hod!g-kin’s dIisease, two with lymphosarcoma and
01W Witll neuroblastonia. This suggested that
548 ACTINOMYCIN I)
uI’
FI(;. 4. i0e11tgefl0gra11l of chest of CF. (Case 1) made on I)eceiiiber 27, 1956, before therapy witi#{236}
dctinOIllVciIl I) (left) miel (right) on August 7. 1958. showing 10 r(C’llrreflc(’.
to destructioll of tumor. Tile otiler tilrec
a-tients \vitil increased excretion of uric acid
indludledi one Witil Hodgkin’s disease who
iladi subjective improvement, one with
Wilms’ tumor wilo received x-ray therapy
simultaneously and showed regression of
pulmonary metastascs, and one dilildl witil metastatic hepatomna who
showed
no
meas-urable regression of the tumor.
Therapeutic Response
Tile oi)jectix’e response in patients treatedl
with actinomycin D alone and with
actino-mycin D and x-ray tilera)y is silown in
Table I. These objective responses
repre-sented a decrease in size of the tunlor by
actual measurements or roentgenograms,
and lasted for a ieriod! of at least 4 weeks.
The first group of patients with tile
excep-tion of C. F. (Case 1) had eitiler not
re-ceived x-ray tilerapy or had been irradiated!
at least 2 montils before receiving
actiilOmv-cm D. Tilerefore, the objective repose
shown was considered to be due to
actino-mycin
D alone.
The
second
group
receivedl
actinomvcin
0
either
simultaneously
orwithin a period of 1 to 2 weeks before or
after x-ray tilerapy.
CASE REPORTS: THERAPY WITH ACTINOMYCIN D ALONE
Wilms’ Tumor
Of the sixteen patients with Wilms’
tu-mor treated with actinonlycin D alone, and
suitable
for
e’a1uation,
six
had (lefimteevidence of objective response.
Case 1
HISTORY: G.F., t 2-year-old male, had left ne1)hrectonl\’ and! diagnosis of WillllS tumor made in August, 1956. Post-operativei, x-ray therap’ to the di)(iOIlleIl “as giveli. Three
IllOIlths later, d no(lular (leIlSitV most likely
nletastatic, (levelo1)e(l in the lower libe of the right lung, although he ssaS aSvlilptOfllatic,
and had no evidence of (lisease elsewhere. He
was given a total tumor (lost’ of 1 60() r to the
right lower lol)e, from November 26 to
1)ecem-her 5, 1956. However. after irradiation the nodule increased in SIZ(’ fronl 1 to :3 diii iii
diameter as shovn in the roentgenograni of the chest taken on December 27, 1956.
THERAPY WITH AcTINor1YcIN D: He was
given a single course of actinonlycin D intra-venously from December :30, 1956, to January 2, 1957. Three weeks later tile nodule (lisa1)-1)eared completely . He continued to receive actinom’cin D orally, at first 1 to 2 mg dail’ and later increasing to 3 to 4 mg daily fronl
February, 1957, to Septenlbcr, 1958; there has been no recurrence in 2 ‘ears (Fig. 4). Physical
growth has been normal.
COMMENT: The inten’al l)etween the x-ray therapy and adnlinistration of actinonivcin D xvas about 1 month. It is CDIlceiVal)le that the conq)lete regression of the 1)uinlonarv
nietasta-sis might i)e dela’ec! effect of x-ray thera1)V or due to the combination of effects of actinomycin
D and x-ray therapy. The fact that tile nodlule
HEIGHT
(inches
WEIGHT(IbS)35aE;3f
41V2
42Y2
_____
36
37
37
3836
37
35
NODULE, LT.SUBSTERNAL
2000r AREA
J
Sept
Oct
19552-7mg /d
Mcmy
1956
LT. CHEST WHOLE CHEST Li CHEST Li QIEST 2OOOr l000r gOQQr 12OOr
I I
..‘,.
4-LV-MEDROL P0.
I I I I I I I I I I I I I
Jan
Jan
1957
1958
B.C., 3 YRS.,
cf,
WILM’S TUMORBIRTHOATE 11-13-52
/J(\\
I(:
\m-\
7#{231}\ 1)(\
:L
:TL:L]L
(JL
Expired-,
___
4436
xl000
600
ABD
CHEST 2000r
-Lt Nephrectomy
TOTAL 7/ KG 90 125 103 i
Actinomycin
0[
-
-I.V.on-I I I I
FIC. 5. Temporary regression of pulmonary nietastases of B.C. (Case 2) after therapy with actinomycin I).
d11i Ilot l)(.’ definitely attributed to tile con-tiiiuous a(lmninistration of actillofli\’cill D orally. ActiIloIil’cin D did not seem to imihibit physical groxvth.
Case 2
HISTORY : B.C., a 3-year-old boy, had a \Vil Ills’ tunior renloved in September, 1955
(Fig. 5). Pulmonary mnetastases were present
at that time. Post-operatively, he received 003 r timnior dose to the right lung aIld! 20G0 r to tile dl)d!olllen. The pulmonary metastases
dis-11)l)’lre(! i)ut recurred 6 ni:nths later.
THERAPY WITH ACTINOMYCIN D: Five (fl5(5 of actmonl’cin D xs’ere givems
intra-venously and! actinomnycin D xvas given orally,
2 to 7 ng (hilly for a periol of 1 ‘ear.
COURSE: Three months after the start of
tilerapy with actinomvcin D, the pulnionar’ metastases regressed! except for the presence of one nO(lIli(.’ i)ChiIl(! the sternum, which xvas later givemi x-ray’ tllerapv. After this, he
(Ic-\‘(‘iOI)C(l niother slllaii llOdltli(’ ill tile left lung, Wilile receix’ing actilloln\’cin D oralk’. There xs’ere OCClsiOIldl episodes of Imausea, anorexia dud! (‘1)iStdXiS l)tlt 110 Iiltrk(’(l cilalige in the plat(’let coillit (luring the course of treatmnent.
J)cspite fuither courses of intravenous thertj)y
xvith actinoniycin D and x-ray therapy, the ptII-monary metastases contmuedl to progress and he diiedl 21 months after the start of
actino-Illycill D therap’.
COMMENT: This child, with pulmonary mc-tastases at the onset (If the disease, survived for
27 nlonths. Actinom’cin D, which causedi re-gression of pulmonar’ metastases, may have sloved the progression of the disease.
Case 3
HISTORY: A.V.,#{176}a 5-year-old l)oy, had a left nephrectom for \7ilms’ tumor in juk’, 1957.
Post-operatively, lie received :300() r tumor close to the abdomen. He developed massive bilateral l)uhlnollary metastases svith dspnea
dlldl fever in Max’, 1958.
THERAPY WITH ACTINOMYCIN D: Actinomy-cm D, 75 i.g /kg of body x’eight was given
in-travenously to the point of toxicit’ from May
19 to May 23, 1958.
COURSE : Pulmonary rnetastascs began to
recede 01) tile fifth clay’ of therap’ audi almost
completely regressed in 4 weeks (Fig. 6). Eight weeks later three flo(lUles reappeared in the
right lung field. This rcspon(l(’(l to a second
I
6-19-58
550
ACTINO\IYCIN
D
COMIENT : hid’ ttllllor l’S1)0n(le(! to
intra-L
F’ic. 6. Appearance of tlu roentgenogranl of the chest of A.V. (Case :3) lwforc aP(l after the initial
ultra-venous (ourse of actiIlOIllVciI1 I).
course of actiIlOlll\ciu D, i)tlt this tiiiie
tue
remission Ollly lasted! for :3 seeks. A tilird course of actmomycin D resulted! in severe toxicity l)Ut no regression of tunlor, although some s\lilptolllatic relief was obtained after tumor (lose of 1800 r to the chest given silortlv after the third! course of actillolilycill D.
COMMENT: Tile m(i’5Ph15 obtained in this 1)atiellt were striking although the remissions were short. Since no previous x-ray therapy had
i)een givell to tile area of the tulTior, this
regres-sioll seemedl definitely attrii)Utal)le to
actinomy-dill D.
Neuroblastoma
Of the seyen
I)atieflts
witii neuroblastoma, suitai)le for evaluation, treated \vitilactillo-mycin
D
alone, one patient had decreased joint swelling (Inc to metastasis inassocia-tion with increased! serum concentration and urinary excretion of uric acidi. Two had regression of metastatic subcutaneous scalp
nodiules associated \Vitll markedi improve-ment in general condition. These regressions lastedi for 1 to 3 months. There were no cilangeS ill other lesions.
Other Types of Tumors
Three 1)Utiellts Witil sarconia of bone, one
Witil sarcoma botryoides, two with sarcomas
of soft tissues, two with uleduhid)hlaStOlilas and one vitii carcinoma of kidiiev, suital)le
for evaluatioll, (lid! not show objective
re-after tileral)v with actiflolllycill
D
alone.Case 4
Embryonal Carcinoma
HISTORY : \I.C., a 23-year-old girl, had em-l)1’’Oildl carcinonia of tile IllesoCOiofl renloe(l
in March, 1956, dll(I P5t-Per1ti\’’lY received! x-ray therapy to the al)(lonlen. Ts’o liloIltilS
later, she dieveloped 1)u1lli1llrY nietastasis in the left lung field.
THERAPY WITH ACTINOMYCIN D: After a smigle course of actinoni’cin D intravenousl\’, there vas (Onll)lete regression of tile nletastatic nodlule ill
tue
lung (Fig. 7). Oral administrationof actinomycin D, 2 to :3 mug daily, sas
comi-tinned for 7 lllollths; (loses s’ere occasionally
oniitted because of toxicity . \Vhen recurrence of
)t1l111111ry and ai)dOlliiIldl tunlors occurred
after 7 IllolithS, six separate courses of actino-nivcin D intravenously in ad(!itiofl to local x-ra’ therapy u1’ Pr!llcd’(l yc’r\ transient dll(l
sligilt regression (If tile tunlor. She die(l of
ic-currenc(’ of til(’ pulmonary all(I al)(ionlinal
tunior 16 fllolitilS aftem’ tile onset of her
FIG. 7. Roentgenogram of chest of MC. (Case 4). Embryonal carcinoma with metastatic nodule
2.5 cn in (hianieter in left lung field which developed 2 months after abdominal surgery. There was
complete regression of this nodule for a period of 7 months after a single course of actinomycin D intravenously and orally.
%‘eIlOtl5 adlministration of actinomycin
D
and
maintenance therap with oral actinomycin D nlight have been responsible for the apparent
inhibition of recurrent disease for 7 months.
Recurrences were resistant to further therapy
s’ith actinonlvcin D.
Lymphoma
Of the 12 patients with lymphomas, 8
were suitable for evaluation. Objective
cvi-dence of improvement was found in 2 of 4
patients with Hodgkin’s disease, 1 of 2 with
reticulum cell sarcoma and 2 with
lympho-sarcomas.
Hodgkin’s
DiseaseTwo boys, 8 and 13 years of age,
re-spectively,
with
Hodgkin’s
disease
had
no
previous
therapy;
both
patients
had
large
cervical nodes, and the older had
enlarge-ment
of mediastinal
nodes
in addition.
Mod-crate regression of the enlarged cervical
nodes was seen after a
single
course
of
intra-venous administration of actinomycin D in
both cases. These patients had complete
re-gression of disease when later given x-ray
therapy and have had no recurrence after a
period
of 23 months.
Two other patients had decrease in fever
alld improvement in general condition for
2 to
4
weeks.Case 5: Reticulum Cell Sarcoma
HISTORY: R.S., a 14-year-old boy with
reticulum cell sarcoma and multiple metastases
of skin and bone, received inethvl-bis-(beta
chloroethyl) amine hydrochloride (Mustar-gen#{174}), triethylene melamine (TEM), cortisone, 6-mercaptopurine (Purinethol#{174}) and
o-diazo-acet\lLserine (azaserine) with no beneficial
response. The skin nodules (lisappeared
mi-tially after x-ray therapy, and when they re-curred, he was given chlorambucil (CB 1348) (p-bis (2-chloroethvi) aminophen’lbut’ric acid),(Leukeran#{174}), for 4 months to the point of marked depression of the platelet coullt, again
with no response.
THERAPY WITH AcTIN0MYcIN D: After a
single course of actinomycin
D intravenously
there was marked regression of the skin nodules within 1 week; they recurred, however, after3 weeks. Skin nodules regressed again when
actinomycin
D
was given orally in dosage of 16 mg/kg in 13 weeks. Because of persistentgastrointestinal symptoms, the oral dose then was interrupted for 2 weeks amid the nodules
recurred. Repeated administration of
actino-mycin D both orally and intravenously caused
no further improvement. The skin nodules
sub-sequentl\? disappeared after x-ray therapy.
COMMENT: This patient presented an
un-usual picture of reticulum cell sarcoma with
multiple
subcutaneous and osseous involve-ment. The generalized process has continuedfor 43 years. The disease was responsive to
x-ray therapy but did not respond to
Purin-ethol#{174}, cortisone, or alkylating agents.
Actino-mycin D caused a striking response in
ACTINOMYCIN D
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Fic. 8. G.C. (Case 6). Response of the elevated leukocyte count of the cerebro-spinal fluid (protein changes not shown in graph) after each course of actinornycin I) administered. Also shown are the concentrations of uric acid in the serum and
the levels of urinary excretion of uric acid.
oral routes. There was no change in the roent-genographic appearance of the metastatic bone
lesions. However, he has no evidence of
dis-ease elsewhere.
Forty-eight patients received actinomycin D
orally to the point of toxicity. Of these, six
re-ceived actinomycin D only by the oral route and
42 also received it intravenously but at a
dif-ferent time. This was the only case in which there was an objective response.
Case 6: Lymphosarcoma
HISTORY:
G.C.,
a 9-year-old boy, hadlvm-phosarcoma with a mediastinal mass which
was given x-ray therapy and did not recur.
However, subsequently, lie developed
metas-tases to testes and central nervous system.
THERAPY WITH ACTINOMYCIN D: After a first
course of actinomycin D, the testicular mass
decreased
in size and did not recur. After eachof the five intravenous courses of actinomvcin D (Fig. 8), the elevated leukocvte count and
concentration of protein of the cerebrospinal
fluid returned to normal and he improved
clini-cally for several weeks. This response was
as-sociated
with a temporary elevation of serumconcentration and urinary excretion of uric acid
on two occasions. The responses i)ecanle
pro-gressively less satisfactory, and he later showed improvement after administration of
Mustar-gen#{174}and x-ray therap’ to the skull and spine.
He
died
20 months after the clinical onset ofthe disease.
COMMENT: It is of interest that the response
of the mediastinal mass to x-ray therapy and
the testicular mass to actinomycin D lasted for
16 and 12 months, respectively (before death).
There was no clinical evidence of recurrence
of disease at these sites. However, the response
of the central nervous system involvement both
to x-ray therapy amid to administration of
actinomcin
D
was of short duration, and hedied of the disease of the central neryous
.
6-
I3
51Fic. 9. G.S. (Case 7). Roentgenogranl of the chest made before and after tllerapy with actinomycin, showing disappearance of the mediastinal mass and left pleural effusion.
IhId’l( \s’as 110 cross-resistance l)etween
ac-tii(Olliy(ill 1) dll(l \tustargcn in this patient.
Case 7: Lymphosarcoma
HIsToRY: CS., a 5-year-old boy, developed niediastinal and cervical adenopathy in April,
1958; biopsy of the cervical node showed
lym-phosarcoma. No aspiration of the bone marrow
was done. He was given a total tumor dose of 900 r to the mediastinuni in addition to
Mus-targen#{174} intravenously followed by thio-TEPA
(trieth’lenethiophosphoramide) orally for 2
months with no depression of the leukocyte
count or Platelet count. There was regression of the mediastinal nodes initially, but enlarge-ment recurred while receiving thio-TEPA oralh.
PHYSICAL AND BONE MARROW FINDINGS: In
J
umne, he was seen at Memorial Hospital. Hehad enlargement of cervical and mediastinal
nodes, swelling of the right side of the hard
palate, and aspiration of the bone marrow
showed 50% stem cells.
THERAPY WITH ACTINOMYCIN D: Two courses of actinomycin D intravenously, 75
i.g/kg were given from June 9, 1958, to June 13, 1958, and June 17, 1958, to Juiie 20, 1958,
respectively. Roentgenogram of the chest made
oIl July 21, 1958 (Fig. 9) showed complete
regression of the mediastinal mass. The
swell-ing of the hard palate disappeared and the
appearance of sniears of bone marrow returned
to normal.
COURSE : However, there was recurrence of the mediastinal mass 9 weeks later and further
response, though less satisfactory, was ob-tamed after two more courses of actinomycin D
intravenously. X-ray therapy to the chest
mi-mediately after the last course of actinomycinD resulted in regression of the mediastinal mass
which has not recurred in 4 months. Leukemic
cells which reappeared in the peripheral blood disappeared after treatment with
6-mercapto-purine.
COMMENT: Actinomycimi D alone produced complete regression for only 9 weeks. The re-gression of the mediastinal mass after x-ray
therapy, Mustargen#{174} and thio-TEPA was also
of short duration. This disease is usually
char-acterized by rapid recurrence and frequently
terminates in leukemia.
Acute Leukemia
Two children with acute leukemia who
had received conventional therapy,
Purin-ethol#{174},Methotrexate#{174}, and adrenal steroids
and had become resistant, were given
ac-tinomycin
D.
Case 8
One patient received a single course of
actino-mycin D intravenously. The total dose was
given in 21 days because of the
thrombocyto-penia due to the disease. The patient was also
receiving prednisone because of the bleeding tendency. After administration of actinomycin D, the leukocyte count dropped from 82,000 to
1200/mm3, but there was no change in the
progress of the disease. She died 1 week after the completion of therapy with actinomycin D.
Case
9
554 ACTINOMYCIN D
a total dose of 22.5 mg/kg of body weight in
I 4 (lays. At that time, the bone marrow showed
rapid relapse followed by thrombocytopenia
and the kukocyte count decreased from 4000 to 900/mm3. Because of the rapid progression
of the disease, therapy was changed to adrenal
steroids and she died of the disease 2 weeks
later.
Chronic Granulocytic Leukemia
Case 10
A 15-year-old girl with chronic granulocytic
leukemia with marked splenomegaly who had
become resistant to Purinethol#{174} and Myleran#{174},
received a single course of actinomycin D in-travenously in 19 days, to the point of toxicity.
There was no change in the size of the spleen;
later, x-ray therapy at 600 r tumor dose to the
spleen did not alter the size of the spleen. She
died of the disease 6 months after the therapy
with actinomycin.
CASE REPORTS: ACTINOMYCIN D AND
X-RAY
THERAPY
The
additive
effects
of
actinomycin
D
and x-ray therapy are difficult to evaluate
because of the inability to predict
accu-rately the degree of response of the tumor
in individual patients with various doses of
these agents, given separately. Patients
were treated with approximately 50% of
the estimated therapeutic dose of x-rays
and one or more courses of actinomycin D
intravenously. Wilms’ tumor and
neuro-blastoma are considered to be
radiosensi-tive, and actinomycin D in 18 of 28 patients
(Table I
)
appeared to have enhanced thepredicted degree of response to x-ray
ther-apy. In more radioresistant tumors, though
some were relatively radiosensitive, such as rhabdomyosarcoma and bone sarcoma,
actinomycin D sometimes appeared to
in-crease the response to x-ray therapy. This
suggests that the effect of actinomycin D
and x-ray therapy are additive in certain
responsive tumors, but we had no
convinc-ing evidence that actinomycin D sensitizes
radioresistant tumors to the action of x-ray
therapy.
Case
11Embryonal Rhabdomyosarcoma
HISTORY: A 5-year-old boy developed a swell-ing over the right perineal region, which was
diagnosed as embryonal rhabdomyosarcoma in
July, 1957. From September 17 to October 29,
1957, he was given a total tumor dose of
3000 r to the pelvic region. During x-ray
therapy, he developed hepatic enlargement
which regressed after treatment with
Mustar-gen#{174}and Methotrexate#{174}. In May, 1958, while receiving Methotrexate#{174}, he developed bilateral
pulmonary metastases, recurrent enlargement of the liver, ascites and edema of the lower cx-tremities.
THERAPY WITH ACTINOMYCIN D: He was
then seen at Memorial Hospital; a course of
actinomycin
D intravenously
at 91 hug/kg of body weight was given to the point of toxicity,from May 2 to May 8, 1959.
X-RAY THERAPY: A total tumor dose of 1700
r was given to the abdomen from May 12 to
May 29, 1958, and resulted in complete
regres-sion of the hepatic enlargement, ascites, and
edema.
COURSE : Although no x-ray therapy was given to the lungs, there was marked regression
of pulmonary metastases bilaterally as shown
in Figure 10, but this recurred within 4 weeks
and later responded to x-ray therapy for about
2 months. He died of the disease 5 months after
the start of therapy with actinomycin D.
COMMENT: The therapeutic dose of 3000 r
to the pelvic region produced temporary and
partial regression of the tumor while hepatic
metastases were appearing concurrently.
Sub-sequent treatment with Mustargen#{174} and
Metho-trexate#{174} again produced regression of the
he-patic metastases but pulmonary and abdominal
metastatic disease appeared during therapy
with Methotrexate#{174}. A combination of x-ray
therapy to the abdomen and administration of
actinomycin
D produced
regression
of both ab-dominal and pulmonary metastases. There is the suggestion from this latter course of therapythat the regression of pulmonary disease might
have been due to the actinomycin D, since x-ray
therapy was not given to this area. The
sponse of the local abdominal disease at a
dose of 1700 r was approximately the same as that previously seen with 3000 r, suggesting an
Fic. 10. Roentgenograni of the chest in Case 11 showing the bilateral decrease in number and size of
pulmonary lll(’taStases; this effect was probably (hue to actinornycin I) alone, since x-ray therapy was not given to this area.
Case 12
Neuroblastoma
HISTORY: J.L., 4l years of age, had swelling of the right jaw in October, 1956 (Fig. 11), and
was treated with antibiotics with no response.
The first biopsy of the right side of the jaw was
negative; the second biopsy showed malignant tumor cells.
PHYSICAL AND LABORATORY FINDINGS: In
December, 1956, at the age of years, he was seen for the first time at Memorial Center. The
abdomen was large and the intravenous
pye-logram showed that the left kidney was de-viated and depressed by a tumor mass with
calcification. Roentgenogram of the chest showed infiltration of the right lung and
widen-ing of the superior mediastinum; the right side of the mandible showed a destructive bone
lesion.
FINDINGS AT LAPAROTOMY: Laparotomy on January 3, 1957, showed a large, firm, lobulated
mass oIl the left extending from the sub-diaphragmatic space to below the level of the
umbilicus and attached to large vessels. Only
three-fourths of the mass was removed.
THERAPY WITH X-RAYS AND ACTINOMYCIN D:
Postoperatively, he was given x-ray therapy to
the paraortic lymph nodes from the level of the
seventh dorsal vertebra to the lumbar vertebra; and to the left renal area (21 by 12 cm), a
total tumor dose of 2190 r in 2 weeks, and to
the right side of the mandible, a tumor dose of
1 160 r in 1 week. At the same time, he received two separate courses of actinomycin D
intra-venously, and from February, 1957, to
Feb-ruary, 1958, he ‘as given actinonicin D oralh 2 to 4 mg daily.
COURSE: In April, 1957, roentgenogram of
the chest showed clearing of the infiltration of
the lung and decreased mediastinal widening.
Since September, 1957, repeated roentgeno-grams revealed normal chest findings, and the
right side of the mandible showed recalcifica-tion of the metastatic lesion. Intravenous
pye-logram showed extensive calcification in the
left upper quadrant. He has no evidence of ac-tive disease 2 years after the onset of metastasis
to bone due to neuroblastoma. He received
actinomycin D during the first 14 months of the
disease and is now receiving no therapy
COMMENT: Metastases to bone in patients
with neuroblastoma are usually considered to
indicate poor prognosis. This child had a lesion of bone as a presenting sign of the disease and is now without evidence of disease 2 years
after therapy. Because of the multiple sites of
involvement and poor prognosis, he was given
both x-ray therapy and actinomycin
D. He
de-veloped toxic effects after both intravenous
courses and after oral doses. During the 1-year
period while he was receiving actinomycin
D
orally he had occasional episodes of nausea,
vomiting, and diarrhea. The concentration of hemoglobin remained between 8 and 9 gm/100
ml and the body weight remained 13.5 kg.
Ad-ministration of actinomycin D was then
discon-tinued. He was given iron orally for a period of
6 months. In the past months, the concentration
of hemoglobin rose to 10 to 1 1 gm/100 ml. He
has gained 6 kg during the last year. The lack
PLT Hb
600-15
xl000
P0 1-3 ma/day
I I I III
JAN
1958I I I I I I I
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556
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JAN
1957
Fic. 11. Diagnosis of neurobiastoma was made at 23 years of age in patient J.L. ( Case 12), with metastasis to bone at the onset. After partial removal of the adrenal tumor, the patient received 2190 r
and 1160 r to the abdomen and right side of the mandible, respectively. He had two courses of
actinomycin D intravenously and maintenance therapy with actinomycin I) orally for 1 year. He is now
4l years of age with no evidence of disease.
hemoglobill previously may have been due to nutritional deficiency because of gatrointesti-nal disturbances caused by oral administration
of actinomycin D.
It is difficult to determine whether this pro-longed arrest of the disease was due to the
effect of x-ray therapy alone or combination
with actinomycin D or possibly spontaneous
re-gression.
DISCUSSION
Actinomycin D is highly toxic clinically.
The therapeutic intravenous dose per
course of treatment is approximately 75
bug/kg in children. Its mechanism of action
is unknown. It has produced a consistent
pattern
of
toxicity
in humans,
including
a
local
effect
on
the
digestive
tract,
depres-sion of
the
formed
elements
of the
periph-eral
blood
and,
sometimes
of
the
bone
marrow,
exacerbation of
skin
reaction
in a
previously irradiatedi area, and nonspecific
effect on the hair follicles. Oral
adminis-tration of actinomycin D caused a more
severe local effect on the digestive tract.
The duration of improvement after a single
course of actinomycin D was usually short.
It would be desirable to have a suitable
preparation for oral maintainance therapy,
but such is not yet available. Actinomycin
D does not have a wide spectrum of
ther-apeutic activity in childhood cancer, but
its use seems indicated, on the basis of our
experience, in the following situations.
Wilms’
TumorIn
metastatic
Wilms’
tumor,
6 of
16
pa-tients receiving actinomycin D alone showed
an objective response and in five of these
pa-tients
there was substantial clinical benefit.age md is now 4 years of age and has no
evidence of disease. Another child, who had
pulmonary metastases at the onset at the
age of 3 years, survived 27 months. One
had no recurrence for 7 months; the other
two showed remarkable regression of
pul-monary metastases for 6 to 8 weeks.
Actinomycin D, therefore, appears to
have an appreciable degree of therapeutic
activity in about one third of the patients
in this series with metastatic Wilms’ tumor.
We believe that it deserves an adequate
trial in patients with metastatic Wilms’
tumor not satisfactorily controlled by x-ray
therapy.
The role of actinomycin D in connection
with local x-ray therapy has not been
defi-nitely established in Wilms’ tumors.
One suggestion would be to use
acti-nomycin D as the initial form of therapy
in patients with pulmonary metastases. If
there is evidence of complete regression of
pulmonary metastasis by roentgenogram,
no further therapy should be given until
signs of recurrence are present. Then more
courses of actinomycin D are administered.
When the disease recurs despite further
therapy with actinomycin D x-ray therapy
to the pulmonary metastasis would be
in-dicated. If only partial regression can be
obtained by a course of actinomycin D,
more actinomycin D should be given to the
point of toxicity. If again, the regression
is still incomplete, it should be followed by
x-ray therapy.
Another approach is to give x-ray therapy
first and later actinomycin D when
metas-tases recur. The simultaneous administration
of x-ray therapy and actinomycin D may be
considered, particularly if the patient has
had a previous course of x-ray therapy to
the lungs. In combination with actinomycin
D, regression may be produced with smaller
and less hazardous doses of irradiation.
Neuroblastoma
En patients with neuroblastoma, our
ex-perience has not been as favorable. When
the (lisease is far advanced there is usually
infiltration of the hone marrow with
extrin-sic cells; therefore, in these patients the
disease behaves somewhat like leukemia and
further
depression
in the platelet countre-suiting from actinomycin D may be
suffi-cient
to
cause severe hemorrhage andpre-vent
adequate further therapy. However, intwo of the three patients with
neuroblas-toma, when there was no infiltration of the
bone
marrow, there was remarkableregres-sion of the nodules in the scalp and
improve-ment in the general condition for several
months. In cases of extensive involvement
without infiltration of the bone marrow,
ade-quate courses of actinomycin D
intravenous-ly, either alone or in combination with x-ray
therapy, should be considered. With
involve-ment of the bone marrow, the total dose of
actinomycin D may be given in 8 or 10 days;
thus, therapy can be stopped if there is
depression of the platelets. If there is
in-filtration of the bone marrow and local
metastases to the abdomen or lung, then
local x-ray therapy is more desirable.
Rha bdomyosarcoma
In patients with rhabdomyosarcoma and
pulmonary metastases, actinomycin D may
be a useful agent. Pulmonary metastases
have shown regression with actinomycin
D
alone. If the metastases involve a largerarea, such as an abdominal tumor, x-ray
therapy at a smaller dosage and actinomycin
D intravenously may produce favorable
re-suits. This may be especially helpful if such
an area has had previous x-ray therapy.
Bone Sarcoma
In patients with osteogenic sarcoma or
Ewing’s sarcoma who have developed
pul-monary metastases in one lung, actinomycin
D intravenously may be tried alone; if no
response occurs, then the combination of
actinomycin D audI x-ray therapy may he used.
In bilateral pulmonary mnetastases, a
rela-tively large dose of x-ray therapy is usually
required to produce an effect with the
at-tendant
hazard
of irradiation-induced
pui-monary fibrosis. Therefore, in this situation,
558 ACTINOMYCIN D
may be tried in combination with a smaller
dose of x-ray therapy.
Sarcoma Botryoides and Other
Metastatic
Sarcomas
and
Carcinomas
This group is usually considered
radio-resistant. Irradiation alone may produce
partial, temporary regression of the tumor.
Actinomycin D in these situations should be
given in addition to x-ray therapy in an
attempt to achieve an additive effect.
Lymphomas
The two patients with acute leukemia
who were treated did not respond because
of the rapid progression of the disease and
accompanying
hemorrhagic
tendency.
The
therapy given was, therefore, not adequate.
More studies should be done in patients
with leukemia whose disease is not too far
advanced.
There did not seem to be cross-resistance
between actinomycin D and the alkylating
agents; therefore, when patients with
lym-phoma become unresponsive to the
alkylat-ing agents, actinomycin
D might
be a useful
agent in producing further regression of the
tumor.
SUMMARY
Actinomycin
D
has
a slight
but
definite
effect in producing regression of tumors inpatients with cancer. Wilms’ tumor and
lymphomas have shown better response
than other tumors. Although the effect of
the combination of actinomycin D and
x-ray therapy is difficult to evaluate, these
agents appear to be additive in producing
temporary regression of the tumor in some
patients.
The usual single course of actinomycin
D intravenously is 75 .g/kg of body weight
divided into four or five daily doses. The
oral dose of actinomycin
D is 3 to
10 mg
daily. About 5% of actinomycin D given
orally is absorbed as evidenced by
produc-tion of systemic toxicity. However, severe
local gastrointestinal effect usually prevents
adequate oral administration of the drug.
The toxic effects of actinomycin D are
local on the gastrointestinal tract with
ul-ceration of the mouth, nausea, vomiting,
anorexia,
occasional
abdominal pain anddiarrhea; exacerbation of skin reaction in
previously irradiated areas; alopecia;
de-crease in leukocyte and platelet counts. The
toxicity after intravenous administration of
actinomycin
D
usually develops within thefirst 2 weeks and disappears within the
next
2 weeks.The duration of improvement after a
single course of actinomycin D
intra-venously was usually from 1 to 10 weeks.
Two children, one with Wilms’ tumor and
one with embryonal carcinoma, had no
re-currence for 24 and 7 months, respectively.
Both received maintenance doses of
actino-mycin D orally.
Acknowledgment
We acknowledge with appreciation the
sup-ply of actinomycin D from Merck, Sharp &
Dohme, Division of Merck and Company, West
Point, Pennsylvania.
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THE CHILD WITH A HANDICAP, edited by
Edgar E. Martmer, M.D. Springfield,
Illi-Ibis, Charles C Thomas, Publisher.
Occasionally, a simple, heart-warming
docu-ment appears unexpectedly to win the public’s
heart. In the parlance of show business, such
a presentation is called a “sleeper,” i.e., a film
or play that makes a hit.
The Child with a Handicap, edited by Dr.
Martmer, a past-president of the American Academy of Pediatrics, deserves the right to
be called a “sleeper.” Those of us who devote a major part of our practice to the handicapped
child are often exposed to articles and
text-books which more often complicate an already
complicated subject. The Child with a
Handi-cap helps neutralize material which tends
to-wards frightening pediatricians away from
knowing more about an important phase of
pediatric practice.
Dr. Martmer was able to gather material
from experts who were interested in children
rather than diseases. He put his book together like a sandwich: 15 chapters of meaty material
on 15 different chronic disabilities of children,
are held together on topside by material
deal-ing with various roles of the rehabilitation team
and on the bottom by guides for pediatricians
and families about important aspects of
handi-capping conditions of childhood.
At the top of the batting order, Dr. Samuel
Wishik describes 25 basic philosophies for
physicians who deal with children with
crip-pling conditions. These principles should be
imprinted on the top of every pediatrician’s desk blotter.
The next batter is a parent of a retarded
child who punches through a hit when she
emphasizes some points on pediatrician-hmiI relationships that makes one pause for thought.
To quote:
“Confidence
in
Professional
Corn-Petence is Often Lost. Why doesn’t this bab’
have a soft spot?, I asked my pediatrician when
the child was very young. ‘Oh, you just had a
lot of good calcium when you were carrying him,’ he replied. Such supposed to be satisfying
but incompetent answers onh’ served to
bul-wark my natural defenses towards the truth
when it was finally given us by a physician
skilled in diagnosis, a skill which I had
ex-pected of my pediatrician.”
Such succulent yet pertinent comments are
found in each of the successive sections which
deal with the role of the psychiatrist, the social
worker, the teacher, adoption agencies, and the
counselor in medical genetics.
As to the meaty center of the sandwich, for
the first time the pediatrician can find in one
place pertinent practical information about the
pediatric approach to most of the childhood handicapping conditions.
Each chapter is written to fulfill the special
needs of pediatricians and is written in a way
which can guide the pediatrician towards the
“next step.” Each chapter has good reference
material for additional help or more specialized
inforniation.
The bottom side of the sandwich includes
guides for discipline for parents, for play
ma-terial, for reading material, for health
educa-tion material, for community programs, and
directories for camps, school services, and other